ATP2A2 Mutations in Darier's Disease: Variant Cutaneous Phenotypes Are Associated with Missense Mutations, But Neuropsychiatry Features Are Independent of Mutation Class

Abstract

Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratinization. Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap, schizophrenia, bipolar disorder and epilepsy, have also been reported. The cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24.1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 40 different patient-specific mutations in 47 families. The majority (23/40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.

Up-Regulation of Transient Receptor Potential Canonical 1 (TRPC1) following Sarco(endo)plasmic Reticulum Ca2+ATPase 2 Gene Silencing Promotes Cell Survival: A Potential Role for TRPC1 in Darier's Disease

“…Most physiological systems are able to compensate for the loss of function of SERCA2b, possibly because of expression of other SERCA isoforms within those tissues (Dhitavat et al, 2003;Tavadia et al, 2004). However, of the multiple isoforms of SERCA1, -2, or -3, only SERCA2b is expressed in keratinocytes (Lytton and MacLennan, 1988;Ruiz-Perez et al, 1999). The mutated SERCA2 fails to sequester cytosolic Ca 2ϩ into the endoplasmic reticulum (ER) lumen, thereby disturbing the otherwise normal Ca 2ϩ homeostasis circuitry within the cells (Zhao et al, 2001;Ahn et al, 2003).…”

Redox-assisted regulation of Ca 2+ homeostasis in the endoplasmic reticulum by disulfide reductase ERdj5

“…However, our findings shed light on coordinated cross talk among protein, redox, and calcium homeostasis, which are three major types of homeostasis in the ER. Darier's disease, an autosomal dominant inherited disorder of the skin, was reported to be caused by an anomaly of Ca 2+ signaling due to mutations of SERCA2b (29)(30)(31)(32). Because of lossof-function mutations in SERCA2b, keratinocytes in Darier's disease patients were reported to have a reduced pool of Ca 2+ in the ER.…”

Sarcoendoplasmic reticulum Ca2+ ATPase type 2 downregulated in human oral squamous cell carcinoma

“…26 A variety of missense, nonsense, frameshift and splicing mutations in the ATP2A2 gene have been identified in familial Darier's disease, an autosomal skin disorder, demonstrating that this gene is closely related to this disease. [12][13][14] Interestingly, some patients with Darier's disease (30 -50%) have OPLs (hyperkeratosis). 29,30 However, in vitro studies showed that the calcium content of the ER lumen is a key determinant in the control of apoptosis induced by physiologic stimuli.…”

“…The sequence of each primer and each PCR condition was based on those reported previously. 13 After amplification, PCR products were electrophoresed on 10% polyacrylamide gels under several different conditions at 4°C, 15°C and room temperature. After electrophoresis, the gel was silver-stained using the DNA Silver Staining Kit (Amersham, Piscataway, NJ).…”

“…11 In particular, inactivation of the ATP2A2 gene due to null or heterozygous mutations, resulting in impaired uptake of cytosolic Ca 2ϩ into the ER and consequent disruption of Ca 2ϩ signaling, causes Darier's disease, an autosomal-dominant skin disorder characterized by loss of cellular adhesion, proliferation and abnormal keratinization. [12][13][14] Moreover, Liu et al 15 demonstrated that aged mice with a single functional Atp2a2 allele (Atp2a2 ϩ/-) have a high prevalence of spontaneously developing SCCs and premalignant lesions in keratinized epithelial cells of the upper digestive organs, including the oral cavity. Thus, ATP2A2 appears to be a good candidate for OSCC as a novel tumor-suppressor gene.…”