Genomic Amplification of the Human Plakophilin 1 Gene and Detection of a New Mutation in Ectodermal Dysplasia/Skin Fragility Syndrome

Abstract

Ectodermal dysplasia/skin fragility syndrome is a recently described autosomal recessive disease affecting skin, nails, and hair (MIM 604536), that results from mutations in plakophilin 1, a structural component of desmosomes. We report a new plakophilin 1 mutation in an affected patient as well as detailing the intron-exon organization of the gene to facilitate future polymerase chain reaction-based mutation screening. Using polymerase chain reaction amplification of genomic DNA, we identified 15 exons spanning approximately 50 kb. Direct sequencing disclosed several nonpathogenic intragenic polymorphisms, as well as a homozygous splice site mutation (1233-2 A-->T; GenBank Z73678) in a 17 y old affected male. The clinical features comprised skin erosions, dystrophic nails, sparse hair, and painful thickening and cracking of palms and soles. Skin biopsy showed negative immunolabeling with an anti-plakophilin 1 antibody and small desmosomes. These results expand the database of plakophilin 1 mutations and demonstrate the importance of this protein in the stabilization of desmosomal adhesion in terminally differentiating keratinocytes.

Clinical Expression of Plakophilin-2 Mutations in Familial Arrhythmogenic Right Ventricular Cardiomyopathy

“…Conversely, mutations in PKP1 result in ectodermal dysplasia/skin fragility syndrome characterized by skin, hair, and nail abnormalities but no cardiac phenotype. [22][23][24] Mutations in PKP2 were first described by Gerull et al 18 in a study that evaluated only 2 of a possible 32 kindreds with ARVC. Our study is the first to provide comprehensive clinical evaluation of ARVC families harboring mutations in PKP2.…”

Ectodermal dysplasia–skin fragility syndrome resulting from a new homozygous mutation, 888delC, in the desmosomal protein plakophilin 1

“…Eight previous individuals with this disorder have been reported. [1][2][3][4][5][6][7] Plakophilin is a structural component of desmosomes, cell-cell adhesion complexes found in stratified squamous epithelia, myocardium, meninges, and parts of lymph nodes. 8 It also is expressed as a nuclear protein in several other cell types that lack desmosomes.…”

Lack of plakophilin 1 increases keratinocyte migration and reduces desmosome stability

“…Although PKP1 had been identified previously as a desmosomal component (Kapprell et al, 1988;Hatzfeld et al, 1994;Heid et al, 1994), it was not until the correlation of its absence with a human skin fragility disease that the importance of plakophilins in desmosomal adhesion was recognised. To date, three patients displaying complete ablation of PKP1 (McGrath et al, 1997;McGrath et al, 1999;Whittock et al, 2000) have been reported. These naturally occurring mutations provide valuable resources for the investigation of human PKP1 function.…”