Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 608649 (trait) , 604194 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0012089: ichthyosis prematurity syndrome

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2015

Mapping: The disease locus was mapped to chromosome 9 by a genome-wide association study (GWAS) using 9 affected and 13 control dogs and illumina canine_HD SNP chip genotypes (Metzger et al. 2015). The most significantly associated markers were located in the 740 kb interval from 54,031,320 to 54,772,131 (CanFam3.1).

Molecular basis: Metzger et al. (2015) identified a single nucleotide sustitution in exon 8, c.1250G>A, as the most likely causative variant. This variant alters the encoded amino acid seqeunce (p.Arg417Gln). However, the variant predominantly leads to aberrant splicing as it generates a cryptic splice acceptor site within exon 8. Metzger et al. (2015) identified a transcript lacking 54 nucleotides from the beginning of exon 8 in affected dogs. Western blot analysis demonstrated that the SLC27A4 protein is only expressed at very low levels in the skin of affected dogs compared to control dogs.

Clinical features: Clinical examination revealed signs of a generalized severe hyperkeratosis in all cases with a formation of a strongly wrinkled, thickened and scaling skin especially in the region of the eyes and nose. These changes led to a dry inelastic and lichenified skin of an untidy appearance in the affected dogs and a markedly swollen periocular skin which impeded the opening of the puppy’s eyes in some cases. In-between the wrinkles the exudative character of the skin promoted secondary infections. Due to the poor prognosis, all affected dogs were euthanized at the age of 7–40 days. Additional computer tomographic and endoscopic examinations after euthanasia in two five week old affected dogs revealed a ventrally displaced auditory canal with an atypically wrinkled shape but no signs of other anomalies (Metzger et al. 2015).

Pathology: Affected Great Dane puppies had epidermal and follicular orthokeratotic hyperkeratosis, enlarged keratohyaline granules, vacuolated keratinocytes, and accumulations of an eosinophilic and alcianophilic, lipid-rich material within dilated hair follicular lumina and the cytoplasm of sebocytes. The macroscopic, histopathologic, and ultrastructural skin changes indicated a new variant of a primary disorder of cornification with congenital, non-epidermolytic, lamellar ichthyosiform appearance (Hoffmann et al. 2016)

Breed: Great Dane (Dog) (VBO_0200623).
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: