A Homozygous Missense Mutation in TGM5 Abolishes Epidermal Transglutaminase 5 Activity and Causes Acral Peeling Skin Syndrome Andrew J. Cassidy, Maurice.

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A Homozygous Missense Mutation in TGM5 Abolishes Epidermal Transglutaminase 5 Activity and Causes Acral Peeling Skin Syndrome Andrew J. Cassidy, Maurice A.M. van Steensel, Peter M. Steijlen, Michel van Geel, Jaap van der Velden, Susan M. Morley, Alessandro Terrinoni, Gerry Melino, Eleonora Candi, W.H. Irwin McLean The American Journal of Human Genetics Volume 77, Issue 6, Pages 909-917 (December 2005) DOI: 10.1086/497707 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinicopathological features of APSS. a–d, Superficial peeling of the skin, leaving residual, painless erythema (best seen in a and d). d, Painless, manual skin removal is also possible, demonstrating that the peeling is limited to the stratum corneum. e, Light microscopy of a representative skin lesion on the dorsum of the foot (proband of family 2). The arrows point to the level of dehiscence, where cytolysis can be seen. No other abnormalities are evident. f, Electron microscopy of a similar lesion (proband of family 1, 20,000× magnification), where B denotes a blister. The level of separation is evidently between the uppermost granular layer cells (GC) and the acellular stratum corneum (SC). The asterisks mark tonofilaments that appear intact. Widened spaces (s) were observed in the stratum corneum, but these can be seen in skin from normal individuals (not shown) and are probably artefactual. The American Journal of Human Genetics 2005 77, 909-917DOI: (10.1086/497707) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigrees of APSS families 1 and 2 showing haplotype information in the vicinity of the TGM5 locus on 15q15. In family 1, of Dutch origin, two brothers married two sisters in generation II, and both resulting sibships produced affected children with APSS. At the outset, consanguinity could not be formally established, so compound heterozygous linkage was sought. This was identified for markers in the interval between D15S1040 (recombinant) and D15S1016 (recombinant), where all affected persons inherited the same two haplotypes (red and black boxes), whereas the unaffected individuals III-1 and III-5 inherited only one or the other of these haplotypes. Within the interval, homozygosity-by-descent was identified with markers flanking the TGM5 gene (bold type). Subsequently, a genealogical connection between the grandparents in generation I (dotted lines) was traced back to the 1780s, confirming the distant consanguinity implied by the genotype data. Interestingly, the proband in family 2 was homozygous for the same haplotype close to the TGM5 gene. This family was nonconsanguineous and of Scottish origin, with no history of Dutch ancestry. The American Journal of Human Genetics 2005 77, 909-917DOI: (10.1086/497707) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 3 Summary of genome scan data obtained for APSS family 1, chromosomes 1–10, with microsatellite markers from Applied Biosystems Linkage Mapping Set version 2. This legend is available in its entirety in the online edition of The American Journal of Human Genetics. The American Journal of Human Genetics 2005 77, 909-917DOI: (10.1086/497707) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 4 Summary of genome scan data obtained for APSS family 1, chromosomes 11–22, with microsatellite markers from Applied Biosystems Linkage Mapping Set version 2. This legend is available in its entirety in the online edition of The American Journal of Human Genetics. The American Journal of Human Genetics 2005 77, 909-917DOI: (10.1086/497707) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 5 Identification of homozygous missense mutations in TGM5 in persons affected by APSS. a, Normal coding-strand DNA sequence derived from exon 3 of the TGM5 gene, showing codons 108–114 inclusive. b, The same region of TGM5, derived from the proband in family 1 (individual III-3). Two homozygous missense mutations are shown: 326C→T (left arrow) and 337G→T (right arrow), predicting the amino acid changes T109M and G113C, respectively. c, The same region of TGM5, derived from a heterozygous carrier in family 1 (individual III-5). All affected persons in families 1 and 2 were homozygous for both changes. The American Journal of Human Genetics 2005 77, 909-917DOI: (10.1086/497707) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 6 Biochemical studies of TG5 mutant forms. NHEK (a) and HEK-293 (b) cells were transfected for 48 h with the use of wild-type TG5 and the three mutant forms indicated. Total TG5 activities were measured for insoluble and fractions and standardized for transfection efficiency (GFP). The control vector indicates the endogenous TG5 activity (cells transfected only with the GFP control vector). The data obtained are reported as percentages of TG activity, with 100% corresponding to the activity for cells transfected with the wild-type construct. The data presented are the averages of two independent experiments. c, View of the entire TG5 model with the four main structural domains. The mutations described here are located in the N-terminal domain at the interface between the N-terminal domain and the catalytic domain. d, Effects of the mutations in a local environment. The G113C mutation, close to the active site, would probably cause a local change in the main protein structure. The poorly conserved residue T109 is present on the surface and is, therefore, unlikely to be functionally critical. Green indicates the mutated residues, and red represents wild-type TG5 residues. The American Journal of Human Genetics 2005 77, 909-917DOI: (10.1086/497707) Copyright © 2005 The American Society of Human Genetics Terms and Conditions