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. 2009 Oct;85(4):515-20.
doi: 10.1016/j.ajhg.2009.08.015. Epub 2009 Sep 17.

A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles

Muhammad Ayub  1 , Sulman Basit, Musharraf Jelani, Fazal Ur Rehman, Muhammad Iqbal, Masoom Yasinzai, Wasim Ahmad
Affiliations

A homozygous nonsense mutation in the human desmocollin-3 (DSC3) gene underlies hereditary hypotrichosis and recurrent skin vesicles

Muhammad Ayub et al. Am J Hum Genet. 2009 Oct.

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.

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Figures

Figure 1
Figure 1
Pedigree of a Consanguineous Family from Afghanistan Segregating Autosomal-Recessive Hypotrichosis Double lines are indicative of consanguineous unions. Clear symbols represent unaffected individuals, whereas filled symbols represent affected individuals. The disease interval is flanked by two markers, D18S66 and D18S1139. For genotyped individuals, haplotypes are shown beneath each symbol, revealing that all affected individuals are homozygous for the same haplotype, whereas normal parents and healthy siblings are heterozygous carriers between markers D18S66 and D18S1139. Genetic distances in centiMorgans (cM) are depicted according to the Rutgers combined linkage-physical map (build 36.2).
Figure 2
Figure 2
Clinical Findings of Affected Individuals with Hereditary Hypotrichosis (A and B) Affected female individuals IV-3 and IV-5 at 18 and 12 years of age, respectively. Both individuals have sparse and fragile hair on scalp. (C) Right arm of an affected individual, IV-5, showing vesicles on the skin. (D) Scalp biopsy of an affected individual, IV-3. Histological examination shows: hf, hair follicle; epi, epidermis; sg, sebaceous glands; swg, sweat glands.
Figure 3
Figure 3
Sequence Analysis of the DSC3 Gene Mutation c.2129T > G in the Family Partial DNA sequence of the DSC3 gene from (A) a homozygous (affected) individual, showing a transversion (T>G); (B) a heterozygous carrier; and (C) a control individual, showing wild-type sequence. Arrows indicate position of the mutation.
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Comment in

References

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