A mutation in the FAM83G gene in dogs with hereditary footpad hyperkeratosis (HFH)

PLoS Genet. 2014 May 15;10(5):e1004370. doi: 10.1371/journal.pgen.1004370. eCollection 2014.

Abstract

Hereditary footpad hyperkeratosis (HFH) represents a palmoplantar hyperkeratosis, which is inherited as a monogenic autosomal recessive trait in several dog breeds, such as e.g. Kromfohrländer and Irish Terriers. We performed genome-wide association studies (GWAS) in both breeds. In Kromfohrländer we obtained a single strong association signal on chromosome 5 (p(raw) = 1.0×10(-13)) using 13 HFH cases and 29 controls. The association signal replicated in an independent cohort of Irish Terriers with 10 cases and 21 controls (p(raw) = 6.9×10(-10)). The analysis of shared haplotypes among the combined Kromfohrländer and Irish Terrier cases defined a critical interval of 611 kb with 13 predicted genes. We re-sequenced the genome of one affected Kromfohrländer at 23.5× coverage. The comparison of the sequence data with 46 genomes of non-affected dogs from other breeds revealed a single private non-synonymous variant in the critical interval with respect to the reference genome assembly. The variant is a missense variant (c.155G>C) in the FAM83G gene encoding a protein with largely unknown function. It is predicted to change an evolutionary conserved arginine into a proline residue (p.R52P). We genotyped this variant in a larger cohort of dogs and found perfect association with the HFH phenotype. We further studied the clinical and histopathological alterations in the epidermis in vivo. Affected dogs show a moderate to severe orthokeratotic hyperplasia of the palmoplantar epidermis. Thus, our data provide the first evidence that FAM83G has an essential role for maintaining the integrity of the palmoplantar epidermis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breeding*
  • Dog Diseases / genetics*
  • Dog Diseases / pathology
  • Dogs
  • Genome-Wide Association Study*
  • Haplotypes
  • Intracellular Signaling Peptides and Proteins / genetics
  • Male
  • Mutation
  • Pedigree
  • Proteins / genetics*

Substances

  • Intracellular Signaling Peptides and Proteins
  • PAWS1 protein, human
  • Proteins

Grant support

This work was funded in part by grants from the Albert-Heim Foundation and the European Commission (LUPA, GA-201370). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.