A Mutation in the FAM83G Gene in Dogs with Hereditary Footpad Hyperkeratosis (HFH)

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.

Author Summary

The palms and soles of mammals are covered by the palmoplantar epidermis, which has to bear immense mechanical forces and has therefore a special composition in comparison to the epidermis on regular skin. We studied a Mendelian disease in dogs, termed hereditary footpad hyperkeratosis (HFH). HFH affected dogs develop deep fissures in the paw pads, which are the consequence of a pathological thickening of the outermost layer of the epidermis. We mapped the disease causing genetic variant in the Kromfohrländer and Irish Terrier breeds to a 611 kb interval on chromosome 5. HFH affected Kromfohrländer and Irish Terriers shared the same haplotype indicating descent from a common founder. We re-sequenced the genome of an affected dog and compared it to genome sequences of 46 control dogs. The HFH affected dog had only one private non-synonymous variant in the critical interval, a missense variant of the FAM83G gene. We genotyped this variant in more than 500 dogs and found perfect association with the HFH phenotype. Our data very strongly suggest that the FAM83G variant is causative for HFH. FAM83G is a protein with unknown biochemical function. Our study thus provides the first link between this protein and the palmoplantar epidermis.