151. A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome
- Author
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Maurice A.M. van Steensel, Peter M. Steijlen, Eleonora Candi, S.M. Morley, Michel van Geel, W.H. Irwin McLean, Alessandro Terrinoni, Jaap J A J van der Velden, Gerry Melino, and Andrew Cassidy
- Subjects
Models, Molecular ,Male ,Secondary ,Genetic Linkage ,DNA Mutational Analysis ,medicine.disease_cause ,Protein Structure, Secondary ,Catalytic Domain ,Syndrome ,Cross Reactions ,Homozygote ,Mutation, Missense ,Transglutaminases ,Epidermis ,Microsatellite Repeats ,Haplotypes ,Molecular Sequence Data ,Pedigree ,Chromosome Mapping ,Protein Structure, Tertiary ,Cell Line ,Skin Diseases ,Female ,Consanguinity ,Genes, Recessive ,Binding Sites ,Humans ,Sequence Analysis, DNA ,Genetic Vectors ,Genetic Markers ,030207 dermatology & venereal diseases ,0302 clinical medicine ,Models ,Missense mutation ,Genetics(clinical) ,Genetics (clinical) ,Genetics ,0303 health sciences ,Mutation ,integumentary system ,Settore BIO/11 ,Articles ,Phenotype ,Peeling skin syndrome ,Sequence Analysis ,Transglutaminase 5 ,Protein Structure ,Biology ,03 medical and health sciences ,medicine ,Recessive ,030304 developmental biology ,Epidermis (botany) ,Haplotype ,Genodermatosis ,Molecular ,DNA ,medicine.disease ,Molecular biology ,Genes ,Missense ,Tertiary - Abstract
Peeling skin syndrome is an autosomal recessive genodermatosis characterized by the shedding of the outer epidermis. In the acral form, the dorsa of the hands and feet are predominantly affected. Ultrastructural analysis has revealed tissue separation at the junction between the granular cells and the stratum corneum in the outer epidermis. Genomewide linkage analysis in a consanguineous Dutch kindred mapped the gene to 15q15.2 in the interval between markers D15S1040 and D15S1016. Two homozygous missense mutations, T109M and G113C, were found in TGM5, which encodes transglutaminase 5 (TG5), in all affected persons in two unrelated families. The mutation was present on the same haplotype in both kindreds, indicating a probable ancestral mutation. TG5 is strongly expressed in the epidermal granular cells, where it cross-links a variety of structural proteins in the terminal differentiation of the epidermis to form the cornified cell envelope. An established, in vitro, biochemical cross-linking assay revealed that, although T109M is not pathogenic, G113C completely abolishes TG5 activity. Three-dimensional modeling of TG5 showed that G113C lies close to the catalytic domain, and, furthermore, that this glycine residue is conserved in all known transglutaminases, which is consistent with pathogenicity. Other families with more-widespread peeling skin phenotypes lacked TGM5 mutations. This study identifies the first causative gene in this heterogeneous group of skin disorders and demonstrates that the protein cross-linking function performed by TG5 is vital for maintaining cell-cell adhesion between the outermost layers of the epidermis.
- Published
- 2005