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Frew J.W.,University of New South Wales | Frew J.W.,Kings College London | Dopping-Hepenstal P.J.H.,National Diagnostic Epidermolysis Bullosa Laboratory | McGrath J.A.,Kings College London
Australasian Journal of Dermatology | Year: 2010

Epidermolysis bullosa with pyloric atresia is a form of junctional epidermolysis bullosa associated with gastrointestinal abnormalities, which may include pyloric atresia. Genotype phenotype correlation is poorly understood and prognosis is difficult, if not impossible, to predict. Immunoflourescence mapping is an ideal candidate for developing a broad prognostic indicator for epidermolysis bullosa with pyloric atresia without the need for genetic mutation analysis. However, the tool developed in this paper does have limitations due to the small number of cases available and the effects of deleterious mutations in highly conserved cysteine residues on the predicted length of survival. © 2010 The Australasian College of Dermatologists. Source


Petrof G.,Kings College London | Nanda A.,Asad Al Hamad Dermatology Center | Howden J.,Kings College London | Takeichi T.,Kings College London | And 14 more authors.
American Journal of Human Genetics | Year: 2014

Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. Haploinsufficiency for GRHL2 has been implicated in autosomal-dominant deafness, but mutations have not yet been associated with any skin pathology. We investigated two unrelated Kuwaiti families in which a total of six individuals have had lifelong ectodermal defects. The clinical features comprised nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. In addition, three individuals had sensorineural deafness, and three had bronchial asthma. Taken together, the features were consistent with an unusual autosomal-recessive ectodermal dysplasia syndrome. Because of consanguinity in both families, we used whole-exome sequencing to search for novel homozygous DNA variants and found GRHL2 mutations common to both families: affected subjects in one family were homozygous for c.1192T>C (p.Tyr398His) in exon 9, and subjects in the other family were homozygous for c.1445T>A (p.Ile482Lys) in exon 11. Immortalized keratinocytes (p.Ile482Lys) showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2. Whole-skin transcriptomic analysis (p.Ile482Lys) disclosed changes in genes implicated in networks of cell-cell and cell-matrix adhesion. Our clinical findings of an autosomal-recessive ectodermal dysplasia syndrome provide insight into the role of GRHL2 in skin development, homeostasis, and human disease. © 2014 The Authors. Source


Cabral R.M.,University of London | Liu L.,National Diagnostic Epidermolysis Bullosa Laboratory | Hogan C.,University of Dundee | Dopping-Hepenstal P.J.C.,National Diagnostic Epidermolysis Bullosa Laboratory | And 12 more authors.
Journal of Investigative Dermatology | Year: 2010

Desmosomes are intercellular adhesive junctions and attachment sites for the intermediate filament (IF) cytoskeleton, prominent in tissues subject to high levels of mechanical stress such as the epidermis and heart. The obligate desmosomal constituent, plakoglobin (PG), is involved in coupling transmembrane desmosomal components with IFs. PG also contributes to intercellular adhesion through adherens junctions and has additional signaling roles. To date, two mutations in the gene encoding PG, JUP, have been described, and in both instances, patients harboring pathogenic mutations suffered from arrhythmogenic right ventricular cardiomyopathy with or without skin abnormalities. We describe homozygous nonsense mutation, p.S24X, and homozygous splice site mutation, c.468G > A, in the JUP gene that results in skin fragility, diffuse palmoplantar keratoderma, and woolly hair with no symptoms of cardiomyopathy. We show barely detectable levels of PG immunostaining in skin sections from patients harboring these mutations and show that an alternative AUG codon in p.S24X mRNA translates a 42-amino-acid N-terminal truncation. We conclude that PG is required for correct maintenance of skin integrity, and the absence of heart phenotype in patients suggests that aberrant PG expression does not compromise normal human heart development in children. Our findings provide new insight into the distinct roles that PG has in the epidermis and heart. © 2010 The Society for Investigative Dermatology. Source


Petrof G.,Kings College London | Nanda A.,Asad Al Hamad Dermatology Center | Howden J.,Kings College London | Takeichi T.,Kings College London | And 16 more authors.
American Journal of Human Genetics | Year: 2014

Grainyhead-like 2, encoded by GRHL2, is a member of a highly conserved family of transcription factors that play essential roles during epithelial development. Haploinsufficiency for GRHL2 has been implicated in autosomal-dominant deafness, but mutations have not yet been associated with any skin pathology. We investigated two unrelated Kuwaiti families in which a total of six individuals have had lifelong ectodermal defects. The clinical features comprised nail dystrophy or nail loss, marginal palmoplantar keratoderma, hypodontia, enamel hypoplasia, oral hyperpigmentation, and dysphagia. In addition, three individuals had sensorineural deafness, and three had bronchial asthma. Taken together, the features were consistent with an unusual autosomal-recessive ectodermal dysplasia syndrome. Because of consanguinity in both families, we used whole-exome sequencing to search for novel homozygous DNA variants and found GRHL2 mutations common to both families: affected subjects in one family were homozygous for c.1192TC (p.Tyr398His) in exon 9, and subjects in the other family were homozygous for c.1445TA (p.Ile482Lys) in exon 11. Immortalized keratinocytes (p.Ile482Lys) showed altered cell morphology, impaired tight junctions, adhesion defects, and cytoplasmic translocation of GRHL2. Whole-skin transcriptomic analysis (p.Ile482Lys) disclosed changes in genes implicated in networks of cell-cell and cell-matrix adhesion. Our clinical findings of an autosomal-recessive ectodermal dysplasia syndrome provide insight into the role of GRHL2 in skin development, homeostasis, and human disease.. © 2014 by The American Society of Human Genetics. All rights reserved. Source

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