Categories: Integument (skin) phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 613000 (trait) , 148067 (gene)

Links to MONDO diseases:

• MONDO:0013073: palmoplantar keratoderma, nonepidermolytic, focal 1

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2015

Cross-species summary: Also known as Focal Non-Epidermolytic Palmoplantar Keratoderma (FNEPPK). Since this disorder in humans is known to be due to mutations in two different genes, KRT16 and TRPV3, it has been subdivided in FNEPPK1 and FNEPPK2, respectively.

Mapping: From a linkage analysis of a Dogue de Bordeaux family comprising 14 affected and 54 normal dogs, each genotyped with the canine 173,000 Illumina SNP chip, Plassais et al. (2015) mapped this disorder to a 20Mb region of chromosome CFA9 that contains the "type I keratin cluster".

Molecular basis: Plassais et al. (2015) "carried out mutation screening on several keratins [located in the candidate region of CFA9] in 14 affected dogs and 16 controls and identified a complex mutation in KRT16 corresponding to an insertion/deletion (indel) of four nucleotides and a separate 1 bp deletion 15 nucleotides downstream in exon 6 . . . . This complex indel results in an insertion of 1 bp in affected dogs and introduces a frameshift changing the sequence of 10 amino acids and creating a premature stop codon (p.Glu392*) in the open reading frame of the gene. This stop codon located in the 2B domain leads to the loss of the last 85 amino acids of K16, including the helix termination motif. . . . To confirm that this mutation is causative and specific to the Dogue de Bordeaux, [Plassais et al.] sequenced a set of 334 Dogues de Bordeaux with known clinical status. All affected dogs were homozygous for the complex mutation, and all unaffected dogs were either homozygous for the wild-type alleles or heterozygous (245/306 and 61/306, respectively). Furthermore, the mutated allele was never detected in a panel of 344 unaffected dogs from 80 different breeds."

Clinical features: Plassais et al. (2015): "The onset usually occurred between 10 weeks and 1 year of age. First described by Paradis (1992), affected dogs exhibit a painful thickening of the footpads with severe keratinous proliferations and fissures only at the ground contact locations similar to those observed in FNEPPK patients . . . . Cracks predispose the dogs to secondary infections, leading to lameness, causing the dog to be reluctant to walk. Nails did not seem to be affected . . . Similarly, no other cutaneous sign such as oral leukoplakia, cysts, or follicular keratosis was reported."

Breed: Dogue de Bordeaux.

Associated gene: