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

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. Kromfohrlander and Irish Terriers. We performed genome-wide association studies (GWAS) in both breeds. In Kromfohrlander we obtained a single strong association signal on chromosome 5 (p(raw) = 1.0x10(-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) = 6.9x10(-10)). The analysis of shared haplotypes among the combined Kromfohrlander and Irish Terrier cases defined a critical interval of 611 kb with 13 predicted genes. We resequenced the genome of one affected Kromfohrlander at 23.5x 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.