ATP2A2 Mutations in Darier's Disease and Their Relationship to Neuropsychiatric Phenotypes

Abstract

Darier's disease (DD) is a rare, dominantly inherited disorder that affects the skin producing a variety of types of lesion. Close examination of lesional DD skin shows the presence of abnormal keratinization (epidermal differentiation) and acantholysis (loss of cohesion) of keratinocytes. A number of clinical studies have described the co-occurrence of various neurological and psychiatric symptoms with DD, including mood disorders, epilepsy, mental retardation and a slowly progressive encephalopathy. A single locus for DD has been mapped to chromosome 12q23-q24.1, and a variety of missense, nonsense, frameshift and splicing mutations in the ATP2A2 gene have been described recently in families with DD. This gene encodes the sarcoplasmic/endoplasmic reticulum calcium-pumping ATPase SERCA2, which has a central role in intra-cellular calcium signalling. In this study, we performed mutation analysis on ATP2A2 in 19 unrelated DD patients, of whom 10 had neuropsychiatric phenotypes. We identified and verified 17 novel mutations predicting conservative and non-conservative amino acid changes, potential premature translation terminations and potential altered splicing. Our findings confirm that mutations in ATP2A2 are associated with DD. In neuropsychiatric cases, there was a non-random clustering of mutations in the 3' end of the gene ( P = 0.01), and a predominance of the missense type (70% versus 38% in DD patients). This supports the hypothesis that the DD gene has pleiotropic effects in brain and that mutations in SERCA2 are implicated in the pathogenesis of neuropsychiatric disorders.

Deletions of Any Single Residues in Glu40-Ser48 Loop Connecting A Domain and the First Transmembrane Helix of Sarcoplasmic Reticulum Ca2+-ATPase Result in Almost Complete Inhibition of Conformational Transition and Hydrolysis of Phosphoenzyme Intermediate

“…Single deletions or substitutions of the residues in the adjacent N-terminal (His 32 -Asn 39 ) and C-terminal (Leu 49 -Ile 54 ) regions of the Glu 40 -Ser 48 loop had only slight or moderate effect on the activity, except that the specific substitutions of Asn 39 (N39D and N39T, but not N39A) had a significantly reduced activity. Quadruple alanine substitutions of Asn 39 , Glu 40 , Glu 44 , and Glu 45 were previously shown to cause no loss of function (22), and the present results are in essential agreement.…”

“…Mutants in Darier's Disease-Darier's disease, a human autosomal dominant skin disorder, was shown to be caused by mutations in the SERCA2b protein (43,44), and deletions and substitutions ⌬41, ⌬42, N39D, and N39T were found in the Darier's disease pedigrees (45,46). It was indicated very recently (47) that these mutants have no Ca 2ϩ transport activity.…”

Neuroplasticity and cellular resilience in mood disorders

“…Furthermore, a variety of missense, nonsense, frameshift and splicing mutations have recently been identified in the gene encoding the sarcoplasmic/endoplasmic reticulum calcium-pumping ATPase (SERCA2) in patients with Darier's disease (predominantly a skin disorder), many of whom exhibited neuropsychiatric (including affective) phenotypes. 69 These findings are intriguing since abnormalities of Ca 2+ handling have also been observed when peripheral cells obtained from BPD patients have been treated with the SERCA inhibitor thapsigargin. 70 The potential role for abnormalities of Ca 2+ signaling in the pathophysiology of BPD is also highlighted by the recent observations that the chronic administration of the most effective mood stabilizers, lithium and valproate (VPA), robustly increases the expression of two proteins known to play important roles in calcium sequestration.…”

Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier's disease

“…PCR amplification of ATP2A2 coding sequence and mutation detection was as previously described 14 but briefly consisted of mutation detection by denaturing high performance liquid chromatography (DHPLC) 20 with samples showing heteroduplexes undergoing radioactive DNA cycle sequencing. Three microsatellite markers-D12S 84, D12S 105 and D12S 1333-were typed using semi-automated fluorescent methodology.…”

“…12,13 The DD gene has recently been identified as the ATP2A2 gene with various missense, frameshift, nonsense and splicing mutations described in families with DD. 3,[14][15][16] The gene encodes SERCA2-a sarcoplasmic/endoplasmic reticulum calcium pump that plays a role in intracellular calcium signalling and is therefore a plausible candidate gene for involvement in mood disorder. The possibility that ATP2A2 has pleiotropic effects in DD and BP disorder was supported by our findings of a predominance of missense mutations and a non random clustering of mutations in the 3Ј end of the gene in 10 unrelated DD patients with neuropsychiatric phenotypes.…”