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

Cassidy, Andrew J.; Steensel, M.A.M. van; Steijlen, P.M.; Geel, Michel van; Velden, J. van der; Morley, Susan M.; Terrinoni, Alessandro; Melino, Gerry; Candi, Eleonora; McLean, W.H. Irwin

doi:10.1086/497707

Cited by 126 publications

(120 citation statements)

References 28 publications

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“…Two forms of peeling skin syndrome are recognized: acral PSS (APSS; MIM 609796) which is caused by mutations in the TGM5 gene, encoding transglutaminase 5 [3,10], and generalized PSS (MIM 270300) [2,15]. Generalized PSS shows an autosomal recessive pattern of inheritance and has been subclassiWed into two main subtypes: non-inXammatory (type A PSS) and inXammatory (type B PSS).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory peeling skin syndrome caused a novel mutation in CDSN

et al. 2011

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Generalized peeling skin syndrome (PSS) is a rare autosomal recessive dermatosis manifesting with continuous exfoliation of the stratum corneum. The inflammatory (type B) subtype of PSS was recently found to be caused by deleterious mutations in the CDSN gene encoding corneodesmosin, a major component of desmosomal junctions in the uppermost layers of the epidermis. In the present study, we assessed a 10-month-old baby, who presented with generalized superficial peeling of the skin. Using PCR amplification and direct sequencing, we identified the third PSS-associated mutation in CDSN, a homozygous 4 bp duplication in the second exon of the gene (c.164_167dup GCCT; p.Thr57ProfsX6). These data further support the notion that corneodesmosin deficiency impairs cell-cell adhesion in the upper epidermis, paving the way for an abnormal inflammatory response due to epidermal barrier disruption.

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Section: Introductionmentioning

confidence: 99%

Inflammatory peeling skin syndrome caused a novel mutation in CDSN

et al. 2011

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“…The numbers of variants of other transglutaminases in the databases are fewer than 40. Among them there are two interesting mutations in TGM5 which show association with the Acral Peeling Skin Syndrome (Gly113Cys, Cassidy et al 2005;Trp255Arg, Lys445Asn, Kharfi et al 2009). …”

Section: Comparison Of the Frequency Of Genetic Variations In Genes Omentioning

confidence: 99%

Polymorphism of transglutaminase 2: unusually low frequency of genomic variants with deficient functions

2011

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Transglutaminase 2 (TG2) is a multifunctional member of an enzyme family: it modifies glutamine residues by cross-linking proteins and incorporating primary amines into them, has protein disulphide isomerase and protein kinase activities, mediates trans-membrane signal transduction and interactions between cell surface proteins and the extracellular matrix. These unusual multiple roles encoded into one polypeptide chain suggest that genomic variations in the TGM2 gene should be limited. Indeed, the available information in databases shows that unlike in the case of most other transglutaminases there are no common single nucleotide polymorphisms in exons of human TGM2. We collected data on and produced some of the rare genetic variants of TGM2 by site directed mutagenesis and found that some were less stable than the most abundant (wild type) enzyme variant and the majority had deficient transamidating activity. Further studies are required to clarify the pathologic significance of these rare TGM2 alleles in the human population.

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“…23 Thus, fine tuning of proteases and inhibitors in upper layers is apparently a major task of HBP1. Additional coregulation is observed for ROBO3, a transmembrane receptor, and for one of its ligands, SLIT1.…”

Section: à5mentioning

confidence: 99%

The p63 target HBP1 is required for skin differentiation and stratification

Borrelli

Candi

et al. 2010

Cell Death Differ

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Genetic experiments established that p63 is crucial for the development and maintenance of pluristratified epithelia. In the RNA interference (RNAi) screening for targets of p63 in keratinocytes, we identified the transcription factor, High Mobility Group (HMG) box protein 1 (HBP1). HBP1 is an HMG-containing repressor transiently induced during differentiation of several cell lineages. We investigated the relationship between the two factors: using RNAi, overexpression, chromatin immunoprecipitations and transient transfections with reporter constructs, we established that HBP1 is directly repressed by p63. This was further confirmed in vivo by evaluating expression in p63 knockout mice and in transgenics expressing p63 in basal keratinocytes. Consistent with these findings, expression of HBP1 increases upon differentiation of primary keratinocytes and HaCaT cells in culture, and it is higher in the upper layers of human skin. Inactivation of HBP1 by RNAi prevents differentiation of keratinocytes and stratification of organotypic skin cultures. Finally, we analyzed the keratinocyte transcriptomes after HBP1 RNAi; in addition to repression of growth-promoting genes, unexpected activation of differentiation genes was uncovered, coexisting with repression of other genes involved in epithelial cornification. Our data indicate that suppression of HBP1 is part of the growth-promoting strategy of p63 in the lower layers of epidermis and that HBP1 temporally coordinates expression of genes involved in stratification, leading to the formation of the skin barrier. Cell Death and Differentiation (2010) 17, 1896-1907 doi:10.1038/cdd.2010; published online 4 June 2010 p63 is a transcription factor (TF) homologous to p53 and p73. p53 directs the response to DNA damage by impinging on cell-cycle control and pro-apoptotic pathways, 1 whereas p63 is involved in the development and maintenance of pluri-stratified epithelia.2 Six p63 proteins have been described, resulting from two distinct promoters -amino-terminal transcriptional activation domain-containing p63 (TAp63) and transcriptional activation domain-deleted p63 (DNp63) -and from alternative mRNA splicing -a, b and g -at the 3 0 end of the gene. TAp63 contains a transcriptional activation domain that is missing in the N-terminally deleted DNp63 isoforms; differential splicing generates isoforms with or without a sterile a-motif (SAM) domain, allegedly implicated in protein-protein interactions. The relative properties and functions of these isoforms are still not fully understood, but the major isoform present in keratinocytes and other multi-layered epithelia -DNp63a -is essential for ectodermal development in zebrafish, as well as in mammals. Indeed, the importance of p63 in skin development is shown by mice lacking p63, which die soon after birth with severe defects in limb and craniofacial development and absence of skin. In humans, several syndromes showing abnormalities in limbs, skin and epithelial annexes are caused by missense mutations in the p63 gene. 3 p63 is ...

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

Cited by 126 publications

References 28 publications

Inflammatory peeling skin syndrome caused a novel mutation in CDSN

Inflammatory peeling skin syndrome caused a novel mutation in CDSN

Polymorphism of transglutaminase 2: unusually low frequency of genomic variants with deficient functions

The p63 target HBP1 is required for skin differentiation and stratification

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