Nonsense variant in COL7A1 causes recessive dystrophic epidermolysis bullosa in Central Asian Shepherd dogs

PLoS One. 2017 May 11;12(5):e0177527. doi: 10.1371/journal.pone.0177527. eCollection 2017.

Abstract

A rare hereditary mechanobullous disorder called epidermolysis bullosa (EB) causes blistering in the skin and the mucosal membranes. To date, nineteen EB-related genes have been discovered in human and other species. We describe here a novel EB variant in dogs. Two newborn littermates of Central Asian Shepherd dogs with severe signs of skin blistering were brought to a veterinary clinic and euthanized due to poor prognosis. In post-mortem examination, the puppies were shown to have findings in the skin and the mucosal membranes characteristic of EB. A whole-genome sequencing of one of the affected puppies was performed to identify the genetic cause. The resequencing data were filtered under a recessive model against variants from 31 other dog genomes, revealing a homozygous case-specific nonsense variant in one of the known EB-causing genes, COL7A1 (c.4579C>T, p.R1527*). The variant results in a premature stop codon and likely absence of the functional protein in the basement membrane of the skin in the affected dogs. This was confirmed by immunohistochemistry using a COL7A1 antibody. Additional screening of the variant indicated full penetrance and breed specificity at ~28% carrier frequency. In summary, this study reveals a novel COL7A1 variant causing recessive dystrophic EB and provides a genetic test for the eradication of the disease from the breed.

MeSH terms

  • Animals
  • Asia
  • Base Sequence
  • Case-Control Studies
  • Codon, Nonsense / genetics*
  • Cohort Studies
  • Collagen Type VII / genetics*
  • Dogs
  • Epidermolysis Bullosa Dystrophica / genetics*
  • Epidermolysis Bullosa Dystrophica / pathology
  • Epidermolysis Bullosa Dystrophica / veterinary*
  • Female
  • Genome
  • Immunohistochemistry
  • Male
  • Pedigree

Substances

  • Codon, Nonsense
  • Collagen Type VII

Grants and funding

This work was supported by the Academy of Finland, grant number 1268091 (http://www.aka.fi/) (HL); the Jane and Aatos Erkko Foundation (http://jaes.fi/) (HL); Biocentrum Helsinki (http://www.helsinki.fi/biocentrum/) (HL); the Orion Research Foundation (http://www.orion.fi/en/rd) (HL); the Morris Animal Foundation-D13CA-403 (http://www.morrisanimalfoundation.org/) (MKH); and the Jenny and Antti Wihuri Foundation (http://wihurinrahasto.fi/) (ES).