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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.

Psoriasis is a chronic inflammatory dermatitis, affecting approximately 2% of the population. Major clinical features include red, scaly patches on scalp, elbows, and knees, with or without severe arthritis. Several putative susceptibility loci have been mapped by parametric and non-parametric linkage analysis to chromosome regions 2p, 4q, 6p, 8q, 16q, 17q, and 20p; however, the most significant results and confirmation of linkage are only available for the 17q and 6p chromosome regions at present. In this study, 22 multiplex Italian families were investigated for linkage to 6p and 17q susceptibility regions, using a set of four microsatellites. These analyses failed to detect significant linkage with any of the examined markers. A genome-wide scan was then performed on one of the largest pedigrees, searching for an additional susceptibility locus. This study disclosed a putative linkage to chromosome 1cen-q21 markers. When these microsatellites were analyzed in the remaining families of the sample, a significant linkage was observed using both parametric and non-parametric methods. The highest two-point lod score value was obtained with D1S305 marker (3.75 at 0 = 0.05). Non-parametric analysis at this locus also demonstrated a significant excess of allele sharing (p = 0.0001).

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