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

Drögemüller, MichaelaMichaelaDrögemüllerJagannathan, VidyaVidyaJagannathanBecker, DoreenDoreenBeckerDrögemüller, CordCordDrögemüller0000-0001-9773-522XSchelling, ClaudeClaudeSchellingPlassais, JocelynJocelynPlassaisKaerle, CécileCécileKaerleDufaure de Citres, CarolineCarolineDufaure de CitresThomas, AnneAnneThomasMüller, Eliane JasmineEliane JasmineMüllerWelle, Monika MariaMonika MariaWelleRoosje Hasler, PieternellaPieternellaRoosje HaslerLeeb, TossoTossoLeeb0000-0003-0553-48802025-01-082025-01-082014https://boris-portal.unibe.ch/handle/20.500.12422/197455Hereditary 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.en600 - Technology::610 - Medicine & health600 - Technology::630 - Agriculture500 - Science::590 - Animals (Zoology)A mutation in the FAM83G gene in dogs with hereditary footpad hyperkeratosis (HFH)article10.7892/boris.624202483224310.1371/journal.pgen.1004370