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A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome
- Publication Year :
- 2005
-
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.
- 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
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....84b1cc7a92143b43c8869e50f9d6f06f