ATP2A2 SINE Insertion in an Irish Terrier with Darier Disease and Associated Infundibular Cyst Formation

Abstract

A 4-month-old female Irish Terrier presented with a well demarcated ulcerative and crusting lesion in the right ear canal. Histological analysis revealed epidermal hyperplasia with severe acantholysis affecting all suprabasal layers of the epidermis, which prompted a presumptive diagnosis of canine Darier disease. The lesion was successfully treated by repeated laser ablation of the affected epidermis. 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. Histology of the excised tissue 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. Whole genome sequencing of the affected dog was performed, and the 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. As Darier disease in humans is caused by haploinsufficiency of ATP2A2, our genetic findings are in agreement with the clinical and histopathological data and support the diagnosis of canine Darier disease.

Heterozygous ATP2A2 missense variant identified in a Shih Tzu with Darier disease

“…The clinical and histopathological findings in the studied Shih Tzu largely resembled previous descriptions of confirmed or suspected Darier disease in dogs (Linek et al, 2020; Müller et al, 2006; Olivry & Linder, 2009; Sueki et al, 1997). In humans, Darier disease is characterized by waxing‐and‐waning development of warty papules and plaques in seborrheic areas (central trunk, flexures, scalp, and forehead) associated with distinctive nail abnormalities.…”

“…This calcium pump plays a key role in intracellular calcium signaling which in turn is central to the regulation of cell‐to‐cell adhesion, differentiation, and cornification in the epidermis (Foggia & Hovnanian, 2004). A canine form of Darier disease has been reported in an Irish Terrier with a heterozygous intronic SINE insertion in ATP2A2 that resulted in a near‐complete loss of functional transcripts from the mutant allele (OMIA 002265‐9615; Linek et al, 2020).…”

“…Disease onset in human patients is highly variable with reports ranging from age 3 to 75 years, but most frequently starts around puberty and usually before the third decade (Foggia & Hovnanian, 2004;Li et al, 2017;Nellen et al, 2017). Clinical signs in the previously reported Irish Terrier with Darier disease started with a lesion in the ear canal and subsequent ear infection at age 4 months (Linek et al, 2020). The present case also started with ear infection but had a much later age of onset, with the 8-year-old dog resembling the huge variability in disease onset seen in human patients.…”

Identification of Genetic Risk Factors for Monogenic and Complex Canine Diseases

“…Dogs have a sizeable population of active long interspersed nuclear element (LINE)-1 insertions (52). Both short interspersed nucleotide element (SINE) and LINE-1 insertions are a common cause of inherited diseases in dogs (75)(76)(77)(78)(79)(80)(81)(82)(83)(84). Retrogene insertions represent one particular class of structural sequence variation that has occurred several times in dogs (85) and that may be relevant for diseases, for example, as in chondrodysplasia and chondrodystrophy (25,26).…”

Inheritance of Monogenic Hereditary Skin Disease and Related Canine Breeds

“…Several mutations in different genes have been associated with this disease, including mutations in the genes encoding keratin 2 and 9, and desmoglein 1 [132], and a variant is the missense c.155G > C in the FAM83G gene, which encodes a protein that has a largely unknown function [133]. In this same breed, the heterozygous SINE insertion into the ATP2A2 gene is associated with Darier canine disease, a rare form of genodermatosis that affects different breeds [134,135]. Concretely, Linek et al (2020) showed a demarcated ulcerative and crusting lesion in the ear canal in one Irish Terrier, related to canine Darier disease [135].…”