Academic literature on the topic 'Palmoplantar keratoderma'

Thema dieser Arbeit war die klinische sowie molekulargenetische Analyse einer Familie mit der Verdachtsdiagnose autosomal dominante lamelläre Ichthyose (ADLI). Mit direkter Sequenzierung des Loricrin-Gens (LOR) wurde die Mutation 730insG identifiziert und die Diagnose Loricrin-Keratoderma gestellt. Durch Analyse weiterer Patienten wurde gezeigt, dass ADLI keine Loricrin-Keratoderma darstellt. Nach eingehender klinischer Untersuchung und Literaturanalyse konnten für die hier beschriebene Entität folgende Merkmale definiert werden: Als Hauptmerkmale eine honigwabenförmige Palmoplantarkeratose sowie eine leichte Ichthyose, als Nebenmerkmale Pseudoainhums, Autoamputationen, Kollodiumbaby, prominente Fingerknöchel sowie Hyperkeratosen an Knien und Ellenbögen. Die genetisch als Loricrin-Keratoderma charakterisierte Verhornungsstörung in der beschriebenen Familie sollte nunmehr klinisch als honigwabenförmige Palmoplantarkeratose mit Ichthyose bezeichnet werden. Zur Standarddiagnostik von Loricrin-Keratoderma wurde die direkte Sequenzierung von LOR auf DNA-Basis etabliert. Die Mutation 730insG resultiert in einer neuen argininreichen Domäne und einer Verlängerung des Proteins um 22 Aminosäuren. Eine Expressionsanalyse mittels Pyrosequenzierung zeigte eine gleichwertige Expression des mutierten und des Wildtyp-Allels. Dies unterstützt die „gain-of-function“-Theorie für das veränderte Loricrin und stützt die Aussage des für Loricrin-Keratoderma existierenden transgenen Mausmodells.<br>The main focus of this thesis was the clinical and genetic analysis of a family referred to us with the diagnosis of autosomal dominant lamellar ichthyosis (ADLI). Through direct sequencing of the loricrin gene (LOR) the mutation 730insG was identified and the family was diagnosed as having loricrin keratoderma. By sequencing further patients it was shown that ADLI is not a loricrin keratoderma. Based on refined clinical examination and analysis of the literature the following criteria could be defined for the entity seen: Compulsory features are honeycomb-like palmoplantar keratoderma and ichthyosis, optional features are pseudoainhums, autoamputations, collodion baby, prominent knuckle pads as well as hyperkeratotic lesions on knees and elbows. Therefore the disorder of keratinisation of the family described here genetically characterised as loricrin keratoderma should be clinically termed “honeycomb-like palmoplantar keradoderma with ichthyosis”. To molecularly diagnose loricrin keratoderma direct sequencing of LOR with DNA samples was established. The mutation 730insG results in a new arginine rich domain and an elongation of the protein by 22 residues. Expression analysis showed an equal expression of mutant and wild-type allele. This underlined the “gain-of-function” theory of the modified loricrin and supported the findings in the transgenic mouse model for loricrin keratoderma.

Desmosomes are intercellular junctions that anchor intermediate filaments to the sites of intercellular contacts. They are critical for maintaining the integrity of tissues that experience constant mechanical and structural stresses, like the skin and heart. Perturbation of desmosomal adhesion can lead to devastating epidermal and myocardial diseases. However, little is known about the regulators of desmosomes and the role of desmosomes in cell signalling events. Recent work has suggested that iASPP, an inhibitor of the p53 family of proteins, localises at the intercalated discs where desmosomes reside. However, its role at the desmosomes has remained elusive. Thus, in this thesis, it was investigated whether iASPP is a dual function protein that links desmosome adhesion to gene expression and if desmosome-related diseases develop in the absence of iASPP. iASPP was found to be a novel regulator of desmosomes, co-localising with them by physically interacting with the desmosomal components desmoplakin and K5 intermediate filaments. Loss of iASPP resulted in increased phosphorylation and solubilisation of desmoplakin, leading to the formation of K5 aggregates. This culminated in disrupted intercellular adhesion and enhanced cellular migration. Consistent with the role of iASPP in the maintenance of desmosomal adhesion integrity, focal palmoplantar keratoderma was observed in iASPP-deficient mice — a disorder often associated with desmosome dysfunction. This was accompanied by disrupted intracellular signalling, as exemplified by the disrupted expression of differentiation markers; an increase in the thickness of cell layers expressing differentiation marker K1 was noted, and K5 and K6 cells were ectopically expressed throughout the diseased palmoplantar epidermis. Impaired intercellular adhesion and migration had consequences for wound healing, as iASPP-deficient mice exhibited delayed wound closure. Furthermore, defects in eyelid closure in iASPP-deficient mice were found to be due to increased apoptosis. The localisation of apoptotic cells at the leading edge of the eyelid epidermis implied that apoptosis might have occurred due to a loss of cell-matrix or cell-cell contact, i.e. anoikis. Taken together, these results suggest that iASPP is involved in pathological (palmoplantar keratoderma), physiological (wound healing) and developmental processes (embryonic eyelid closure) through its regulation of desmosomes and their dynamics. Therefore, iASPP represents a new candidate gene in cutaneous disorders and could be implicated in a variety of epidermal and myocardial diseases.

Keratoderma – pathological hyperkeratosis of palms and soles - is a cause of disability in many clinical situations, including the rare and heterogeneous group of inherited palmoplantar keratodermas (PPKs). The aim of this study was to work towards better understanding of molecular mechanisms active in the pathogenesis of PPK by the creation of a cell and tissue culture resource and its initial application to laboratory studies. My study was based on a diverse group of autosomal dominant disorders, previously ascertained in families from Scotland, in whom the precise genetic aetiology was known. I established a tissue and cell culture resource of inherited keratodermas of known single-gene aetiology from patients with proven keratin 1, 9, 17, loricrin and mitochondrial mutations. An additional pedigree with striate keratoderma with an unknown mutation was recruited, and the causative mutation identified as a novel heterozygous A-to-T transversion in exon 5 (c.430A>T) of the desmoglein 1 gene, converting an arginine residue to a premature termination codon (p. Arg144stop). The keratinocyte culture resource was established from patients with keratin 1, 9, 17 and loricrin mutations, as well as controls. Due to the pain associated with direct infiltration of plantar skin, biopsies were obtained using peripheral nerve block for plantar biopsy. The effectiveness of this approach, which may be useful for future administration of treatment, was made the subject of an open clinical trial. Histological and immunocytochemical studies were carried out on affected plantar skin obtained from PPK patients and compared to control tissue, in an attempt to identify common and distinct pathways resulting in hyperkeratosis. Histological changes, e.g. hypergranulosis, extent of hyperkeratosis, acanthosis or acantholysis, were not uniform across different subtypes of inherited PPK and varied even between individuals within subtypes. Prominent eosin staining of spinous cells was a common feature in inherited PPK due to underlying K1 and K17 mutations. Electron microscopy showed abnormal keratin filaments in PPK with underlying keratin mutations only but was not a uniform finding within subtypes, and other electron microscopic features also varied between individuals. Immunocytochemical study did not demonstrate significant differences in expression of a selection of markers of differentiation (keratins 1, 9, 14 and 17), and cornified envelope protein filaggrin. Abnormal involucrin expression was observed, with premature expression in basal and lower spinous layers in all PPK subtypes raising the possibility of a common underlying mechanism in the development of hyperkeratosis. Prominent loricrin staining was noted in areas of acantholysis in K1 and K9 subtypes, but was uniform across other subtypes. Markers of proliferation and apoptosis demonstrated no overt change in epidermal turnover, although it is possible that only small changes in proliferative index are required to produce plantar hyperkeratosis. Overall, using morphological criteria, plantar hyperkeratosis was not readily distinguishable between inherited PPK of different underlying genetic causes. This raises the possibility that many of the reported structural features of inherited PPK are secondary phenomena as opposed to critical steps in the pathogenesis of hyperkeratosis. Initial attempts at RNA extraction using laser and manual microdissection have to date been unsuccessful in generating RNA of the quality and concentration to run a pilot microarray experiment, using standard RNA extraction kits. Plans for future projects include the further development of a possible microarray experiment in the Pachyonychia Congenita type 2 pedigree with the McLean laboratory in Dundee. The tissue resource has been made available for collaborative study via the GENESKIN project, as well as through the McLean and Lane laboratories, Dundee for both functional studies and immortalisation of cell lines.