A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome

Andrew Cassidy, Maurice A. M. van Steensel, Peter M. Steijlen, Michel van Geel, Jaap van der Velden, Susan Morley, Alessandro Terrinoni, Gerry Melino, Eleonora Candi, Irwin McLean (Lead / Corresponding author)

Research output: Contribution to journalArticle

88 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)909-917
Number of pages9
JournalAmerican Journal of Human Genetics
Volume77
Issue number6
DOIs
Publication statusPublished - Dec 2005

Fingerprint

Missense Mutation
Epidermis
Mutation
Skin
Transglutaminases
Cell Adhesion
Cornea
Glycine
Haplotypes
Genes
Virulence
Foot
Catalytic Domain
Proteins
Extremities
Hand
transglutaminase 5
Acral type Peeling skin syndrome
Phenotype

Cite this

Cassidy, Andrew ; van Steensel, Maurice A. M. ; Steijlen, Peter M. ; van Geel, Michel ; van der Velden, Jaap ; Morley, Susan ; Terrinoni, Alessandro ; Melino, Gerry ; Candi, Eleonora ; McLean, Irwin. / A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome. In: American Journal of Human Genetics. 2005 ; Vol. 77, No. 6. pp. 909-917.
@article{c71a7523d4e84250bacbce7c8a3a3c28,
title = "A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome",
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.",
author = "Andrew Cassidy and {van Steensel}, {Maurice A. M.} and Steijlen, {Peter M.} and {van Geel}, Michel and {van der Velden}, Jaap and Susan Morley and Alessandro Terrinoni and Gerry Melino and Eleonora Candi and Irwin McLean",
note = "dc.publisher: Elsevier Senior author responsible for overall strategy, funding, planning, analysis and writing of the first paper to show that mutations in the transglutaminase-5 gene, encoding an enzyme essential for protein cross-linking in epidermal barrier formation, are the cause of peeling skin syndrome. dc.description.sponsorship: Wellcome Trust Senior Research Fellowship Dystrophic Epidermolysis Bullosa Research Association (DEBRA) UK The Pachyonychia Congenita Project",
year = "2005",
month = "12",
doi = "10.1086/497707",
language = "English",
volume = "77",
pages = "909--917",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Elsevier",
number = "6",

}

Cassidy, A, van Steensel, MAM, Steijlen, PM, van Geel, M, van der Velden, J, Morley, S, Terrinoni, A, Melino, G, Candi, E & McLean, I 2005, 'A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome', American Journal of Human Genetics, vol. 77, no. 6, pp. 909-917. https://doi.org/10.1086/497707

A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome. / Cassidy, Andrew; van Steensel, Maurice A. M.; Steijlen, Peter M.; van Geel, Michel; van der Velden, Jaap; Morley, Susan; Terrinoni, Alessandro; Melino, Gerry; Candi, Eleonora; McLean, Irwin (Lead / Corresponding author).

In: American Journal of Human Genetics, Vol. 77, No. 6, 12.2005, p. 909-917.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A homozygous missense mutation in TGM5 abolishes epidermal transglutaminase 5 activity and causes acral peeling skin syndrome

AU - Cassidy, Andrew

AU - van Steensel, Maurice A. M.

AU - Steijlen, Peter M.

AU - van Geel, Michel

AU - van der Velden, Jaap

AU - Morley, Susan

AU - Terrinoni, Alessandro

AU - Melino, Gerry

AU - Candi, Eleonora

AU - McLean, Irwin

N1 - dc.publisher: Elsevier Senior author responsible for overall strategy, funding, planning, analysis and writing of the first paper to show that mutations in the transglutaminase-5 gene, encoding an enzyme essential for protein cross-linking in epidermal barrier formation, are the cause of peeling skin syndrome. dc.description.sponsorship: Wellcome Trust Senior Research Fellowship Dystrophic Epidermolysis Bullosa Research Association (DEBRA) UK The Pachyonychia Congenita Project

PY - 2005/12

Y1 - 2005/12

N2 - 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.

AB - 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.

U2 - 10.1086/497707

DO - 10.1086/497707

M3 - Article

VL - 77

SP - 909

EP - 917

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 6

ER -