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

• Published in: PLoS genetics Vol. 10; no. 5; p. e1004370
• Main Authors: Drögemüller, Michaela, Jagannathan, Vidhya, Becker, Doreen, Drögemüller, Cord, Schelling, Claude, Plassais, Jocelyn, Kaerle, Cécile, Dufaure de Citres, Caroline, Thomas, Anne, Müller, Eliane J, Welle, Monika M, Roosje, Petra, Leeb, Tosso
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.05.2014; Public Library of Science (PLoS)
• Subjects: Animals; Biology and Life Sciences; Breeding; Diseases; Dog Diseases - genetics; Dog Diseases - pathology; Dogs; Gene mutations; Genes; Genetic aspects; Genetic research; Genetics; Genome-Wide Association Study; Genomics; Haplotypes; Intracellular Signaling Peptides and Proteins - genetics; Keratosis; Life Sciences; Male; Medicine and Health Sciences; Mutation; Pedigree; Proteins - genetics; Zoological research; PALMOPLANTAR KERATODERMA; IRISH TERRIERS; KERATIN-16; DISORDERS; SEQUENCING DATA; INHERITANCE; ASSOCIATION; GENOME; PACHYONYCHIA-CONGENITA; TOOL
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1004370

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.