Darier disease – novel mutations in ATP2A2 and genotype–phenotype correlation

Abstract

Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively common genodermatosis with autosomal dominant inheritance and late age of onset. The progressive skin manifestations are variable, but often debilitating and disfiguring, and may be associated with a wide range of neuropsychiatric problems, such as epilepsy and depression. On histology, acantholysis and dyskeratosis are prominent findings, implicating impaired functionality of desmosomes. Recently, mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the endo/sacrcoplasmic reticulum, have been identified as the molecular basis of DD. This slow-twitched calcium ATPase has two splice variants, one of which is highly expressed in epidermis, and maintains low intracellular calcium levels by facilitating transport of cytosolic calcium into the endoplasmic reticulum. Thus, it may confer a direct effect on the established calcium-dependent assembly of desmosomes. We screened ATP2A2 in a cohort of 24 DD families using conformation sensitive gel electrophoresis and direct sequencing, and detected 14 distinct mutations, 9 of which were novel. The mutational spectrum included 9 missense mutations, 1 nonsense mutation, 3 small in-frame deletions, and a 19-basepair insertion. Mutations were scattered over the entire gene with a slight preponderance in the first 8 exons, and affected exclusively residues conserved among all SERCAs. In addition, we found 2 silent polymorphisms, 1 of which occurred in 4 unrelated families. Comparison of molecular data and phenotypic features, such as severity and type of disease, occurrence of mucosal involvement, or association with neuropsychiatric disorders, did not reveal an obvious genotype-phenotype correlation in our cohort.

Darier’s disease: a calcium-signaling perspective

“…Although DD has been genetically linked to dominant mutations in SERCA2, the phenotypic manifestations are, surprisingly, restricted to skin. Extra-cutaneous manifestations of DD remain largely enigmatic; however, certain neurophyschiatric disorders such as schizophrenia, epilepsy, and depression have been associated with the disease, albeit with no prominent genotype-to-phenotype correlation [17,18,21]. Sporadic salivary gland abnormalities, indicated by gland obstruction and metaplastic histology, have been reported [17,22], but a lack of studies demonstrating glandular dysfunction in larger patient population fails to corroborate these findings.…”

“…The potential role of Ca 2+ in the growth and differentiation of epithelial cells as well as keratinocytes is recognized [3,5,30]. Interestingly, the majority of SERCA2 mutations associated with classical DD reveal a reduction in the expression and activity of the pump [15][16][17][18][19][20]. Hence, an imbalance in cellular Ca 2+ signaling is an obvious readout of DD.…”

“…Since the identification of the gene responsible for DD, about 140 different mutations of SERCA2 have been evaluated with different degrees of phenotypic severity associated with the levels of expression and function of the pump. However, mutations rendering a state of SERCA2 haploinsufficiency are congruent with the classical DD phenotype [12,[15][16][17][18][19][20].…”

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

“…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.…”

Comprehensive Analysis of Expression and Function of 51 Sarco(endo)plasmic Reticulum Ca2+-ATPase Mutants Associated with Darier Disease

“…Mutations in the SERCA2 gene (ATP2A2) and the resulting defects in the SERCA2b housekeeping isoform cause an autosomal dominant genetic skin disease, Darier disease (DD) (11,12). Over 100 mutations have been found with the DD pedigrees (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). They include many nonsense mutations, and also substitution and deletion mutations of amino acid residues.…”