Compound Heterozygosity for Non-Sense and Mis-Sense Mutations in Desmoplakin Underlies Skin Fragility/Woolly Hair Syndrome

University of Dundee, Dundee, Scotland, United Kingdom
Journal of Investigative Dermatology (Impact Factor: 7.22). 03/2002; 118(2):232-8. DOI: 10.1046/j.0022-202x.2001.01664.x
Source: PubMed


The constitutive desmosomal plaque protein desmoplakin plays a vital part in keratinocyte adhesion in linking the transmembranous desmosomal cadherins to the cytoplasmic keratin filament network. Recently, mutations in desmoplakin have been shown to underlie some cases of the autosomal dominant disorder, striate palmoplantar keratoderma, as well as an autosomal recessive condition characterized by dilated cardiomyopathy, woolly hair, and keratoderma. Here, we describe two unrelated individuals with a new autosomal recessive genodermatosis characterized by focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, varying degrees of alopecia, but no apparent cardiac anomalies. Mutation screening of desmoplakin demonstrated compound heterozygosity for a non-sense/mis-sense combination of mutations in both cases, C809X/N287K and Q664X/R2366C, respectively. Heterozygous carriers of any of these mutations displayed no phenotypic abnormalities. Immunohistochemistry of skin biopsies from both affected individuals revealed that desmoplakin was not just located at the cell periphery but there was also cytoplasmic staining. In addition, electron microscopy demonstrated acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal keratin intermediate filament network. Clinicopathologic and mutational analyses therefore demonstrate that desmoplakin haploinsufficiency can be tolerated in some cases, but that in combination with a mis-sense mutation on the other allele, the consequences are a severe genodermatosis with specific clinical manifestations.

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Available from: Robin A J Eady, Apr 02, 2014
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    • "(d) Hematoxylin and eosin (H&E) sections of a skin biopsy show only a single, discontinuous row of basal keratinocytes (KCs; arrows). (e) Desmoplakin schematic showing gene exons, protein domains, and protein sites of homozygous or compound heterozygous mutations identified from patients with either LAEB (p.I958LfsX5 (Bolling et al., 2010); p.R1934X/p.L203GfsX28 (Jonkman et al., 2005)), cardiocutaneous disorders similar to Carvajal/Naxos syndrome (p.K2542SfsX18 (Norgett et al., 2000); p.R1267X (Uzumcu et al., 2006); p.Q673X/Q1446X (Asimaki et al., 2009); p.G2375R (Alcalai et al., 2003); p.T2104QfsX11/p.A2655D (Mahoney et al., 2010)), or skin fragility/wooly hair syndrome (p.C809X/N287K, p.Q664X/R2366C (Whittock et al., 2002)). Bar = 20 μm. "
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    ABSTRACT: DP, desmoplakin; IF, intermediate filament; LAEB, lethal acantholytic epidermolysis bullosa
    Full-text · Article · Nov 2010 · Journal of Investigative Dermatology
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    • "For example, desmoplakin haploinsufficiency causes striate palmoplantar keratoderma (Armstrong et al. 1999; Whittock et al. 1999). Compound heterozygosity with aminoterminal missense mutations and carboxyterminal nonsense mutations leads to a more severe keratoderma, skin fragility, and woolly hair/alopecia (Whittock et al. 2002). One patient harboring compound heterozygous mutations that truncated the desmoplakin "
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    ABSTRACT: Desmosomes are intercellular junctions that tether intermediate filaments to the plasma membrane. Desmogleins and desmocollins, members of the cadherin superfamily, mediate adhesion at desmosomes. Cytoplasmic components of the desmosome associate with the desmosomal cadherin tails through a series of protein interactions, which serve to recruit intermediate filaments to sites of desmosome assembly. These desmosomal plaque components include plakoglobin and the plakophilins, members of the armadillo gene family. Linkage to the cytoskeleton is mediated by the intermediate filament binding protein, desmoplakin, which associates with both plakoglobin and plakophilins. Although desmosomes are critical for maintaining stable cell-cell adhesion, emerging evidence indicates that they are also dynamic structures that contribute to cellular processes beyond that of cell adhesion. This article outlines the structure and function of the major desmosomal proteins, and explores the contributions of this protein complex to tissue architecture and morphogenesis.
    Preview · Article · Aug 2009 · Cold Spring Harbor perspectives in biology
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    • "Desmosomal proteins including plakoglobin form plaques that are responsible for cell-cell adhesion (Green and Gaudry 2000). Mutations in many of these proteins have been linked to various cutaneous diseases including striate palmoplantal keratoderma and skin fragility/ wooly hair syndrome (Armstrong et al. 1999; Whittock et al. 2002). Moreover, defects in desmosomal cadherins are thought to contribute to a number of skin diseases including pemphigus foliaceous, pemphigus vulgaris, fogo selvagem and staphylococcal scalded skin syndrome (Kljuic et al. 2003; Whittock and Bower 2003; Wu et al. 2000). "
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    ABSTRACT: Mutations in genes encoding desmosomal proteins have been implicated in the pathogenesis of heart and skin diseases. This has led to the hypothesis that defective cell-cell adhesion is the underlying cause of injury in tissues that repeatedly bear high mechanical loads. In this study, we examined the effects of two different mutations in plakoglobin on cell migration, stiffness, and adhesion. One is a C-terminal mutation causing Naxos disease, a recessive syndrome of arrhythmogenic right ventricular cardiomyopathy (ARVC) and abnormal skin and hair. The other is an N-terminal mutation causing dominant inheritance of ARVC without cutaneous abnormalities. To assess the effects of plakoglobin mutations on a broad range of cell mechanical behavior, we characterized a model system consisting of stably transfected HEK cells which are particularly well suited for analyses of cell migration and adhesion. Both mutations increased the speed of wound healing which appeared to be related to increased cell motility rather than increased cell proliferation. However, the C-terminal mutation led to dramatically decreased cell-cell adhesion, whereas the N-terminal mutation caused a decrease in cell stiffness. These results indicate that different mutations in plakoglobin have markedly disparate effects on cell mechanical behavior, suggesting complex biomechanical roles for this protein.
    Preview · Article · Dec 2008 · Cell Motility and the Cytoskeleton
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