Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 606503 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2013

Species-specific name: Hereditary nasal parakeratosis

Species-specific symbol: HNPK

Inheritance: Page et al. (2003) reported evidence consistent with autosomal recessive inheritance.

Mapping: A GWAS conducted by Jagannathan et al. (2013) on 13 affected and 23 control Labrador retrievers, each genotyped with the Illumina canine HD chip (yielding 106,681 informative SNPs), mapped this disorder to an approximately 4Mb region on chromosome CFA2. Subsequest homozygosity mapping narrowed the candidate region to approximately 1.6Mb "from 20,818,258–22,414,948 bp (CanFam 3.1 assembly)" which contains 15 annotated genes.

Molecular basis: Whole-genome sequencing of one of the affected dogs by Jagannathan et al. (2013), and comparison of this sequence in the ~1.6Mb candidate region with the canine reference sequence revealed four non-synonymous variants, one of which "turned out to represent an artifact due to an error in the reference genome assembly". Genotyping of the other three variants in a large (>500) cohort of affected and control dogs identifed the causal mutation as c.972T>G in the SUV39H2 gene "encoding the “suppressor of variegation 3-9 homolog 2 (Drosophila)”, a histone 3 lysine 9 (H3K9) methyltransferase". "The variant results in the change of an asparagine residue in the catalytically active SET domain to a lysine (p.N324K). The SET domain has been named according to the first proteins, in which it has been identified, Suvar(3)9, enhancer of zeste, and trithorax. SIFT and Polyphen-2 predict that the p.N324K variant affects protein function . . . . The asparagine at position 324 is highly conserved across all known SUV39H2 orthologs and even across many other related H3K9 methyltransferases". The same authors also comment that "A loss of SUV39H2 function is predicted to result in delayed differentiation, which is compatible with the histopathological changes that we observed in biopsies from nasal epidermis of HNPK affected Labrador Retrievers." Bauer et al. (2018): "Whole genome sequencing of one affected Greyhound revealed a 4-bp deletion at the 5′-end of intron 4 of the SUV39H2 gene that was absent in 188 control dog and three wolf genomes. The variant was predicted to disrupt the 5′-splice site with subsequent loss of SUV39H2 function. The six affected puppies were homozygous for the variant, whereas the two non-affected littermates were heterozygous."

Clinical features: As summarised by Jagannathan et al. (2013), "HNPK affected dogs develop crusts and fissuring of the nasal planum at a young age but are otherwise healthy. The pathognomonic histopathological changes consist of a marked diffuse parakeratotic hyperkeratosis characterized by the retention of nuclei in the stratum corneum and an accumulation of proteinaceous fluid (“serum lakes”) within the stratum corneum".

Breeds: Greyhound (Dog) (VBO_0200638), Labrador Retriever (Dog) (VBO_0200800).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: