Fine Mapping of the Darier's Disease Locus on Chromosome 12q

Richard, G.; Wright, A; Harris, Sz.; Doyle, Sharon Z.; Korge, Bernhard; Mazzanti, Cinzia; Tanaka, Takayuki; Harth, W.; McBride, O W; Compton, John G.; Bale, Sherri J.; DiGiovanna, John J.

doi:10.1111/1523-1747.ep12398429

Cited by 14 publications

(5 citation statements)

References 20 publications

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“…We ascertained 24 unrelated DD families (50 affected members), in 10 of which DD was previously mapped to 12q23‐q24 (6). Informed consent was obtained, and blood or buccal cell samples were collected from all individuals.…”

Section: Methodsmentioning

confidence: 99%

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

Ringpfeil

Raus

DiGiovanna

et al. 2001

Experimental Dermatology

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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.

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Section: Methodsmentioning

confidence: 99%

“…DD was previously linked to the long arm of chromosome 12 (6–9), and subsequently the critical region was confined to 2.4 Mb (10). Recently, mutations in the ATP2A2 gene encoding a Ca 2+ ‐ATPase of the endo/sarcoplasmic reticulum (SERCA2) have been discovered in several series of European DD patients (11–14).…”

Section: Introductionmentioning

confidence: 99%

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

Ringpfeil

Raus

DiGiovanna

et al. 2001

Experimental Dermatology

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“…A single locus for DD has been mapped to chromosome 12q23-q24.1 (3)(4)(5)(6)(7). A variety of missense, nonsense, frameshift and splicing mutations in the ATP2A2 gene have been described recently in families with DD (8).…”

Section: Introductionmentioning

confidence: 99%

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

Jacobsen

Lyons

Hoogendoorn

et al. 1999

Human Molecular Genetics

129

128

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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.

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“…2 The onset usually occurs in adolescence, and the disease runs a persistent and slowly progressive course, with preferential involvement of the so-called seborrheic areas. The typical eruption consists of keratotic and crusted papules that coalesce to form verrucous plaques, although several clinical variants have been described.…”

Section: Casementioning

confidence: 99%