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1
Mihelec, Marija, Luke St Heaps, Maree Flaherty, Frank Billson, Christina Rudduck, Patrick P. L. Tam, John R. Grigg, Greg B. Peters, and Robyn V. Jamieson. "Chromosomal Rearrangements and Novel Genes in Disorders of Eye Development, Cataract and Glaucoma." Twin Research and Human Genetics 11, no. 4 (August 1, 2008): 412–21. http://dx.doi.org/10.1375/twin.11.4.412.
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AbstractDisorders of eye development such as microphthalmia and anophthalmia (small and absent eyes respectively), anterior segment dysgenesis where there may be pupillary and iris anomalies, and associated cataract and glaucoma, often lead to visual impairment or blindness. Currently treatment options are limited, as much is unknown about the molecular pathways that control normal eye development and induce the aberrant processes that lead to ocular defects. Mutation detection rates in most of the known genes are generally low, emphasizing the genetic heterogeneity of developmental ocular defects. Identification of the disease genes in these conditions improves the clinical information available for affected individuals and families, and provides new insights into the underlying biological processes for facilitation of better treatment options. Investigation of chromosomal rearrangements associated with an ocular phenotype has been especially powerful for disease gene identification. Molecular characterization of such rearrangements, which pinpoints the region by physically disrupting the causative gene or its regulatory sequences, allows for rapid elucidation of underlying genetic factors that contribute to the phenotype. Genes including PAX6, PITX2, FOXC1, MAF, TMEM114, SOX2, OTX2 and BMP4 have been identified in this way to be associated with developmental eye disorders. More recently, new methods in chromosomal analysis such as comparative genomic hybridization (CGH) microarray, have also enhanced our ability in disease gene identification.
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Harding and Moosajee. "The Molecular Basis of Human Anophthalmia and Microphthalmia." Journal of Developmental Biology 7, no. 3 (August 14, 2019): 16. http://dx.doi.org/10.3390/jdb7030016.
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Human eye development is coordinated through an extensive network of genetic signalling pathways. Disruption of key regulatory genes in the early stages of eye development can result in aborted eye formation, resulting in an absent eye (anophthalmia) or a small underdeveloped eye (microphthalmia) phenotype. Anophthalmia and microphthalmia (AM) are part of the same clinical spectrum and have high genetic heterogeneity, with >90 identified associated genes. By understanding the roles of these genes in development, including their temporal expression, the phenotypic variation associated with AM can be better understood, improving diagnosis and management. This review describes the genetic and structural basis of eye development, focusing on the function of key genes known to be associated with AM. In addition, we highlight some promising avenues of research involving multiomic approaches and disease modelling with induced pluripotent stem cell (iPSC) technology, which will aid in developing novel therapies.
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Sheng, Minjie, Haiying Cai, Ming Cheng, Jing Li, Jian Zhang, and Lihua Liu. "Identification of Novel Choroidal Neovascularization-Related Genes Using Laplacian Heat Diffusion Algorithm." BioMed Research International 2021 (September 6, 2021): 1–10. http://dx.doi.org/10.1155/2021/2295412.
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Choroidal neovascularization (CNV) is a type of eye disease that can cause vision loss. In recent years, many studies have attempted to investigate the major pathological processes and molecular pathogenic mechanisms of CNV. Because many diseases are related to genes, the genes associated with CNV need to be identified. In this study, we proposed a network-based approach for identifying novel CNV-associated genes. To execute such method, we first employed a protein-protein interaction network reported in STRING. Then, we applied a network diffusion algorithm, Laplacian heat diffusion, on this network by selecting validated CNV-related genes as the seed nodes. As a result, some novel genes that had unknown but strong relationships with validated genes were identified. Furthermore, we used a screening procedure to extract the most essential genes. Eleven latent CNV-related genes were finally obtained. Extensive analyses were performed to confirm that these genes are novel CNV-related genes.
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Wang, Likun, Jinlu Zhang, Ningning Chen, Lei Wang, Fengsheng Zhang, Zhizhong Ma, Genlin Li, and Liping Yang. "Application of Whole Exome and Targeted Panel Sequencing in the Clinical Molecular Diagnosis of 319 Chinese Families with Inherited Retinal Dystrophy and Comparison Study." Genes 9, no. 7 (July 19, 2018): 360. http://dx.doi.org/10.3390/genes9070360.
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Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous diseases involving more than 280 genes and no less than 20 different clinical phenotypes. In this study, our aims were to identify the disease-causing gene variants of 319 Chinese patients with IRD, and compare the pros and cons of targeted panel sequencing and whole exome sequencing (WES). Patients were assigned for analysis with a hereditary eye disease enrichment panel (HEDEP) or WES examination based on time of recruitment. This HEDEP was able to capture 441 hereditary eye disease genes, which included 291 genes related to IRD. As RPGR ORF15 was difficult to capture, all samples were subjected to Sanger sequencing for this region. Among the 163 disease-causing variants identified in this study, 73 had been previously reported, and the other 90 were novel. Genes most commonly implicated in different inheritances of IRDs in this cohort were presented. HEDEP and WES achieved diagnostic yield with 41.2% and 33.0%, respectively. In addition, nine patients were found to carry pathogenic mutations in the RPGR ORF15 region with Sanger sequencing. Our study demonstrates that HEDEP can be used as a first-tier test for patients with IRDs.
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Lee, Bradford W., Virender B. Kumar, Pooja Biswas, Audrey C. Ko, Ramzi M. Alameddine, David B. Granet, Radha Ayyagari, Don O. Kikkawa, and Bobby S. Korn. "Transcriptome Analysis of Orbital Adipose Tissue in Active Thyroid Eye Disease Using Next Generation RNA Sequencing Technology." Open Ophthalmology Journal 12, no. 1 (April 16, 2018): 41–52. http://dx.doi.org/10.2174/1874364101812010041.
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Objective: This study utilized Next Generation Sequencing (NGS) to identify differentially expressed transcripts in orbital adipose tissue from patients with active Thyroid Eye Disease (TED) versus healthy controls. Method: This prospective, case-control study enrolled three patients with severe, active thyroid eye disease undergoing orbital decompression, and three healthy controls undergoing routine eyelid surgery with removal of orbital fat. RNA Sequencing (RNA-Seq) was performed on freshly obtained orbital adipose tissue from study patients to analyze the transcriptome. Bioinformatics analysis was performed to determine pathways and processes enriched for the differential expression profile. Quantitative Reverse Transcriptase-Polymerase Chain Reaction (qRT-PCR) was performed to validate the differential expression of selected genes identified by RNA-Seq. Results: RNA-Seq identified 328 differentially expressed genes associated with active thyroid eye disease, many of which were responsible for mediating inflammation, cytokine signaling, adipogenesis, IGF-1 signaling, and glycosaminoglycan binding. The IL-5 and chemokine signaling pathways were highly enriched, and very-low-density-lipoprotein receptor activity and statin medications were implicated as having a potential role in TED. Conclusion: This study is the first to use RNA-Seq technology to elucidate differential gene expression associated with active, severe TED. This study suggests a transcriptional basis for the role of statins in modulating differentially expressed genes that mediate the pathogenesis of thyroid eye disease. Furthermore, the identification of genes with altered levels of expression in active, severe TED may inform the molecular pathways central to this clinical phenotype and guide the development of novel therapeutic agents.
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Violanti, Sara Silvia, Ilaria Bononi, Carla Enrica Gallenga, Fernanda Martini, Mauro Tognon, and Paolo Perri. "New Insights into Molecular Oncogenesis and Therapy of Uveal Melanoma." Cancers 11, no. 5 (May 19, 2019): 694. http://dx.doi.org/10.3390/cancers11050694.
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Uveal melanoma (UM), which is the most common cancer of the eye, was investigated in recent years by many teams in the field of biomedical sciences and eye clinicians. New knowledge was acquired on molecular pathways found to be dysregulated during the multistep process of oncogenesis, whereas novel therapeutic approaches gave significant results in the clinical applications. Uveal melanoma-affected patients greatly benefited from recent advances of the research in this eye cancer. Tumour biology, genetics, epigenetics and immunology contributed significantly in elucidating the role of different genes and related pathways during uveal melanoma onset/progression and UM treatments. Indeed, these investigations allowed identification of new target genes and to develop new therapeutic strategies/compounds to cure this aggressive melanoma of the eye. Unfortunately, the advances reported in the treatment of cutaneous melanoma have not produced analogous benefits in metastatic uveal melanoma. Nowadays, no systemic adjuvant therapy has been shown to improve overall survival or reduce the risk of metastasis. However, the increasing knowledge of this disease, and the encouraging results seen in clinical trials, offer promise for future effective therapies. Herein, different pathways/genes involved in uveal melanoma onset/progression were taken into consideration, together with novel therapeutic approaches.
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Reis, Linda M., Huban Atilla, Peter Kannu, Adele Schneider, Samuel Thompson, Tanya Bardakjian, and Elena V. Semina. "Distinct Roles of Histone Lysine Demethylases and Methyltransferases in Developmental Eye Disease." Genes 14, no. 1 (January 14, 2023): 216. http://dx.doi.org/10.3390/genes14010216.
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Histone lysine methyltransferase and demethylase enzymes play a central role in chromatin organization and gene expression through the dynamic regulation of histone lysine methylation. Consistent with this, genes encoding for histone lysine methyltransferases (KMTs) and demethylases (KDMs) are involved in complex human syndromes, termed congenital regulopathies. In this report, we present several lines of evidence for the involvement of these genes in developmental ocular phenotypes, suggesting that individuals with structural eye defects, especially when accompanied by craniofacial, neurodevelopmental and growth abnormalities, should be examined for possible variants in these genes. We identified nine heterozygous damaging genetic variants in KMT2D (5) and four other histone lysine methyltransferases/demethylases (KMT2C, SETD1A/KMT2F, KDM6A and KDM5C) in unrelated families affected with developmental eye disease, such as Peters anomaly, sclerocornea, Axenfeld-Rieger spectrum, microphthalmia and coloboma. Two families were clinically diagnosed with Axenfeld-Rieger syndrome and two were diagnosed with Peters plus-like syndrome; others received no specific diagnosis prior to genetic testing. All nine alleles were novel and five of them occurred de novo; five variants resulted in premature truncation, three were missense changes and one was an in-frame deletion/insertion; and seven variants were categorized as pathogenic or likely pathogenic and two were variants of uncertain significance. This study expands the phenotypic spectra associated with KMT and KDM factors and highlights the importance of genetic testing for correct clinical diagnosis.
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Choy, K. W., C. C. Wang, A. Ogura, T. K. Lau, M. S. Rogers, K. Ikeo, T. Gojobori, D. S. C. Lam, and C. P. Pang. "Genomic annotation of 15,809 ESTs identified from pooled early gestation human eyes." Physiological Genomics 25, no. 1 (March 13, 2006): 9–15. http://dx.doi.org/10.1152/physiolgenomics.00121.2005.
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To complement cDNA libraries from the human eye at early gestation and to discover candidate genes associated with early ocular development, we used freshly dissected human eyeballs from week 9–14 of gestation to construct the early human fetal eye cDNA library. A total of 15,809 clones were isolated and sequenced from the unamplified and unnormalized library. We screened 11,246 good-quality ESTs, leading to the identification of 5,534 nonredundant clusters. Among them, 4,010 (72%) genes matched in the human protein database (Ensembl). The remaining 28% (1,524) corresponded to potentially novel or previously unidentified ESTs. We used BLASTX to compare our EST data with eight organisms and found common expression of a high portion of genes: Caenorhabditis briggsae (26%), Caenorhabditis elegans (27%), Anopheles gambiae (37%), Drosophila melanogaster (32%), Danio rerio (42%), Fugu rubripes (49%), Rattus norvegicusvalitus (52%), and Mus musculus (59%). Nevertheless, 48% (2,680 of 5,534) of the genes expressed in the early developing eye were not shared with current NEIBank human eye cDNA data. In addition, eight known retinal disease genes existed in our ESTs. Among them, six ( COL11A1, BBS5, PDE6B, OAT, VMD2, and PGK1) were conserved among the genomes of other organisms, indicating that our annotated EST set provides not only a valuable resource for gene discovery and functional genomic analysis but also for phylogenetic analysis. Our foremost early gestation human eye cDNA library could provide detailed comparisons across species to identify physiological functions of genes and to elucidate evolutionary mechanisms.
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Lin, Ting-Yi, Yun-Chia Chang, Yu-Jer Hsiao, Yueh Chien, Ying-Chun Jheng, Jing-Rong Wu, Lo-Jei Ching, et al. "Identification of Novel Genomic-Variant Patterns of OR56A5, OR52L1, and CTSD in Retinitis Pigmentosa Patients by Whole-Exome Sequencing." International Journal of Molecular Sciences 22, no. 11 (May 25, 2021): 5594. http://dx.doi.org/10.3390/ijms22115594.
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Inherited retinal dystrophies (IRDs) are rare but highly heterogeneous genetic disorders that affect individuals and families worldwide. However, given its wide variability, its analysis of the driver genes for over 50% of the cases remains unexplored. The present study aims to identify novel driver genes, disease-causing variants, and retinitis pigmentosa (RP)-associated pathways. Using family-based whole-exome sequencing (WES) to identify putative RP-causing rare variants, we identified a total of five potentially pathogenic variants located in genes OR56A5, OR52L1, CTSD, PRF1, KBTBD13, and ATP2B4. Of the variants present in all affected individuals, genes OR56A5, OR52L1, CTSD, KBTBD13, and ATP2B4 present as missense mutations, while PRF1 and CTSD present as frameshift variants. Sanger sequencing confirmed the presence of the novel pathogenic variant PRF1 (c.124_128del) that has not been reported previously. More causal-effect or evidence-based studies will be required to elucidate the precise roles of these SNPs in the RP pathogenesis. Taken together, our findings may allow us to explore the risk variants based on the sequencing data and upgrade the existing variant annotation database in Taiwan. It may help detect specific eye diseases such as retinitis pigmentosa in East Asia.
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Yang, Xue, Vafa Bayat, Nataliya DiDonato, Yang Zhao, Brian Zarnegar, Zurab Siprashvili, Vanessa Lopez-Pajares, et al. "Genetic and genomic studies of pathogenic EXOSC2 mutations in the newly described disease SHRF implicate the autophagy pathway in disease pathogenesis." Human Molecular Genetics 29, no. 4 (October 19, 2019): 541–53. http://dx.doi.org/10.1093/hmg/ddz251.
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Abstract Missense mutations in the RNA exosome component exosome component 2 (EXOSC2), also known as ribosomal RNA-processing protein 4 (RRP4), were recently identified in two unrelated families with a novel syndrome known as Short stature, Hearing loss, Retinitis pigmentosa and distinctive Facies (SHRF, #OMIM 617763). Little is known about the mechanism of the SHRF pathogenesis. Here we have studied the effect of mutations in EXOSC2/RRP4 in patient-derived lymphoblasts, clustered regularly interspaced short palindromic repeats (CRISPR)-generated mutant fetal keratinocytes and Drosophila. We determined that human EXOSC2 is an essential gene and that the pathogenic G198D mutation prevents binding to other RNA exosome components, resulting in protein and complex instability and altered expression and/or activities of critical genes, including those in the autophagy pathway. In parallel, we generated multiple CRISPR knockouts of the fly rrp4 gene. Using these flies, as well as rrp4 mutants with Piggy Bac (PBac) transposon insertion in the 3′UTR and RNAi flies, we determined that fly rrp4 was also essential, that fly rrp4 phenotypes could be rescued by wild-type human EXOSC2 but not the pathogenic form and that fly rrp4 is critical for eye development and maintenance, muscle ultrastructure and wing vein development. We found that overexpression of the transcription factor MITF was sufficient to rescue the small eye and adult lethal phenotypes caused by rrp4 inhibition. The autophagy genes ATG1 and ATG17, which are regulated by MITF, had similar effect. Pharmacological stimulation of autophagy with rapamycin also rescued the lethality caused by rrp4 inactivation. Our results implicate defective autophagy in SHRF pathogenesis and suggest therapeutic strategies.
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Won, Jungyeon, Lan Ying Shi, Wanda Hicks, Jieping Wang, Ronald Hurd, Jürgen K. Naggert, Bo Chang, and Patsy M. Nishina. "Mouse Model Resources for Vision Research." Journal of Ophthalmology 2011 (2011): 1–12. http://dx.doi.org/10.1155/2011/391384.
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The need for mouse models, with their well-developed genetics and similarity to human physiology and anatomy, is clear and their central role in furthering our understanding of human disease is readily apparent in the literature. Mice carrying mutations that alter developmental pathways or cellular function provide model systems for analyzing defects in comparable human disorders and for testing therapeutic strategies. Mutant mice also provide reproducible, experimental systems for elucidating pathways of normal development and function. Two programs, the Eye Mutant Resource and the Translational Vision Research Models, focused on providing such models to the vision research community are described herein. Over 100 mutant lines from the Eye Mutant Resource and 60 mutant lines from the Translational Vision Research Models have been developed. The ocular diseases of the mutant lines include a wide range of phenotypes, including cataracts, retinal dysplasia and degeneration, and abnormal blood vessel formation. The mutations in disease genes have been mapped and in some cases identified by direct sequencing. Here, we report 3 novel alleles ofCrxtvrm65,Rp1tvrm64, andRpe65tvrm148as successful examples of the TVRM program, that closely resemble previously reported knockout models.
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Li, Huiping, Shiqin Yuan, Yuriko Minegishi, Akiko Suga, Kazutoshi Yoshitake, Xunlun Sheng, Jianping Ye, et al. "Novel mutations in malonyl-CoA-acyl carrier protein transacylase provoke autosomal recessive optic neuropathy." Human Molecular Genetics 29, no. 3 (January 9, 2020): 444–58. http://dx.doi.org/10.1093/hmg/ddz311.
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Abstract Inherited optic neuropathies are rare eye diseases of optic nerve dysfunction that present in various genetic forms. Previously, mutation in three genes encoding mitochondrial proteins has been implicated in autosomal recessive forms of optic atrophy that involve progressive degeneration of optic nerve and retinal ganglion cells (RGC). Using whole exome analysis, a novel double homozygous mutation p.L81R and pR212W in malonyl CoA-acyl carrier protein transacylase (MCAT), a mitochondrial protein involved in fatty acid biosynthesis, has now been identified as responsible for an autosomal recessive optic neuropathy from a Chinese consanguineous family. MCAT is expressed in RGC that are rich in mitochondria. The disease variants lead to structurally unstable MCAT protein with significantly reduced intracellular expression. RGC-specific knockdown of Mcat in mice, lead to an attenuated retinal neurofiber layer, that resembles the phenotype of optic neuropathy. These results indicated that MCAT plays an essential role in mitochondrial function and maintenance of RGC axons, while novel MCAT p.L81R and p.R212W mutations can lead to optic neuropathy.
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Haug, Patricia, Samuel Koller, Jordi Maggi, Elena Lang, Silke Feil, Agnès Wlodarczyk, Luzy Bähr, et al. "Whole Exome Sequencing in Coloboma/Microphthalmia: Identification of Novel and Recurrent Variants in Seven Genes." Genes 12, no. 1 (January 6, 2021): 65. http://dx.doi.org/10.3390/genes12010065.
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Coloboma and microphthalmia (C/M) are related congenital eye malformations, which can cause significant visual impairment. Molecular diagnosis is challenging as the genes associated to date with C/M account for only a small percentage of cases. Overall, the genetic cause remains unknown in up to 80% of patients. High throughput DNA sequencing technologies, including whole-exome sequencing (WES), are therefore a useful and efficient tool for genetic screening and identification of new mutations and novel genes in C/M. In this study, we analyzed the DNA of 19 patients with C/M from 15 unrelated families using singleton WES and data analysis for 307 genes of interest. We identified seven novel and one recurrent potentially disease-causing variants in CRIM1, CHD7, FAT1, PTCH1, PUF60, BRPF1, and TGFB2 in 47% of our families, three of which occurred de novo. The detection rate in patients with ocular and extraocular manifestations (67%) was higher than in patients with an isolated ocular phenotype (46%). Our study highlights the significant genetic heterogeneity in C/M cohorts and emphasizes the diagnostic power of WES for the screening of patients and families with C/M.
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Blizzard, Lauren E., Chelsea Menke, Shaili D. Patel, Ronald R. Waclaw, Salil A. Lachke, and Rolf W. Stottmann. "A Novel Mutation in Cse1l Disrupts Brain and Eye Development with Specific Effects on Pax6 Expression." Journal of Developmental Biology 9, no. 3 (July 7, 2021): 27. http://dx.doi.org/10.3390/jdb9030027.
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Forward genetics in the mouse continues to be a useful and unbiased approach to identifying new genes and alleles with previously unappreciated roles in mammalian development and disease. Here, we report a new mouse allele of Cse1l that was recovered from an ENU mutagenesis screen. Embryos homozygous for the anteater allele of Cse1l display a number of variable phenotypes, with craniofacial and ocular malformations being the most obvious. We provide evidence that Cse1l is the causal gene through complementation with a novel null allele of Cse1l generated by CRISPR-Cas9 editing. While the variability in the anteater phenotype was high enough to preclude a detailed molecular analysis, we demonstrate a very penetrant reduction in Pax6 levels in the developing eye along with significant ocular developmental phenotypes. The eye gene discovery tool iSyTE shows Cse1l to be significantly expressed in the lens from early eye development stages in embryos through adulthood. Cse1l has not previously been shown to be required for organogenesis as homozygosity for a null allele results in very early lethality. Future detailed studies of Cse1l function in craniofacial and neural development will be best served with a conditional allele to circumvent the variable phenotypes we report here. We suggest that human next-generation (whole genome or exome) sequencing studies yielding variants of unknown significance in CSE1L could consider these findings as part of variant analysis.
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Cvekl, Aleš, and Michael John Camerino. "Generation of Lens Progenitor Cells and Lentoid Bodies from Pluripotent Stem Cells: Novel Tools for Human Lens Development and Ocular Disease Etiology." Cells 11, no. 21 (November 6, 2022): 3516. http://dx.doi.org/10.3390/cells11213516.
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In vitro differentiation of human pluripotent stem cells (hPSCs) into specialized tissues and organs represents a powerful approach to gain insight into those cellular and molecular mechanisms regulating human development. Although normal embryonic eye development is a complex process, generation of ocular organoids and specific ocular tissues from pluripotent stem cells has provided invaluable insights into the formation of lineage-committed progenitor cell populations, signal transduction pathways, and self-organization principles. This review provides a comprehensive summary of recent advances in generation of adenohypophyseal, olfactory, and lens placodes, lens progenitor cells and three-dimensional (3D) primitive lenses, “lentoid bodies”, and “micro-lenses”. These cells are produced alone or “community-grown” with other ocular tissues. Lentoid bodies/micro-lenses generated from human patients carrying mutations in crystallin genes demonstrate proof-of-principle that these cells are suitable for mechanistic studies of cataractogenesis. Taken together, current and emerging advanced in vitro differentiation methods pave the road to understand molecular mechanisms of cataract formation caused by the entire spectrum of mutations in DNA-binding regulatory genes, such as PAX6, SOX2, FOXE3, MAF, PITX3, and HSF4, individual crystallins, and other genes such as BFSP1, BFSP2, EPHA2, GJA3, GJA8, LIM2, MIP, and TDRD7 represented in human cataract patients.
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Asefa, Nigus G., Zoha Kamali, Satyajit Pereira, Ahmad Vaez, Nomdo Jansonius, Arthur A. Bergen, and Harold Snieder. "Bioinformatic Prioritization and Functional Annotation of GWAS-Based Candidate Genes for Primary Open-Angle Glaucoma." Genes 13, no. 6 (June 13, 2022): 1055. http://dx.doi.org/10.3390/genes13061055.
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Background: Primary open-angle glaucoma (POAG) is the most prevalent glaucoma subtype, but its exact etiology is still unknown. In this study, we aimed to prioritize the most likely ‘causal’ genes and identify functional characteristics and underlying biological pathways of POAG candidate genes. Methods: We used the results of a large POAG genome-wide association analysis study from GERA and UK Biobank cohorts. First, we performed systematic gene-prioritization analyses based on: (i) nearest genes; (ii) nonsynonymous single-nucleotide polymorphisms; (iii) co-regulation analysis; (iv) transcriptome-wide association studies; and (v) epigenomic data. Next, we performed functional enrichment analyses to find overrepresented functional pathways and tissues. Results: We identified 142 prioritized genes, of which 64 were novel for POAG. BICC1, AFAP1, and ABCA1 were the most highly prioritized genes based on four or more lines of evidence. The most significant pathways were related to extracellular matrix turnover, transforming growth factor-β, blood vessel development, and retinoic acid receptor signaling. Ocular tissues such as sclera and trabecular meshwork showed enrichment in prioritized gene expression (>1.5 fold). We found pleiotropy of POAG with intraocular pressure and optic-disc parameters, as well as genetic correlation with hypertension and diabetes-related eye disease. Conclusions: Our findings contribute to a better understanding of the molecular mechanisms underlying glaucoma pathogenesis and have prioritized many novel candidate genes for functional follow-up studies.
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Cilloni, Daniela, Francesca Messa, Francesca Arruga, Enrico Bracco, Paolo Nicoli, Emanuela Messa, Stefano Ulisciani, et al. "Development of a Genetic Tool Based on BCR-ABL Transgenic Drosophila Melanogaster for Identification of Genes Involved in CML Progression and Drug Testing." Blood 110, no. 11 (November 16, 2007): 468. http://dx.doi.org/10.1182/blood.v110.11.468.468.
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Abstract Although the role of Bcr-Abl in the pathogenesis of chronic myeloid leukaemia is well established, the molecular mechanisms by which it triggers cellular transformation remains still partially unknown. In addition, the mechanisms responsible for CML progression and the molecules interacting with Bcr-Abl are largely unknown. and many of. In this study, we have developed a novel approach for genetic analysis investigations to identify a number of candidate genes and pathways involved in disease progression and imatinib resistance by using a model of the Drosophila melanogaster. We generated two different stable transgenic fly lines expressing both human p210Bcr-Abl forms (either w.t. or the mutated form T315I) in a tissue specific manner. We have observed that the activation of BCR-ABL led to a particular phenotype in the fly eyes. Transgenic flies will be phenotipically and genotipically characterized carefully by analyzing the eye development. We conducted an extensive genetic screening using both Drosphila transgenic lines overexpressing human Bcr-Abl forms (Bcr-Abl/w.t. and Bcr-Abl/T315I) by making use of P-elements. This technique offers the possibility to randomly insert P-elements into the genome, thus disrupting genomic loci either in correspondence of coding sequences or regulatory elements and altering the gene function. The heterogeneous mutagenized fly population was carefully screened on the basis of the flies phenotype. The first group which we have selected was represented by flies displaying a phenotype even more aggressive than the parental transgenic fly. This kind of flies harbour mutated genes encoding for proteins which enhance the activity of Bcr-Abl, thus being most likely involved in disease progression; A second group was represented by flies displaying a wild-type phenotype. In the latter case the phenotype reversion most likely due to a mutation occurred at a level of a gene encoding for a protein functioning as Bcr-Abl negative regulator. All the data obtained with the use of fly model were confirmed in both cell lines and in primary cells via the overexpression and/or silencing of the genes identified with the Drosophila genetic-screening. Finally we have established and validated a novel tool for drug testing based on the examination of the eye phenotype induced by Bcr-Abl, which can be reverted by the drugs producing a complete block of the kinase activity. With this method we will be able to screen drug libraries to identify molecules able to silence Bcr-AblT315I tyrosine kinase activity. That can be easily accomplished by feeding flies with food previously mixed with the different drug molecules. Molecules showing a good inhibitory activity can be quickly identified because their /ability to revert the abnormal eye phenotype displayed by the transgenic flies. In conclusion, by using a model of the Drosophila melanogaster we have developed a system to identify novel genetic pathways which regulate the development and the progression of CML and we have shown that this novel system can be also used to evaluate the drugs affecting Bcr-Abl regulatory pathway. Moreover, this system does not require a priori knowledge of the function of the genes involved in the disease.
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Mencucci, Rita, Giovanni Strazzabosco, Virginia Cristofori, Andrea Alogna, Daria Bortolotti, Roberta Gafà, Michela Cennamo, et al. "GlicoPro, Novel Standardized and Sterile Snail Mucus Extract for Multi-Modulative Ocular Formulations: New Perspective in Dry Eye Disease Management." Pharmaceutics 13, no. 12 (December 13, 2021): 2139. http://dx.doi.org/10.3390/pharmaceutics13122139.
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This study aimed to evaluate the mucoadhesive and regenerative properties of a novel lubricating multimolecular ophthalmic solution (GlicoPro®) extracted from snail mucus and its potential anti-inflammatory and analgesic role in the management of dry eye disease (DED). GlicoPro bio-adhesive efficacy was assessed using a lectin-based assay, and its regenerative properties were studied in a human corneal epithelial cell line. In vitro DED was induced in human corneal tissues; the histology and mRNA expression of selected genes of inflammatory and corneal damage biomarkers were analyzed in DED tissues treated with GlicoPro. A higher percentage of bio-adhesivity was observed in corneal cells treated with GlicoPro than with sodium hyaluronate-based compounds. In the scratch test GlicoPro improved in vitro corneal wound healing. Histo-morphological analysis revealed restoration of cellular organization of the corneal epithelium, microvilli, and mucin network in DED corneal tissues treated with GlicoPro. A significant reduction in inflammatory and ocular damage biomarkers was observed. High-performance liquid chromatography-mass spectrometry analysis identified an endogenous opioid, opiorphin, in the peptide fraction of GlicoPro. In conclusion, GlicoPro induced regeneration and bio-adhesivity in corneal cells; moreover, considering its anti-inflammatory and analgesic properties, this novel ophthalmic lubricating solution may be an innovative approach for the management of DED.
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Jones, Johanna L., Bennet J. McComish, Sandra E. Staffieri, Emmanuelle Souzeau, Lisa S. Kearns, James E. Elder, Jac C. Charlesworth, et al. "Pathogenic genetic variants identified in Australian families with paediatric cataract." BMJ Open Ophthalmology 7, no. 1 (August 2022): e001064. http://dx.doi.org/10.1136/bmjophth-2022-001064.
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ObjectivePaediatric (childhood or congenital) cataract is an opacification of the normally clear lens of the eye and has a genetic basis in at least 18% of cases in Australia. This study aimed to replicate clinical gene screening to identify variants likely to be causative of disease in an Australian patient cohort.Methods and analysisSixty-three reported isolated cataract genes were screened for rare coding variants in 37 Australian families using genome sequencing.ResultsDisease-causing variants were confirmed in eight families with variant classification as ‘likely pathogenic’. This included novel variants PITX3 p.(Ter303LeuextTer100), BFSP1 p.(Glu375GlyfsTer2), and GJA8 p.(Pro189Ser), as well as, previously described variants identified in genes GJA3, GJA8, CRYAA, BFSP1, PITX3, COL4A1 and HSF4. Additionally, eight variants of uncertain significance with evidence towards pathogenicity were identified in genes: GJA3, GJA8, LEMD2, PRX, CRYBB1, BFSP2, and MIP.ConclusionThese findings expand the genotype–phenotype correlations of both pathogenic and benign variation in cataract-associated genes. They further emphasise the need to develop additional evidence such as functional assays and variant classification criteria specific to paediatric cataract genes to improve interpretation of variants and molecular diagnosis in patients.
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Farré, Xavier, Natalia Blay, Beatriz Cortés, Anna Carreras, Susana Iraola-Guzmán, and Rafael de de Cid. "Skin Phototype and Disease: A Comprehensive Genetic Approach to Pigmentary Traits Pleiotropy Using PRS in the GCAT Cohort." Genes 14, no. 1 (January 5, 2023): 149. http://dx.doi.org/10.3390/genes14010149.
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Human pigmentation has largely been associated with different disease prevalence among populations, but most of these studies are observational and inconclusive. Known to be genetically determined, pigmentary traits have largely been studied by Genome-Wide Association Study (GWAS), mostly in Caucasian ancestry cohorts from North Europe, identifying robustly, several loci involved in many of the pigmentary traits. Here, we conduct a detailed analysis by GWAS and Polygenic Risk Score (PRS) of 13 pigmentary-related traits in a South European cohort of Caucasian ancestry (n = 20,000). We observed fair phototype strongly associated with non-melanoma skin cancer and other dermatoses and confirmed by PRS-approach the shared genetic basis with skin and eye diseases, such as melanoma (OR = 0.95), non-melanoma skin cancer (OR = 0.93), basal cell carcinoma (OR = 0.97) and darker phototype with vitiligo (OR = 1.02), cataracts (OR = 1.04). Detailed genetic analyses revealed 37 risk loci associated with 10 out of 13 analyzed traits, and 16 genes significantly associated with at least two pigmentary traits. Some of them have been widely reported, such as MC1R, HERC2, OCA2, TYR, TYRP1, SLC45A2, and some novel candidate genes C1QTNF3, LINC02876, and C1QTNF3-AMACR have not been reported in the GWAS Catalog, with regulatory potential. These results highlight the importance of the assess phototype as a genetic proxy of skin functionality and disease when evaluating open mixed populations.
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Zhang, Jie, Qian Hou, Weimin Ma, Danian Chen, Weibing Zhang, Ashenafi Kiros Wubshet, Yaozhong Ding, et al. "A Naked-Eye Visual Reverse Transcription Loop-Mediated Isothermal Amplification with Sharp Color Changes for Potential Pen-Side Test of Foot-and-Mouth Disease Virus." Viruses 14, no. 9 (September 7, 2022): 1982. http://dx.doi.org/10.3390/v14091982.
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Visual loop-mediated isothermal amplification (LAMP) is qualified to be applied in the field to detect pathogens due to its simplicity, rapidity and cost saving. However, the color changes in currently reported visual reverse transcription LAMP (RT-LAMP) for foot-and-mouth disease virus (FMDV) detection are not so obvious to the naked eye, so interpretation of results is troublesome. In this study, a new naked-eye visual RT-LAMP to detect all seven distinct serotypes of FMDV was established based on the 3D genes by using pH-sensitive neutral red as the indicator, rendering a sharp contrast of color changes between the negative (light orange) and the positive (pink). Analytical sensitivity tests showed that the detection limit of the visual RT-LAMP was 104 copies/µL while those were 103 and 104 copies/µL for the RT-qPCR and conventional RT-PCR methods, respectively. Specificity tests proved that the established visual RT-LAMP assay had no cross-reactivity with other common livestock viruses. Furthermore, the analysis of 59 clinical samples showed 98.31% and 100% concordance with the RT-qPCR and the RT-PCR, respectively. The pan-serotypic FMD visual RT-LAMP assay could be suitable for a pen-side test of all seven serotypes of FMDV because the results could be easily distinguished by the naked eye without the requirement of complicated instruments and professional technicians. Hence, the novel method may have a promising prospect in field tests which exert an important role in monitoring, preventing, and controlling FMD, especially in regions with no PCR or qPCR instrument available.
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Wang, Yuqing, Shuozhen Deng, Ziyan Li, and Wencai Yang. "Advances in the Characterization of the Mechanism Underlying Bacterial Canker Development and Tomato Plant Resistance." Horticulturae 8, no. 3 (February 27, 2022): 209. http://dx.doi.org/10.3390/horticulturae8030209.
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Bacterial canker caused by the Gram-positive actinobacterium Clavibacter michiganensis is one of the most serious bacterial diseases of tomatoes, responsible for 10–100% yield losses worldwide. The pathogen can systemically colonize tomato vascular bundles, leading to wilting, cankers, bird’s eye lesions, and plant death. Bactericidal agents are insufficient for managing this disease, because the pathogen can rapidly migrate through the vascular system of plants and induce systemic symptoms. Therefore, the use of resistant cultivars is necessary for controlling this disease. We herein summarize the pathogenicity of C. michiganensis in tomato plants and the molecular basis of bacterial canker pathogenesis. Moreover, advances in the characterization of resistance to this pathogen in tomatoes are introduced, and the status of genetics-based research is described. Finally, we propose potential future research on tomato canker resistance. More specifically, there is a need for a thorough analysis of the host–pathogen interaction, the accelerated identification and annotation of resistance genes and molecular mechanisms, the diversification of resistance resources or exhibiting broad-spectrum disease resistance, and the production of novel and effective agents for control or prevention. This review provides researchers with the relevant information for breeding tomato cultivars resistant to bacterial cankers.
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Jankovic, Joseph, and Eng King Tan. "Parkinson’s disease: etiopathogenesis and treatment." Journal of Neurology, Neurosurgery & Psychiatry 91, no. 8 (June 23, 2020): 795–808. http://dx.doi.org/10.1136/jnnp-2019-322338.
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The concept of ‘idiopathic’ Parkinson’s disease (PD) as a single entity has been challenged with the identification of several clinical subtypes, pathogenic genes and putative causative environmental agents. In addition to classic motor symptoms, non-motor manifestations (such as rapid eye movement sleep disorder, anosmia, constipation and depression) appear at prodromic/premotor stage and evolve, along with cognitive impairment and dysautonomia, as the disease progresses, often dominating the advanced stages of the disease. The key molecular pathogenic mechanisms include α-synuclein misfolding and aggregation, mitochondrial dysfunction, impairment of protein clearance (associated with deficient ubiquitin-proteasome and autophagy-lysosomal systems), neuroinflammation and oxidative stress. The involvement of dopaminergic as well as noradrenergic, glutamatergic, serotonergic and adenosine pathways provide insights into the rich and variable clinical phenomenology associated with PD and the possibility of alternative therapeutic approaches beyond traditional dopamine replacement therapies.One of the biggest challenges in the development of potential neuroprotective therapies has been the lack of reliable and sensitive biomarkers of progression. Immunotherapies such as the use of vaccination or monoclonal antibodies directed against aggregated, toxic α-synuclein.as well as anti-aggregation or protein clearance strategies are currently investigated in clinical trials. The application of glucagon-like peptide one receptor agonists, specific PD gene target agents (such as GBA or LRRK2 modifiers) and other potential disease modifying drugs provide cautious optimism that more effective therapies are on the horizon. Emerging therapies, such as new symptomatic drugs, innovative drug delivery systems and novel surgical interventions give hope to patients with PD about their future outcomes and prognosis.
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Mijit, Mahmut, Sheng Liu, Kamakshi Sishtla, Gabriella D. Hartman, Jun Wan, Timothy W. Corson, and Mark R. Kelley. "Identification of Novel Pathways Regulated by APE1/Ref-1 in Human Retinal Endothelial Cells." International Journal of Molecular Sciences 24, no. 2 (January 6, 2023): 1101. http://dx.doi.org/10.3390/ijms24021101.
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APE1/Ref-1 (apurinic/apyrimidinic endonuclease 1, APE1 or APEX1; redox factor-1, Ref-1) is a dual-functional enzyme with crucial roles in DNA repair, reduction/oxidation (redox) signaling, and RNA processing and metabolism. The redox function of Ref-1 regulates several transcription factors, such as NF-κB, STAT3, HIF-1α, and others, which have been implicated in multiple human diseases, including ocular angiogenesis, inflammation, and multiple cancers. To better understand how APE1 influences these disease processes, we investigated the effects of APEX1 knockdown (KD) on gene expression in human retinal endothelial cells. This abolishes both DNA repair and redox signaling functions, as well as RNA interactions. Using RNA-seq analysis, we identified the crucial signaling pathways affected following APEX1 KD, with subsequent validation by qRT-PCR. Gene expression data revealed that multiple genes involved in DNA base excision repair, other DNA repair pathways, purine or pyrimidine metabolism signaling, and histidine/one carbon metabolism pathways were downregulated by APEX1 KD. This is in contrast with the alteration of pathways by APEX1 KD in human cancer lines, such as pancreatic ductal adenocarcinoma, lung, HeLa, and malignant peripheral nerve sheath tumors. These results highlight the unique role of APE1/Ref-1 and the clinical therapeutic potential of targeting APE1 and pathways regulated by APE1 in the eye. These findings provide novel avenues for ocular neovascularization treatment.
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Jiao, Xiaodong, Mariia Viswanathan, Nadiia Fedorivna Bobrova, Tatiana Viktorivna Romanova, and J. Fielding Hejtmancik. "Molecular Genetic Analysis of Ukrainian Families with Congenital Cataracts." Children 10, no. 1 (December 26, 2022): 51. http://dx.doi.org/10.3390/children10010051.
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This study was designed to identify the pathogenic variants in five Ukrainian families with autosomal dominant congenital cataracts. Cataracts can be defined broadly as any opacity of the crystalline lens. Lens development is orchestrated by transcription factors. Disease-causing variants in transcription factors and their developmental target genes, including the lens crystallins, are associated with congenital cataracts and other eye diseases. Whole-exome sequencing identified heterozygous disease-causing variants in five Ukrainian families with autosomal dominant congenital cataracts and cosegregation with cataracts was confirmed using Sanger sequencing. Family 97001 showed a missense variant (c.341T>A: p.L114Q) in HSF4; family 97003 showed a missense variant (c.53A>T: p.N18I) in CRYGA; family 97004 showed a missense variant (c. 82G>A: p.V28M) in GJA3; family 97006 showed a missense variant (c.83C>T: p. P28L) in CRYGC; and family 97008 showed a single-base insertion resulting in a frameshift (c.443_444insA: p. Met148IfsTer51) in PAX6. All five families are associated with congenital cataracts. Overall, we report four novel mutations in HSF4, CRYGA, CRYGC and PAX6, and one previously reported mutation in GJA3 that cause autosomal dominant congenital cataracts.
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Lara-Romero, Rocío, José Luis Cerriteño-Sánchez, Susana Mendoza-Elvira, José Bryan García-Cambrón, María Azucena Castañeda-Montes, José Manuel Pérez-Aguilar, and Julieta Sandra Cuevas-Romero. "Development of Novel Recombinant Antigens of Nucleoprotein and Matrix Proteins of Porcine orthorubulavirus: Antigenicity and Structural Prediction." Viruses 14, no. 9 (September 1, 2022): 1946. http://dx.doi.org/10.3390/v14091946.
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Blue eye disease (BED) is a swine viral infection that affects the pork industry of Mexico. Porcine orthorubulavirus (PRV) is the etiological agent, and the hemagglutinin-neuraminidase protein (HN) is characterized as the best antigen for serological tests, although other structural proteins, including the nucleoprotein (NP) and the matrix (M) protein, have been investigated during the infection of members of the Paramyxoviridae family, generating promising results. Herein, for the first time, we successfully produced and characterized both the NP and M proteins of PRV by using a recombinant strategy in the E. coli heterologous system. The ORF of the NP and M genes were cloned in-frame with the pET-SUMO expression vector. Recombinant proteins proved to be a sensitive target to detect seroconversion at 7 days until 28 days in vaccinated mice (BALB/c) by indirect ELISAs. Immunoreactivity was also tested using porcine serum samples, in which antibodies were recognized from early stages to a persistence of PRV infection, which is indicative that these proteins contain properties similar to native antigens. The predicted tertiary structure showed that both proteins have a conserved structure that resembles those found in others Paramyxovirus. Our results pave the way for developing biotechnological tools based on these proteins for the control and prevention of BED.
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Gafuik, C., J. Agapite, and H. Steller. "A screen for suppressors of apoptosis identifies a novel gain of function mutation in drosphilia RAS1s." Clinical & Investigative Medicine 30, no. 4 (August 1, 2007): 82. http://dx.doi.org/10.25011/cim.v30i4.2853.
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Background: Apoptosis is a morphologically distinct, genetically programmed form of cell death that is evolutionarily highly conserved amongst multi-cellular eukaryotes. Correct regulation of apoptosis is critical for normal development and the prevention of diseases, such as cancer. Genetic analysis of invertebrate model organisms has proven invaluable for the identification and study of key molecules involved in apoptosis. In Drosophila, the proteins Reaper (Rpr), Head involution defective (Hid) and Grim induce cell death in a caspase dependent manner by inhibiting the anti-apoptotic function of diap1.
Methods: To further elucidate the molecular mechanisms underlying the control of apoptosis, we conducted a dominant modifier screen for genes that could suppress the strong eye ablation phenotype caused by expressing hid under the control of an eye-specific promoter.
Results: As previously reported, we identified several loss of function mutants in components of the EGFR/Ras/MAPK pathway that could dominantly suppress hid-induced apoptosis. These mutants proved to be alleles of either sprouty or gap1, two negative regulators of the RTK/Ras1 signaling. Here we report the identification and characterization of the first gain of function mutation in the Drosophila RAS1 gene.
Conclusions: Taken together, these findings provide a molecular paradigm for the anti-apoptotic function of ras oncogenes.
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Hadrami, Mouna, Crystel Bonnet, Fatimetou Veten, Christina Zeitz, Christel Condroyer, Panfeng Wang, Mohamed Biya, et al. "A novel missense mutation of GJA8 causes congenital cataract in a large Mauritanian family." European Journal of Ophthalmology 29, no. 6 (October 29, 2018): 621–28. http://dx.doi.org/10.1177/1120672118804757.
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Objective of the study: Inborn lens opacity is the most frequent cause of childhood blindness. In this study, we aimed to define the presumed genetic cause of a congenital cataract present in a Mauritanian family over the last nine generations. Methods: A family history of the disease and eye examination were carried out for the family members. Next-generation sequencing using a panel of 116 cataract underlying genes was selectively conducted on the proband’s DNA. Nucleotide and amino acid changes and their impact on the phenotype were evaluated using various data analyzing software. Results: Congenital nuclear cataract, with autosomal dominant mode, was observed in the family. All patients had consequences on their vision in the first 2 years of life. Genetic screening revealed a new mutation c.166A>C (p.Thr56Pro) in GJA8, encoding the Cx50 α-connexin protein. This mutation co-segregated in all patients and was not observed in the unaffected family members and controls. The predicted secondary structure impacted by p.Thr56Pro revealed a localized disruption, in the first extra membrane loop of the wild-type sheet, which is replaced in the mutant protein by a turn then a coil. This conformational change was functionally predicted as probably damaging. Conclusion: A new mutation (c.166A>C) in GJA8 underlying a nuclear congenital cataract was identified in this study. Its segregation with the phenotype might be useful as a predicting marker of the disease.
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Pace, Marta, Ilaria Colombi, Matteo Falappa, Andrea Freschi, Mojtaba Bandarabadi, Andrea Armirotti, Blanco María Encarnación, et al. "Loss of Snord116 alters cortical neuronal activity in mice: a preclinical investigation of Prader–Willi syndrome." Human Molecular Genetics 29, no. 12 (May 18, 2020): 2051–64. http://dx.doi.org/10.1093/hmg/ddaa084.
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Abstract Prader–Willi syndrome (PWS) is a neurodevelopmental disorder that is characterized by metabolic alteration and sleep abnormalities mostly related to rapid eye movement (REM) sleep disturbances. The disease is caused by genomic imprinting defects that are inherited through the paternal line. Among the genes located in the PWS region on chromosome 15 (15q11-q13), small nucleolar RNA 116 (Snord116) has been previously associated with intrusions of REM sleep into wakefulness in humans and mice. Here, we further explore sleep regulation of PWS by reporting a study with PWScrm+/p− mouse line, which carries a paternal deletion of Snord116. We focused our study on both macrostructural electrophysiological components of sleep, distributed among REMs and nonrapid eye movements. Of note, here, we study a novel electroencephalography (EEG) graphoelements of sleep for mouse studies, the well-known spindles. EEG biomarkers are often linked to the functional properties of cortical neurons and can be instrumental in translational studies. Thus, to better understand specific properties, we isolated and characterized the intrinsic activity of cortical neurons using in vitro microelectrode array. Our results confirm that the loss of Snord116 gene in mice influences specific properties of REM sleep, such as theta rhythms and, for the first time, the organization of REM episodes throughout sleep–wake cycles. Moreover, the analysis of sleep spindles present novel specific phenotype in PWS mice, indicating that a new catalog of sleep biomarkers can be informative in preclinical studies of PWS.
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Sasamoto, Yuzuru, Siyuan Wu, Catherine A. A. Lee, Jason Y. Jiang, Bruce R. Ksander, Markus H. Frank, and Natasha Y. Frank. "Epigenetic Regulation of Corneal Epithelial Differentiation by TET2." International Journal of Molecular Sciences 24, no. 3 (February 2, 2023): 2841. http://dx.doi.org/10.3390/ijms24032841.
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Epigenetic DNA modification by 5-hydroxymethylcytosine (5hmC), generated by the Ten-eleven translocation (TET) dioxygenases, regulates diverse biological functions in many organ tissues, including the mammalian eye. For example, 5hmC has been shown to be involved in epigenetic regulation of retinal gene expression. However, a functional role of 5hmC in corneal differentiation has not been investigated to date. Here, we examined 5hmC and TET function in the human cornea. We found 5hmC highly expressed in MUC16-positive terminally differentiated cells that also co-expressed the 5hmC-generating enzyme TET2. TET2 knockdown (KD) in cultured corneal epithelial cells led to significant reductions of 5hmC peak distributions and resulted in transcriptional repression of molecular pathways involved in corneal differentiation, as evidenced by downregulation of MUC4, MUC16, and Keratin 12. Additionally, integrated TET2 KD RNA-seq and genome-wide Reduced Representation Hydroxymethylation Profiling revealed novel epigenetically regulated genes expressed by terminally differentiated cells, including KRT78, MYEOV, and MAL. In aggregate, our findings reveal a novel function of TET2 in the epigenetic regulation of corneal epithelial gene expression and identify novel TET2-controlled genes expressed in differentiated corneal epithelial cells. These results point to potential roles for TET2 induction strategies to enhance treatment of corneal diseases associated with abnormal epithelial maturation.
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Bhattacharya, Abhisek, and N. Tony Eissa. "Novel, critical roles of autophagy in dendritic cells and neutrophils to mediate experimental autoimmune encephalomyelitis (EAE) in mice (BA3P.201)." Journal of Immunology 192, no. 1_Supplement (May 1, 2014): 44.7. http://dx.doi.org/10.4049/jimmunol.192.supp.44.7.
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Abstract Multiple sclerosis (MS), an autoimmune disease of the central nervous system, affects more than a million people worldwide. Insufficient understanding of pathogenesis has precluded curative therapy for MS. Autophagy, a conserved bulk degradation process, is important in several immune functions, such as antigen presentation and infection control, but the potential roles of autophagy in regulating autoimmune diseases including MS are not well understood. To test our hypothesis that autophagy in innate immune cells is required to mediate MS, we generated conditional autophagy deficient mice where Atg7 or Atg5, essential autophagy genes, were deleted from dendritic cells (DC) or myeloid cells, induced experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and monitored disease severity. We found that autophagy deficiency in neutrophils ameliorated EAE by reducing neutrophil degranulation, resulting in failure of breakdown of blood-central nervous system barrier, a process required for EAE progression. Moreover, autophagy deficiency in neutrophils resulted in global reduction in neutrophil mediated-inflammation. Autophagy deficiency in DC, on the other hand, reduced both incidence and severity of EAE, secondary to decreased antigen presentation to T cells in the periphery. Our data show that autophagy is required for neutrophil-mediated inflammation. Our data further suggest that autophagy is a potential target for treating autoimmune diseases such as MS.
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Kuo, Ping-Chang, Dennis A. Brown, Barbara A. Scofield, I.-Chen Yu, Fen-Lei Chang, and Jui-Hung Yen. "3H-1,2-Dithiole-3-thione as a novel therapeutic agent for the treatment of experimental autoimmune encephalomyelitis." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 139.1. http://dx.doi.org/10.4049/jimmunol.196.supp.139.1.
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Abstract 3H-1,2-Dithiole-3-thione (D3T), the simplest member of the sulfur-containing dithiolethiones, is found in cruciferous vegetables, and has been previously reported to be a potent inducer of antioxidant genes and glutathione biosynthesis by activation of the transcription factor Nrf2. D3T is a cancer chemopreventive agent and possesses anti-inflammatory properties. Although D3T has been shown to protect against neoplasia, the effect of D3T in the autoimmune inflammatory disease Multiple Sclerosis/Experimental Autoimmune Encephalomyelitis (EAE) is unknown. The present study is the first report of the therapeutic effect of D3T in EAE. Our results show D3T, administered post immunization, not only delays disease onset but also dramatically reduces disease severity in EAE. Strikingly, D3T, administered post disease onset of EAE, effectively prevents disease progression and exacerbation. Mechanistic studies revealed that D3T suppresses the expression of co-stimulatory molecules and production of pro-inflammatory cytokines by dendritic cells, inhibits pathogenic Th1 and Th17 differentiation, reduces the production of inflammatory mediators by microglia, and induces the expression of antioxidant phase II enzymes in microglia. In summary, these results indicate that D3T affects both innate and adaptive immune cells, and the protective effect of D3T in EAE might be attributed to its effects on modulating dendritic cell and microglia activation and pathogenic T cell differentiation.
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Carlson, John H., Stephen F. Porcella, Grant McClarty, and Harlan D. Caldwell. "Comparative Genomic Analysis of Chlamydia trachomatis Oculotropic and Genitotropic Strains." Infection and Immunity 73, no. 10 (October 2005): 6407–18. http://dx.doi.org/10.1128/iai.73.10.6407-6418.2005.
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ABSTRACT Chlamydia trachomatis infection is an important cause of preventable blindness and sexually transmitted disease (STD) in humans. C. trachomatis exists as multiple serovariants that exhibit distinct organotropism for the eye or urogenital tract. We previously reported tissue-tropic correlations with the presence or absence of a functional tryptophan synthase and a putative GTPase-inactivating domain of the chlamydial toxin gene. This suggested that these genes may be the primary factors responsible for chlamydial disease organotropism. To test this hypothesis, the genome of an oculotropic trachoma isolate (A/HAR-13) was sequenced and compared to the genome of a genitotropic (D/UW-3) isolate. Remarkably, the genomes share 99.6% identity, supporting the conclusion that a functional tryptophan synthase enzyme and toxin might be the principal virulence factors underlying disease organotropism. Tarp (translocated actin-recruiting phosphoprotein) was identified to have variable numbers of repeat units within the N and C portions of the protein. A correlation exists between lymphogranuloma venereum serovars and the number of N-terminal repeats. Single-nucleotide polymorphism (SNP) analysis between the two genomes highlighted the minimal genetic variation. A disproportionate number of SNPs were observed within some members of the polymorphic membrane protein (pmp) autotransporter gene family that corresponded to predicted T-cell epitopes that bind HLA class I and II alleles. These results implicate Pmps as novel immune targets, which could advance future chlamydial vaccine strategies. Lastly, a novel target for PCR diagnostics was discovered that can discriminate between ocular and genital strains. This discovery will enhance epidemiological investigations in nations where both trachoma and chlamydial STD are endemic.
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Suman, B., S. Srilekha, M. Lahari, and K. Sandhya. "Automatic Detection of Genetic Diseases in Paediatric Age Using Pupillometry." International Journal for Research in Applied Science and Engineering Technology 10, no. 8 (August 31, 2022): 797–801. http://dx.doi.org/10.22214/ijraset.2022.46176.
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Abstract: Inherited retinal diseases cause severe visual deficits in children. They are classified in outer and inner retina diseases, and often cause blindness in childhood. The diagnosis for this type of illness is challenging, given the wide range of clinical and genetic causes (with over 200 causative genes). It is routinely based on a complex pattern of clinical tests, including invasive ones, not always appropriate for infants or young children. A different approach is thus needed, that exploits Chromatic Pupillometry, a technique increasingly used to assess outer and inner retina functions. This paper presents a novel Clinical Decision Support System (CDSS), based on Machine Learning using Chromatic Pupillometry in order to support diagnosis of Inherited retinal diseases in pediatric subjects. An approach that combines hardware and software is proposed: a dedicated medical equipment (pupillometer) is used with a purposely designed custom machine learning decision support system. Two distinct Support Vector Machines (SVMs), one for each eye, classify the features extracted from the pupillometric data. The designed CDSS has been used for diagnosis of Retinitis Pigmentosa in pediatric subjects. The results, obtained by combining the two SVMs in an ensemble model, show satisfactory performance of the system, that achieved 0.846 accuracy, 0.937 sensitivity and 0.786 specificity. This is the first study that applies machine learning to pupillometric data in order to diagnose a genetic disease in pediatric age
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Enabulele, Egie Elisha, Agnes Ogheneruemu Awharitoma, Scott P. Lawton, and Ruth S. Kirk. "First molecular identification of an agent of diplostomiasis, Diplostomum pseudospathaceum (Niewiadomska 1984) in the United Kingdom and its genetic relationship with populations in Europe." Acta Parasitologica 63, no. 3 (September 25, 2018): 444–53. http://dx.doi.org/10.1515/ap-2018-0054.
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Abstract Trematode genus Diplostomum comprises of parasitic species which cause diplostomiasis, the ‘white eye’ disease in fish and heavy infection can result in mortality. The increasing availability of DNA sequences of accurately identified Diplostomum species on public data base presently enables the rapid identification of species from novel sequences. We report the first molecular evidence of the occurrence of D. pseudospathaceum in the United Kingdom. Two gene regions, nuclear internal transcribed spacer cluster (ITS1-5.8S-ITS2) and mitochondrial cytochrome c oxidase subunit 1 (cox1) of cercariae from infected aquatic snails, Lymnaea stagnalis collected in several locations in Southern England were sequenced. Phylogenetic analysis based on both sequenced genes revealed that the novel sequences were D. pseudospathaceum. Molecular diversity analysis of published D. pseudospathaceum cox1 sequences from seven countries in Europe and the novel sequences from the present study revealed high diversity, but low nucleotide divergence and a lack of gene differentiation between the populations. Haplotype network analysis depicted a star-like pattern and revealed a lack of geographic structure in the population. Fixation indices confirmed gene flow between populations and we suspect high levels of dispersal facilitated by highly mobile second intermediate (fish) and definitive (piscivorous birds) host may be driving gene flow between populations. Neutrality tests and mismatch distribution indicated recent population growth/expansion for D. pseudospathaceum in Europe.
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Ávila-Castellano, Robledo, José-Raúl García-Lozano, Stefan Cimbollek, Alfredo J. Lucendo, Juan-Manuel Bozada, and Joaquín Quiralte. "Genetic variations in the TLR3 locus are associated with eosinophilic esophagitis." United European Gastroenterology Journal 6, no. 3 (September 13, 2017): 349–57. http://dx.doi.org/10.1177/2050640617732643.
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Background Eosinophilic esophagitis (EoE) is an antigen-driven disease mediated by an abnormal immune Th2 response. Objective The objective of this article is to investigate genes associated with regulating immune responses leading to disease susceptibility. Methods Twenty-seven tag single nucleotide polymorphisms (tSNPs) selected in five candidate genes ( TLR3, TLR4, FOXP3, FLG and TSLP) were genotyped in 218 EoE patients and 376 controls. Skin prick tests were carried out in EoE patients with a panel of 17 aeroallergens and 22 plant- and animal-derived foods. Results Five tSNPs located in the TSLP locus and one tSNP located in the TLR3 locus were significantly associated with EoE. The interactions between TLR3 and TSLP loci were analyzed. TLR3+/TSLP– and TLR3–/TSLP+ individuals showed a significantly reduced susceptibility to EoE compared to TLR3–/TSLP– individuals (OR = 0.66, p = 0.036 and OR = 0.23, p = 0.00014, respectively). Likewise, TLR3+/TSLP+ individuals showed the most decreased susceptibility of developing EoE (OR = 0.16, p = 0.0001). However, the interaction gain attributed to the combination of both genes was negative (IG = –4.52%), which indicated redundancy or independent effect. Additionally, TLR3 locus was found to be associated with aeroallergen and food sensitization in EoE patients (OR = 9.67, pc = 0.025 and OR = 0.53, pc = 0.048, respectively). Conclusion TLR3 constitutes a novel genetic susceptibility locus for developing EoE, and the effects would be independent of TSLP.
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Martínez, R., C. Fernández-Ramos, A. Vela, T. Velayos, A. Aguayo, I. Urrutia, I. Rica, L. Castaño, and _. _. "Clinical and genetic characterization of congenital hyperinsulinism in Spain." European Journal of Endocrinology 174, no. 6 (June 2016): 717–26. http://dx.doi.org/10.1530/eje-16-0027.
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Context Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous disease characterized by severe hypoglycemia caused by inappropriate insulin secretion by pancreatic β-cells. Objective To characterize clinically and genetically CHI patients in Spain. Design and methods We included 50 patients with CHI from Spain. Clinical information was provided by the referring clinicians. Mutational analysis was carried out for KCNJ11, ABCC8, and GCK genes. The GLUD1, HNF4A, HNF1A, UCP2, and HADH genes were sequenced depending on the clinical phenotype. Results We identified the genetic etiology in 28 of the 50 CHI patients tested: 21 had a mutation in KATP channel genes (42%), three in GLUD1 (6%), and four in GCK (8%). Most mutations were found in ABCC8 (20/50). Half of these patients (10/20) were homozygous or compound heterozygous, with nine being unresponsive to diazoxide treatment. The other half had heterozygous mutations in ABCC8, six of them being unresponsive to diazoxide treatment and four being responsive to diazoxide treatment. We identified 22 different mutations in the KATP channel genes, of which ten were novel. Notably, patients with ABCC8 mutations were diagnosed earlier, with lower blood glucose levels and required higher doses of diazoxide than those without a genetic diagnosis. Conclusions Genetic analysis revealed mutations in 56% of the CHI patients. ABCC8 mutations are the most frequent cause of CHI in Spain. We found ten novel mutations in the KATP channel genes. The genetic diagnosis is more likely to be achieved in patients with onset within the first week of life and in those who fail to respond to diazoxide treatment.
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Shahi, Shailesh K., Samantha N. Jensen, Sudeep Ghimire, CheyAnne Q. Carter, Natalya V. Guseva, Katherine Gibson-Corley, Aaron D. Bossler, Sukirth M. Ganesan, Nitin J. Karandikar, and Ashutosh K. Mangalam. "Interleukin-17A deficient mice microbiota induced regulatory T cells and suppressed experimental autoimmune encephalomyelitis (EAE) in WT HLA-DR3 transgenic mice." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 105.10. http://dx.doi.org/10.4049/jimmunol.206.supp.105.10.
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Abstract Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system, and among all the genes associated with MS, HLA class II genes have the highest relative risk. Although IL-17A is thought to be a major cytokine in the pathogenesis of MS, the exact role of IL-17A in the MS is still poorly understood. Specifically, it is unclear whether IL-17A is required for disease initiation or disease severity or in both. Therefore, in the present study, utilizing HLA-DR3 transgenic mice lacking IL-17A (HLA-DR3.IL-17A−/−), we investigated the importance of IL-17A in disease development and progression in experimental autoimmune encephalomnyelitis (EAE) an animal model of MS. We observed that HLA-DR3.IL-17A−/− mice had a higher frequency of CD4+CD25+FoxP3+ regulatory T cells (Treg)s and developed milder EAE compared to IL-17 sufficient HLA-DR3 mice. Further characterization of mechanism identified a novel role of IL-17A in regulating the disease progression through modulation of immunoregulatory responses. We also identified an important role of gut microbiota in IL-17A dependent disease regulation specifically depletion of gut bacteria with ability to promote Treg population in IL-17A sufficient HLA-DR3 mice. Fecal transplantation of HLA.DR3 mice with HLA-DR3. IL17A−/− showed milder EAE and an increase in Treg cells in HLA-DR3 mice confirming a role of gut microbiota in shaping Treg repertoire and function. Additionally, we observed higher frequency of metabolic pathway involved with Treg promoting short chain fatty acid (SCFA) metabolism in HLA-DR3.IL17A−/− mice. Thus our study shows a novel role of IL-17A in immune homeostasis and inflammation by regulating levels of Tregs through modulation of gut microbiota.
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Rathi, Sonika, Subhadra Jalali, Ganeswara Rao Musada, Satish Patnaik, Divya Balakrishnan, Anjli Hussain, and Inderjeet Kaur. "Mutation spectrum of NDP, FZD4 and TSPAN12 genes in Indian patients with retinopathy of prematurity." British Journal of Ophthalmology 102, no. 2 (October 5, 2017): 276–81. http://dx.doi.org/10.1136/bjophthalmol-2017-310958.
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AimRetinopathy of prematurity (ROP) is a vasoproliferative eye disease in preterm infants. Based on its phenotypic similarities with familial exudative vitreo retinopathy (FEVR), the present study was conducted to screen the Norrin signalling pathway genes (already been implicated in FEVR) for understanding their involvement among Indian patients with ROP.MethodsThe study cohort consisted of patients with ROP (n=246) and controls (n=300) that included full term (n=110) and preterm babies devoid of ROP (n=190). Screening of the NDP, FZD4, TSPAN12 genes were accomplished by resequencing the entire coding and untranslated regions (UTR). The genotype data of the patients with ROP were analysed in the background of their clinical manifestations and further analysed in conjunction with other available data on these genes worldwide.ResultsTwo novel variants in intron 1 (IVS1 +16A>G) and 3′UTR (c.5 22T>C) along with a previously reported change in the 5′UTR (c.395_409del14bp) were observed in the NDP gene in three patients with ROP. Screening of the FZD4 revealed four heterozygous variants, p.(Pro33Ser), p.(Pro168Ser), p.(Ile192Ile) and p.(Ile360Val), a compound heterozygous (p.(Pro33Ser)/p.(Pro168Ser)) and a 3′UTR (c*G>T) variants in the study cohort. Variants p.(Pro33Ser) and p.(Pro168Ser) were found to be significantly associated with ROP. A heterozygous variant p.(Leu119Arg) in TSPAN12 gene was observed in a patient with threshold ROP. However, a formal genotype–phenotype correlation could not be established due to the low frequencies of the variant alleles in these genes.ConclusionsThis is a first study that revealed association of few variants in Norrin signalling genes among Indian patients with ROP that warrants further detailed investigation worldwide.
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Stingl, Katarina, Britta Baumann, Pietro De Angeli, Ajoy Vincent, Elise Héon, Monique Cordonnier, Elfriede De Baere, et al. "Novel OPN1LW/OPN1MW Exon 3 Haplotype-Associated Splicing Defect in Patients with X-Linked Cone Dysfunction." International Journal of Molecular Sciences 23, no. 12 (June 20, 2022): 6868. http://dx.doi.org/10.3390/ijms23126868.
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Certain combinations of common variants in exon 3 of OPN1LW and OPN1MW, the genes encoding the apo-protein of the long- and middle-wavelength sensitive cone photoreceptor visual pigments in humans, induce splicing defects and have been associated with dyschromatopsia and cone dysfunction syndromes. Here we report the identification of a novel exon 3 haplotype, G-C-G-A-T-T-G-G (referring to nucleotide variants at cDNA positions c.453, c.457, c.465, c.511, c.513, c.521, c.532, and c.538) deduced to encode a pigment with the amino acid residues L-I-V-V-A at positions p.153, p.171, p.174, p.178, and p.180, in OPN1LW or OPN1MW or both in a series of seven patients from four families with cone dysfunction. Applying minigene assays for all observed exon 3 haplotypes in the patients, we demonstrated that the novel exon 3 haplotype L-I-V-V-A induces a strong but incomplete splicing defect with 3–5% of residual correctly spliced transcripts. Minigene splicing outcomes were similar in HEK293 cells and the human retinoblastoma cell line WERI-Rb1, the latter retaining a cone photoreceptor expression profile including endogenous OPN1LW and OPN1MW gene expression. Patients carrying the novel L-I-V-V-A haplotype presented with a mild form of Blue Cone Monochromacy or Bornholm Eye Disease-like phenotype with reduced visual acuity, reduced cone electroretinography responses, red-green color vision defects, and frequently with severe myopia.
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Yi, Zhijian, Jean de Dieu Habimana, Omar Mukama, Zhiyuan Li, Nelson Odiwuor, Hanzhi Jing, Chengrong Nie, et al. "Rational Programming of Cas12a for Early-Stage Detection of COVID-19 by Lateral Flow Assay and Portable Real-Time Fluorescence Readout Facilities." Biosensors 12, no. 1 (December 26, 2021): 11. http://dx.doi.org/10.3390/bios12010011.
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Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has led to a global pandemic with a high spread rate and pathogenicity. Thus, with limited testing solutions, it is imperative to develop early-stage diagnostics for rapid and accurate detection of SARS-CoV-2 to contain the rapid transmission of the ongoing COVID-19 pandemic. In this regard, there remains little knowledge about the integration of the CRISPR collateral cleavage mechanism in the lateral flow assay and fluorophotometer. In the current study, we demonstrate a CRISPR/Cas12a-based collateral cleavage method for COVID-19 diagnosis using the Cas12a/crRNA complex for target recognition, reverse transcription loop-mediated isothermal amplification (RT-LAMP) for sensitivity enhancement, and a novel DNA capture probe-based lateral flow strip (LFS) or real-time fluorescence detector as the parallel system readout facility, termed CRICOLAP. Our novel approach uses a customized reporter that hybridizes an optimized complementary capture probe fixed at the test line for naked-eye result readout. The CRICOLAP system achieved ultra-sensitivity of 1 copy/µL in ~32 min by portable real-time fluorescence detection and ~60 min by LFS. Furthermore, CRICOLAP validation using 60 clinical nasopharyngeal samples previously verified with a commercial RT-PCR kit showed 97.5% and 100% sensitivity for S and N genes, respectively, and 100% specificity for both genes of SARS-CoV-2. CRICOLAP advances the CRISPR/Cas12a collateral cleavage result readout in the lateral flow assay and fluorophotometer, and it can be an alternative method for the decentralized field-deployable diagnosis of COVID-19 in remote and limited-resource locations.
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Mithani, S., S. Yun, C. Pattinson, H. Kim, V. Guedes, A. Fink, A. Weljie, P. Gehrman, and J. Gill. "0021 RNA Sequencing Reveals Transcriptomic Changes in Individuals with Insomnia." Sleep 43, Supplement_1 (April 2020): A8—A9. http://dx.doi.org/10.1093/sleep/zsaa056.020.
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Abstract Introduction Insomnia affects 10–20% of the US population and is associated with negative health and psychosocial sequelae. Despite the public health impact of insomnia little is known about its underlying molecular mechanisms. The purpose of this study is to examine differentially expressed genes in 15 patients with chronic insomnia and age- and sex-matched good sleepers (n=15). Methods We performed total RNA-seq on 30 whole blood samples collected at 09:00 at 150 bp paired-ends on the Illumina NovaSeq-6000 platform. Alignment was performed using the STAR version 2.7.2a software on the human reference genome (GRCh38). Differential gene expression analysis was performed using DESeq2 version 1.24.0. Pathway analysis was performed using IPA, release 2019-08-30. Results An average of 86.7 million paired end reads per sample were sequenced. We found that 289 genes were differentially expressed in insomnia patients with a log fold change (LFC) ±0.50 and had a FDR p-value < 0.05. Top dysregulated genes include CSMD1 (L2FC=-2.78; p=1.35E-06), DUX4L9 (L2FC=3.40; p=2.81E-06) and GRM4 (L2FC=2.45; p=4.50E-05). Among the functionally relevant genes, CSMD encodes a complement control protein that is known to participate in the complement activation and inflammation in the developing central nervous system. UTS2 (L2FC=1.778; p=8.94E-06) is involved in regulation of orexin A and B activity and rapid eye movement during sleep. Ingenuity Pathway Analysis revealed 3 associated networks: Hematological, Hereditary Disorder, Organismal Injury and Abnormalities (score: 46), Developmental, Hereditary Disorder, Metabolic Disease (score: 43), and Cell Cycle, Cell mediated Immune Response, Cellular Development (score: 43). Conclusion Overall, our study revealed dysregulated genes in individuals who suffer from insomnia. Notably, dysregulation of these functionally relevant genes could impair functional brain connectivity and synaptic function. Further investigation of these biological pathways will be useful to elucidate the pathogenesis of insomnia and identify novel biomarkers or drug targets for developing improved diagnostics and therapeutics. Support National Institutes of Nursing Research, Graduate Partnership Program
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Hashemi, Lydia, McKenzi E. Ormsbee, Prashant J. Patel, Jacquelyn A. Nielson, Joseph Ahlander, and Mojgan Padash Barmchi. "A Drosophila model of HPV16-induced cancer reveals conserved disease mechanism." PLOS ONE 17, no. 12 (December 12, 2022): e0278058. http://dx.doi.org/10.1371/journal.pone.0278058.
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High-risk human papillomaviruses (HR-HPVs) cause almost all cervical cancers and a significant number of vaginal, vulvar, penile, anal, and oropharyngeal cancers. HPV16 and 18 are the most prevalent types among HR-HPVs and together cause more than 70% of all cervical cancers. Low vaccination rate and lack of molecularly-targeted therapeutics for primary therapy have led to a slow reduction in cervical cancer incidence and high mortality rate. Hence, creating new models of HPV-induced cancer that can facilitate understanding of the disease mechanism and identification of key cellular targets of HPV oncogenes are important for development of new interventions. Here in this study, we used the tissue-specific expression technique, Gal4-UAS, to establish the first Drosophila model of HPV16-induced cancer. Using this technique, we expressed HPV16 oncogenes E5, E6, E7 and the human E3 ligase (hUBE3A) specifically in the epithelia of Drosophila eye, which allows simple phenotype scoring without affecting the viability of the organism. We found that, as in human cells, hUBE3A is essential for cellular abnormalities caused by HPV16 oncogenes in flies. Several proteins targeted for degradation by HPV16 oncoproteins in human cells were also reduced in the Drosophila epithelial cells. Cell polarity and adhesion were compromised, resulting in impaired epithelial integrity. Cells did not differentiate to the specific cell types of ommatidia, but instead were transformed into neuron-like cells. These cells extended axon-like structures to connect to each other and exhibited malignant behavior, migrating away to distant sites. Our findings suggest that given the high conservation of genes and signaling pathways between humans and flies, the Drosophila model of HPV16- induced cancer could serve as an excellent model for understanding the disease mechanism and discovery of novel molecularly-targeted therapeutics.
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Balikov, Daniel A., Adam Jacobson, and Lev Prasov. "Glaucoma Syndromes: Insights into Glaucoma Genetics and Pathogenesis from Monogenic Syndromic Disorders." Genes 12, no. 9 (September 11, 2021): 1403. http://dx.doi.org/10.3390/genes12091403.
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Monogenic syndromic disorders frequently feature ocular manifestations, one of which is glaucoma. In many cases, glaucoma in children may go undetected, especially in those that have other severe systemic conditions that affect other parts of the eye and the body. Similarly, glaucoma may be the first presenting sign of a systemic syndrome. Awareness of syndromes associated with glaucoma is thus critical both for medical geneticists and ophthalmologists. In this review, we highlight six categories of disorders that feature glaucoma and other ocular or systemic manifestations: anterior segment dysgenesis syndromes, aniridia, metabolic disorders, collagen/vascular disorders, immunogenetic disorders, and nanophthalmos. The genetics, ocular and systemic features, and current and future treatment strategies are discussed. Findings from rare diseases also uncover important genes and pathways that may be involved in more common forms of glaucoma, and potential novel therapeutic strategies to target these pathways.
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Pan, Hong, Shijing Wu, Jing Wang, Tian Zhu, Tengyan Li, Bo Wan, Beihong Liu, et al. "TNFRSF21 mutations cause high myopia." Journal of Medical Genetics 56, no. 10 (June 12, 2019): 671–77. http://dx.doi.org/10.1136/jmedgenet-2018-105684.
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BackgroundHigh myopia (HM) is one of the leading causes of vision impairment worldwide, accompanied by a series of pathological ocular complications. Studies have shown that genetic factors play an important role in the pathogenesis of HM. The aim of our study is to identify a candidate gene for a large family with non-syndromic HM.MethodsA large Chinese family, including 12 patients with non-syndromic HM, and 220 unrelated patients with HM, were recruited from the Department of Ophthalmology, Peking Union Medical College Hospital. Three affected subjects from the large family were selected to perform whole exome sequencing (WES). Rare heterozygous variants shared by all three subjects were retained and then Sanger sequencing was used to determine whether any of the remaining variants cosegregated with the disease phenotype. Furthermore, all coding regions of the candidate genes were analysed in 220 unrelated patients with HM. Immunofluorescence assay was used to detect the expression of the candidate gene in the eye. Annexin V/PI staining and flow cytometry were applied to detect cell apoptotic changes.ResultsWES identified a novel TNF receptor superfamily member 21 (TNFRSF21) variant, P146A, in a large Chinese family with HM, and another three rare heterozygous variants (P202L, E240* and A440G) in TNFRSF21 were found in 220 unrelated cases with HM. Immunofluorescence assay indicated that it is strongly expressed in the mouse eye. Compared with the wild type, the P146A variant could significantly increase adult retinal pigment epithelial cell line-19 cell apoptotic levels.ConclusionsVariants in TNFRSF21 cause non-syndromic HM in Chinese population.
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Pushparaj, P. N., J. J. Aarthi, J. Manikandan, and S. D. Kumar. "siRNA, miRNA, and shRNA: in vivo Applications." Journal of Dental Research 87, no. 11 (November 2008): 992–1003. http://dx.doi.org/10.1177/154405910808701109.
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RNA interference (RNAi), an accurate and potent gene-silencing method, was first experimentally documented in 1998 in Caenorhabditis elegans by Fire et al., who subsequently were awarded the 2006 Nobel Prize in Physiology/Medicine. Subsequent RNAi studies have demonstrated the clinical potential of synthetic small interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) in dental diseases, eye diseases, cancer, metabolic diseases, neurodegenerative disorders, and other illnesses. siRNAs are generally from 21 to 25 base-pairs (bp) in length and have sequence-homology-driven gene-knockdown capability. RNAi offers researchers an effortless tool for investigating biological systems by selectively silencing genes. Key technical aspects—such as optimization of selectivity, stability, in vivo delivery, efficacy, and safety—need to be investigated before RNAi can become a successful therapeutic strategy. Nevertheless, this area shows a huge potential for the pharmaceutical industry around the globe. Interestingly, recent studies have shown that the small RNA molecules, either indigenously produced as microRNAs (miRNAs) or exogenously administered synthetic dsRNAs, could effectively activate a particular gene in a sequence-specific manner instead of silencing it. This novel, but still uncharacterized, phenomenon has been termed ‘RNA activation’ (RNAa). In this review, we analyze these research findings and discussed the in vivo applications of siRNAs, miRNAs, and shRNAs.
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Gombos, Z., R. Hermann, M. Kiviniemi, S. Nejentsev, K. Reimand, V. Fadeyev, P. Peterson, R. Uibo, and J. Ilonen. "Analysis of extended human leukocyte antigen haplotype association with Addison's disease in three populations." European Journal of Endocrinology 157, no. 6 (December 2007): 757–61. http://dx.doi.org/10.1530/eje-07-0290.
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ObjectiveAddison's disease is an organ-specific autoimmune disorder with a polygenic background. The aim of the study was to identify non-class II human leukocyte antigen (HLA) susceptibility genes for Addison's disease.Design and methodsAddison's disease patients from three European populations were analysed for selected HLA–DR–DQ alleles and for 11 microsatellite markers covering ∼4 Mb over the HLA region. Subjects were 69 patients with Addison's disease from Estonia (24), Finland (14) and Russia (31). Consecutively recruited healthy newborns from the same geographical regions were used as controls (269 Estonian, 1000 Finnish and 413 Russian). Association measures for HLA–DRB1, DQB1, DQA1 and 11 microsatellites between D6S273 and D6S2223 were taken. A low-resolution full-house typing was used for HLA class II genes, while microsatellite markers were studied using fluorescence-based DNA fragment sizing technology.ResultsWe confirmed that the HLA–DR3–DQ2 and the DQB1*0302–DRB1*0404 haplotypes confer disease susceptibility. In Russian patients, we also found an increase of DRB1*0403 allele, combined with DQB1*0305 allele in three out of six cases (P<0.0001). Analysis of 11 microsatellite markers including STR MICA confirmed the strong linkage in DR3–DQ2 haplotypes but DRB1*0404–DQB1*0302 haplotypes were diverse. MICA5.1 allele was found in 22 out of 24 Estonian patients, but results from Finnish and Russian patients did not support its independent role in disease susceptibility.ConclusionHLA–DRB1*0403 was identified as a novel susceptibility allele for Addison's disease. Additionally, we found no evidence of a non-class II HLA disease susceptibility locus; however, the HLA–DR3–DQ2 haplotype appeared more conserved in patient groups with high DR–DQ2 frequencies.
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Mangalam, Ashutosh K., Moses Rodriguez, and Chella S. David. "HLA-DQ6 (DQB1*0601) molecule modulate PLPp91-110 induced EAE in DR3 (DRB1*0301) mice through apoptosis. (130.6)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S228. http://dx.doi.org/10.4049/jimmunol.178.supp.130.6.
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Abstract The HLA class II region on chromosome 6p21 accounts for majority of familial clustering in MS and is by far the major susceptibility locus. However due to multiple class II genes, high polymorphism and linkage disequilibrium, it has been difficult to understand the role of individual class II genes and interaction between class II genes in the disease process. Previously, we have shown that PLP91-110 induced classical EAE in DR3.Abo but not in DQ6.Abo transgenic (tg) mice, suggesting that DR3 is a disease susceptible gene in the context of PLP. In this study, we have generated double (tg) mice expressing HLA-DR3/DQ6 to simulate heterozygous haplotype of MS patients. Introduction of DQ6 onto DR3 tg mice led to decrease in disease incidence on immunization with PLP91-110 suggesting a protective role of DQ6. We further characterized that this protective effect was due to expression of high level of IFNγ by DQ6 restricted T cells, which suppressed proliferation of encephalitogenic DR3-restricted T cells by inducing apoptosis in antigen specific T cells. Our IFNγ blocking experiments confirmed an anti-inflammatory role of IFNγ. Our study suggests that DQ6 modifies the PLP91-110 specific T cell response in DR3 through IFNγ mediated activation induced cell death. Thus our double tg mouse model provides a novel tool to study linkage disequilibrium and explain how HLA-DQ molecule might modulate disease in MS-susceptible individual.
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Bell, Suzannah, Samantha Malka, Ian Christopher Lloyd, and Mariya Moosajee. "Clinical Spectrum and Genetic Diagnosis of 54 Consecutive Patients Aged 0–25 with Bilateral Cataracts." Genes 12, no. 2 (January 21, 2021): 131. http://dx.doi.org/10.3390/genes12020131.
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Childhood cataract affects 2.5–3.5 per 10,000 children in the UK, with a genetic mutation identified in 50–90% of bilateral cases. However, cataracts can also manifest in adolescence and early adulthood in isolation, as part of a complex ocular phenotype or with systemic features making accurate diagnosis more challenging. We investigate our real-world experience through a retrospective review of consecutive bilateral cataract patients (0–25 years) presenting to the ocular genetics service at Moorfields Eye Hospital between 2017 and 2020. Fifty-four patients from 44 unrelated families were identified, with a median age of 13.5 years (range 1 to 68 years) and a median age at diagnosis of 43.9 months IQR (1.7–140.3 months); 40.7% were female and 46.3% were Caucasian. Overall, 37 patients from 27 families (61.4%) were genetically solved (50%) or likely solved (additional 11.4%), with 26 disease-causing variants (8 were novel) in 21 genes; the most common were crystallin genes, in 8 (29.6%) families, with half occurring in the CRYBB2 gene. There was no significant difference in the molecular diagnostic rates between sporadic and familial inheritance (P = 0.287). Associated clinical diagnoses were retinal dystrophies in five (18.5%) and aniridia in three (11.1%) families. Bilateral cataracts were the presenting feature in 27.3% (6/22) of either complex or syndromic cases, and isolated cataract patients were 11.5 years younger (rank-sum Z = 3.668, P = 0.0002). Prompt genetic investigation with comprehensive panel testing can aid with diagnosis and optimise management of cataract patients.
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Morales-Briceño, Hugo, Shekeeb S. Mohammad, Bart Post, Alessandro F. Fois, Russell C. Dale, Michel Tchan, and Victor S. C. Fung. "Clinical and neuroimaging phenotypes of genetic parkinsonism from infancy to adolescence." Brain 143, no. 3 (December 4, 2019): 751–70. http://dx.doi.org/10.1093/brain/awz345.
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Abstract Genetic early-onset parkinsonism presenting from infancy to adolescence (≤21 years old) is a clinically diverse syndrome often combined with other hyperkinetic movement disorders, neurological and imaging abnormalities. The syndrome is genetically heterogeneous, with many causative genes already known. With the increased use of next-generation sequencing in clinical practice, there have been novel and unexpected insights into phenotype-genotype correlations and the discovery of new disease-causing genes. It is now recognized that mutations in a single gene can give rise to a broad phenotypic spectrum and that, conversely different genetic disorders can manifest with a similar phenotype. Accurate phenotypic characterization remains an essential step in interpreting genetic findings in undiagnosed patients. However, in the past decade, there has been a marked expansion in knowledge about the number of both disease-causing genes and phenotypic spectrum of early-onset cases. Detailed knowledge of genetic disorders and their clinical expression is required for rational planning of genetic and molecular testing, as well as correct interpretation of next-generation sequencing results. In this review we examine the relevant literature of genetic parkinsonism with ≤21 years onset, extracting data on associated movement disorders as well as other neurological and imaging features, to delineate syndromic patterns associated with early-onset parkinsonism. Excluding PRKN (parkin) mutations, >90% of the presenting phenotypes have a complex or atypical presentation, with dystonia, abnormal cognition, pyramidal signs, neuropsychiatric disorders, abnormal imaging and abnormal eye movements being the most common features. Furthermore, several imaging features and extraneurological manifestations are relatively specific for certain disorders and are important diagnostic clues. From the currently available literature, the most commonly implicated causes of early-onset parkinsonism have been elucidated but diagnosis is still challenging in many cases. Mutations in ∼70 different genes have been associated with early-onset parkinsonism or may feature parkinsonism as part of their phenotypic spectrum. Most of the cases are caused by recessively inherited mutations, followed by dominant and X-linked mutations, and rarely by mitochondrially inherited mutations. In infantile-onset parkinsonism, the phenotype of hypokinetic-rigid syndrome is most commonly caused by disorders of monoamine synthesis. In childhood and juvenile-onset cases, common genotypes include PRKN, HTT, ATP13A2, ATP1A3, FBX07, PINK1 and PLA2G6 mutations. Moreover, Wilson’s disease and mutations in the manganese transporter are potentially treatable conditions and should always be considered in the differential diagnosis in any patient with early-onset parkinsonism.