Novel mutations in Darier disease and association to self-reported disease severity

Abstract

Darier disease is a rare and severe autosomal dominant skin disease characterised by malodorous keratotic papules in seborrheic areas of the skin. Darier disease affects up to 1 in 30 000 people and is caused by mutations in the ATP2A2 gene, which encodes to the sarco/endoplasmic reticulum calcium-ATPase isoform 2 that pumps calcium into the endoplasmic reticulum. Although many ATP2A2 variants have been described, it is not known if genotype correlates with phenotype, which could be important for prognosis and treatment. This is the first study to use whole exome sequencing to screen the ATP2A2 gene in a cohort of 28 clinically diagnosed Darier disease patients. Twenty-one different disease causing variants were identified and 15 of these were novel. Sixteen of the 21 variants were predicted to be pathogenic using in silico prediction programs. There were seven missense, four intronic/splice-sites, three frameshifts, two in-frame deletions, four nonsense and one synonymous mutations. This study also found ten patients who harbour more than one ATP2A2 variant. The phenotype of the patient cohort was assessed by photography and by patient questionnaires. The genotype-phenotype association was examined for all variants in relation to the patient's disease severity score, and no correlation could be established.

Fig 1. The location of all published/reported ATP2A2 variants (in both isoforms) and variants discovered in the current study associated with Darier disease.

ATP2A2 isoform a consists of 21 exons (top row), which encodes for 10 transmembrane domains (M1 –M10, second row), and it is expressed in cardiomyocytes and slow-tiwtch skeletal muscles. The ATP2A2 isoform b consists of 20 exons (fourth row), which encodes for 11 transmembrane domains (M1 –M11, third row) and it is expressed in most tissue types [3]. Both isoforms have an actuator domain (A, orange boxes), phosphorylation domain (P, pink boxes), nucleotide binding domain (N, green boxes) and C-terminus (lime green boxes). All genetic variants are listed in either pale yellow (exon with variants discovered in this study) or blue boxes (exon with no variants from this study). Novel genetic variants found in this study are in bold and coloured red. Variants that were discovered in this study but were not novel are in bold only. Intronic variants are in italics. † indicates ATP2A2 variants with different genetic changes, but resulted in the same amino acid change.

Fig 2. Clinical characteristics of the cohort.

Age of onset (A), total body surface area affected (B), skin symptoms (C), worsening factors (D) and medication type (E) in the patient cohort.

Fig 3. Medication effect (1–5), disease severity (mild–severe) and disease severity (1–5) scores sorted by mutation type.

Medication effect and disease severity score (Top and bottom), a score of 1 = bad, 2 = acceptable, 3 = good, 4 = very good or 5 = excellent. Disease severity rate (Middle), a score of 1 = severe, 2 = moderate and 3 = mild. A score of 0 corresponds to patient’s lack of answer to a particular category. The type of ATP2A2 mutation is shown on the x-axis, and they are sorted into seven categories: No mutations, benign, missense, in-frame deletion, splice-site, frameshift and nonsense mutations. ● represent patients receiving systemic treatment; ▲represents patients receiving topical treatment; ◆ represent patients receiving no treatment and represent patients who have received laser treatment. The different coloured points represent the patients with two ATP2A2 variants. Points with the same colours are variants in the same patient.