A Homozygous Missense Mutation in TGM5 Abolishes Epidermal Transglutaminase 5 Activity and Causes Acral Peeling Skin Syndrome

Epithelial Genetics Group, Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, United Kingdom.
The American Journal of Human Genetics (Impact Factor: 10.93). 01/2006; 77(6):909-17. DOI: 10.1086/497707
Source: PubMed


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.

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Available from: Alessandro Terrinoni, Oct 06, 2015
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    • "In conclusion, we present a case of genetically confirmed APSS, which clinically resembles EBS. Both mutations, c.337G>T, p.G113C and c.2T>C, p.M1T have been published before in the literature in patients with APSS [3, 9]. The parents are both heterozygous carriers of the mutations. "
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    ABSTRACT: The acral peeling skin syndrome (APSS) is a rare autosomal recessive disorder clinically characterized by asymptomatic desquamation of the skin limited to the hands and feet and histologically by cleavage at the stratum granulosum and stratum corneum level [Kiritsi et al.: J Invest Dermatol 2010;130:1741-1746]. We report on a 10-month-old boy with a history of skin peeling limited to the hands and feet since 2 months of age. Clinical examination revealed erythematous erosions with peripheral desquamation and flaccid blisters. DNA mutation analysis detected two heterozygous TGM5 mutations: c.2T>C, p.M1T in exon 1 and c.337G>T, p.G113C in exon 3 in keeping with the diagnosis of APSS. The clinical presentation of APSS alone might be confusing and strongly resemble epidermolysis bullosa simplex making the differential diagnosis difficult.
    Case Reports in Dermatology 08/2013; 5(2):210-4. DOI:10.1159/000354572
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    • "Rare mutations in TGs have been identified in severe recessive epidermal disorders, with mutations in the TGM1 gene causing lamellar ichthyosis [8], [9] and mutations in the TGM5 gene causing the acral form of “the peeling skin syndrome” [10]. Furthermore, in a previously published cDNA microarray study we showed increased expression of the TGM1 and TGM3 transcripts in the skin of AD patients sensitized to skin-colonizing yeast Malassezia sympodialis (Mal s) [11]. "
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    ABSTRACT: Background Atopic dermatitis (AD) is a common chronic inflammatory skin disorder where epidermal barrier dysfunction is a major factor in the pathogenesis. The identification of AD susceptibility genes related to barrier dysfunction is therefore of importance. The epidermal transglutaminases ( TGM1, TGM3 and TGM5) encodes essential cross-linking enzymes in the epidermis. Objective To determine whether genetic variability in the epidermal transglutaminases contributes to AD susceptibility. Methods Forty-seven single nucleotide polymorphisms (SNPs) in the TGM1, TGM3 and TGM5 gene region were tested for genetic association with AD, independently and in relation to FLG genotype, using a pedigree disequilibrium test (PDT) in a Swedish material consisting of 1753 individuals from 539 families. In addition, a German case-control material, consi
    PLoS ONE 11/2012; 7(11-11):e49694. DOI:10.1371/journal.pone.0049694 · 3.23 Impact Factor
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    • "Genomic DNA was extracted from EDTA blood and cultured keratinocytes using the QiAmp DNA Mini Kit, as well as from cryosections using the QiAmp DNA FFPE Tissue Kit (both from Qiagen, Hilden, Germany). Amplification of all 15 TGM5 exons and exon/intron boundaries was performed as described earlier (Cassidy et al., 2005). All PCR products were submitted to automated nucleotide sequencing in an ABI 3130XL genetic analyzer using Big Dye Terminator Chemistry (Applied Biosystems, Darmstadt, Germany). "
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    ABSTRACT: Acral peeling skin syndrome (APSS) is an autosomal recessive skin disorder characterized by acral blistering and peeling of the outermost layers of the epidermis. It is caused by mutations in the gene for transglutaminase 5, TGM5. Here, we report on clinical and molecular findings in 11 patients and extend the TGM5 mutation database by four, to our knowledge, previously unreported mutations: p.M1T, p.L41P, p.L214CfsX15, and p.S604IfsX9. The recurrent mutation p.G113C was found in 9 patients, but also in 3 of 100 control individuals in a heterozygous state, indicating that APSS might be more widespread than hitherto expected. Using quantitative real-time PCR, immunoblotting, and immunofluorescence analysis, we demonstrate that expression and distribution of several epidermal differentiation markers and corneodesmosin (CDSN) is altered in APSS keratinocytes and skin. Although the expression of transglutaminases 1 and 3 was not changed, we found an upregulation of keratin 1, keratin 10, involucrin, loricrin, and CDSN, probably as compensatory mechanisms for stabilization of the epidermal barrier. Our results give insights into the consequences of TGM5 mutations on terminal epidermal differentiation.
    Journal of Investigative Dermatology 05/2012; 132(10):2422-9. DOI:10.1038/jid.2012.166 · 7.22 Impact Factor
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