OMIA:001327-9615 : Hyperkeratosis, palmoplantar, FAM83G-related in Canis lupus familiaris
Categories: Integument (skin) phene
Possibly relevant human trait(s) and/or gene(s) (MIM number): 615886 (gene)
Links to MONDO diseases: No links.
Mendelian trait/disorder: yes
Mode of inheritance: Autosomal recessive
Considered a defect: yes
Key variant known: yes
Year key variant first reported: 2014
Species-specific name: Hereditary Footpad Hyperkeratosis
Species-specific symbol: HFH
Mapping: By conducting a GWAS with the 173k illumina canine HD chip in each of two breeds (Kromfohrländer: 13 cases and 29 controls, with 77,903 informative SNPs; Irish Terrier: 10 cases and 21 controls, with 82,671 informative SNPs), Drögemüller et al. (2014) mapped this disorder to a single region on chromosome CFA5. Homozygosity mapping across the two breeds narrowed the candidate region to 611kb (CFA5: 40,521,040–41,131,739 CanFam 3.1 assembly), containing 13 genes.
Molecular basis: Comparison of sequence in the positional candidate region, from whole-genome sequencing of an affected Kromfohrländer at 23.5x coverage, with relevant sequence from 46 non-affected dogs from other breeds identified the causal mutation as "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)". The causality of this variant was confirmed by genotyping of this mutation in other affected and normal dogs.
In a proof-of-concept project to detect a likely causal mutation without GWAS, Sayyab et al. (2016) reported the first use of whole-genome sequencing of a family trio (affected offspring and its two non-affected parents) which enabled them to confirm the causal mutation reported by Drögemüller et al. (2014): "527 single nucleotide variants (SNVs) and 15 indels were found to be homozygous in the affected offspring and heterozygous in the parents. Using the computer software packages ANNOVAR and SIFT to functionally annotate coding sequence differences and to predict their functional effect, resulted in seven candidate variants located in six different genes. Of these, only FAM83G:c155G>C (p.R52P) was found to be concordant in eight additional cases and 16 healthy Kromfohrländer dogs."
Clinical features: As summarised by Drögemüller et al. (2014): "Hyperkeratosis of the foot pads is noticed by the owners of both breeds at 4–5 months of age and involves all footpads. With time horny protrusions appear on the rims of the footpads and the pad surface becomes hard and develops cracks . . . . Affected animals avoid walking on irregular surfaces and may go lame. The nails of affected dogs are very hard and seem to grow faster. We noticed a duller, less wiry, softer coat on an affected Kromfohrländer . . . . Similar clinical symptoms were noted on 5 HFH affected Irish Terriers."
Breeds: Irish Terrier, Kromfohrländer.
|Symbol||Description||Species||Chr||Location||OMIA gene details page||Other Links|
|FAM83G||family with sequence similarity 83, member G||Canis lupus familiaris||5||NC_051809.1 (41162218..41192723)||FAM83G||Homologene, Ensembl , NCBI gene|
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WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.
Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.
|OMIA Variant ID||Breed(s)||Variant Phenotype||Gene||Allele||Type of Variant||Source of Genetic Variant||Reference Sequence||Chr.||g. or m.||c. or n.||p.||Verbal Description||EVA ID||Inferred EVA rsID||Year Published||PubMed ID(s)||Acknowledgements|
|89||Irish Terrier Kromfohrländer||Hyperkeratosis, palmoplantar||FAM83G||missense||Naturally occurring variant||CanFam3.1||5||g.41055619G>C||c.155G>C||p.(R52P)||2014||24832243||Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool|
Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
|2021||Mauldin, E.A., Elias, P.M. :|
|Ichthyosis and hereditary cornification disorders in dogs. Vet Dermatol 32:567-e154, 2021. Pubmed reference: 34796560 . DOI: 10.1111/vde.13033.|
|2019||Balmer, P., Fellay, A.K., Sayar, B.S., Hariton, W.V.J., Wiener, D.J., Galichet, A., Müller, E.J., Roosje, P.J. :|
|FAM83G/Fam83g genetic variants affect canine and murine hair formation. Exp Dermatol 28:350-354, 2019. Pubmed reference: 29963719 . DOI: 10.1111/exd.13729.|
|2016||Sayyab, S., Viluma, A., Bergvall, K., Brunberg, E., Jagannathan, V., Leeb, T., Andersson, G., Bergström, T.F. :|
|Whole-genome sequencing of a canine Family trio Reveals a FAM83G variant associated with hereditary footpad hyperkeratosis. G3 (Bethesda) 6:521-527, 2016. Pubmed reference: 26747202 . DOI: 10.1534/g3.115.025643.|
|2014||Drögemüller, M., Jagannathan, V., Becker, D., Drögemüller, C., Schelling, C., Plassais, J., Kaerle, C., Dufaure de Citres, C., Thomas, A., Müller, E.J., Welle, M.M., Roosje, P., Leeb, T. :|
|A mutation in the FAM83G gene in dogs with hereditary footpad hyperkeratosis (HFH). PLoS Genet 10:e1004370, 2014. Pubmed reference: 24832243 . DOI: 10.1371/journal.pgen.1004370.|
|2003||Schleifer, S.G., Versteeg, S.A., van Oost, B., Willemse, T. :|
|Familial footpad hyperkeratosis and inheritance of keratin 2, keratin 9, and desmoglein 1 in two pedigrees of Irish Terriers American Journal of Veterinary Research 64:715-20, 2003. Pubmed reference: 12828257 .|
|2000||Binder, H., Arnold, S., Schelling, C., Suter, M., Wild, P. :|
|Palmoplantar hyperkeratosis in Irish terriers: evidence of autosomal recessive inheritance Journal of Small Animal Practice 41:52-55, 2000. Pubmed reference: 10701186 .|
- Created by Frank Nicholas on 05 Oct 2005
- Changed by Frank Nicholas on 04 Apr 2014
- Changed by Frank Nicholas on 20 May 2014
- Changed by Frank Nicholas on 20 Jan 2016
- Changed by Frank Nicholas on 31 Jul 2020