Categories: Integument (skin) phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 124200 (trait) , 108740 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0007417: Darier disease

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal dominant

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2020

Cross-species summary: Keratosis follicularis

Species-specific name: Also described as epidermal acantholysis

Molecular basis: Linek et al. (2020): "Whole genome sequencing of the affected [Irish Terrier] dog was performed, and the [comparative] functional candidate genes for Darier disease (ATP2A2) and Hailey-Hailey disease (ATP2C1) were investigated. The analysis revealed a heterozygous SINE insertion into the ATP2A2 gene, at the end of intron 14, close to the boundary of exon 15. Analysis of the ATP2A2 mRNA from skin of the affected dog demonstrated a splicing defect and marked allelic imbalance, suggesting nonsense-mediated decay of the resulting aberrant transcripts." Kiener et al. (2023) investigated a 9 year old Shih Tzu with characteristic clinical and histopathologic findings of Darier disease: "Whole genome sequencing of the affected dog identified a heterozygous missense variant, p.N809H, affecting an evolutionarily conserved amino acid residue of the ATP2A2 protein."

Clinical features: Sueki et al. (1997) reported skin lesions on the ventral chest of a single 7 month old English Setter and on the head and knee of two of his crossbred offspring: "skin lesions were characterized by hairless, hypertrophic plaques ... The surface of the lesion was rough, with occasional serous crusting and peripheral scaling .... Pruritus was minimal. The lesions enlarged slowly, and no additional lesion developed." Linek et al. (2020) reported a "4-month-old female Irish Terrier ... with a well demarcated ulcerative and crusting lesion in the right ear canal. ... The lesion was successfully treated .... Over the course of three years, the dog additionally developed three dermal nodules of up to 4 cm in diameter that were excised and healed without complications."

Pathology: Sueki et al. (1997): "Histopathologically, these lesions [in the English Setter] showed epidermal hyperplasia with individual enlargement of keratinocytes, extensive acantholysis and minimal dyskeratosis. Ultrastructural analysis revealed that attachment plaques of desmosomes were still intact while some tonofilaments were detached from them in early lesions; there were well-developed microvilli at dissociated cell surfaces." Linek et al. (2020): "clinical, histological, immunohistological, and ultrastructural findings in a male English Setter and two of its female offspring were initially reported as Hailey-Hailey disease [Shanley et al., 1993; Sueki et al., 1997]. A subsequent study found depletion of the ATP2A2-gated stores in cultured keratinocytes from one of these dogs and suggested that these dogs had Darier disease and not Hailey-Hailey disease as previously reported [Müller et al., 2006]." Pathohistology of the Irish Terrier "revealed multiple infundibular cysts extending from the upper dermis to the subcutis. The cysts were lined by squamous epithelium, which presented with abundant acantholysis of suprabasal keratinocytes. Infundibular cysts represent a novel finding not previously reported in Darier patients." (Linek et al., 2020)

Breeds: English Setter (Dog) (VBO_0200495), Irish Terrier (Dog) (VBO_0200704), Shih Tzu (Dog) (VBO_0201223).
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: