A Homozygous Nonsense Mutation in the Human Desmocollin-3 (DSC3) Gene Underlies Hereditary Hypotrichosis and Recurrent Skin Vesicles

Abstract

Desmosomes are the major players in epidermis and cardiac muscles and contribute to intercellular binding and maintenance of tissue integrity. Two important constituents of desmosomes are transmembrane cadherins named desmogleins and desmocollins. The critical role of these desmosomal proteins in epithelial integrity has been illustrated by their disruption in mouse models and human diseases. In the present study, we have investigated a large family from Afghanistan in which four individuals are affected with hereditary hypotrichosis and the appearance of recurrent skin vesicle formation. All four affected individuals showed sparse and fragile hair on scalp, as well as absent eyebrows and eyelashes. Vesicles filled with thin, watery fluid were observed on the affected individuals' scalps and on most of the skin covering their bodies. A scalp-skin biopsy of an affected individual showed mild hair-follicle plugging. Candidate-gene-based homozygosity linkage mapping assigned the disease locus to 8.30 cM (8.51 Mbp) on chromosome 18q12.1. A maximum multipoint LOD score of 3.30 (theta = 0.00) was obtained at marker D18S877. Sequence analysis of four desmoglein and three desmocollin genes, contained within the linkage interval, revealed a homozygous nonsense mutation (c.2129T>G [p.Leu710X]) in exon-14 of the desmocollin-3 (DSC3) gene.

Autoimmunity to Desmocollin 3 in Pemphigus Vulgaris

“…Recently, a mutation in one family with hereditary hypotrichosis was associated with a nonsense mutation in Dsc3, predicted to occur at the junction of the transmembrane and cytoplasmic domains. 26 However, there was no histological evidence of skin blistering, and it is unknown whether truncated Dsc3 protein is expressed in these patients. 27 The finding of anti-Dsc3 autoantibodies in PV patients provides in vivo evidence from humans on the critical role of Dsc3 in epithelial cell adhesion.…”

Genetic skin diseases related to desmosomes and corneodesmosomes

“…A homozygous nonsense mutation in DSC3 was reported in patients with hypotrichosis and recurrent skin vesicles in a consanguineous family demonstrating hereditary transmission as an autosomal recessive trait (Table 1) [9]. The patients showed sparse and fragile hair on the scalp, as well as absent eyebrows and eyelashes.…”

Splice Site Mutations in the P-Cadherin Gene Underlie Hypotrichosis with Juvenile Macular Dystrophy

“…Mutations in DSG4 and corneodesomin (CDSN), contributing to cell-cell adhesion, result in isolated autosomal recessive and dominant hypotrichosis, respectively [12,13]. More recently, desmocollin-3 mutations have been related to hypotrichosis in association with generalized blistering [14]. P-cadherin is a major component of the classical cadherins and cell-cell adhesion and is highly expressed in the hair follicle placode during embryogenesis and the matrix region in postnatal hair follicles [15,16], consistent with the hypotrichosis observed in the setting of HJMD and EEM.…”