ATP2A2 mutations in Darier's disease:: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class
ATP2A2 mutations in Darier's disease:: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class
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DOI：
10.1093/hmg/8.9.1621
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发表时间：
1999-09-01
影响因子：
3.5
通讯作者：
Strachan, T
中科院分区：
文献类型：
--
作者：
Ruiz-Perez, VL;Carter, SA;Strachan, T
Darier病（DD）是一种常染色体显性遗传的皮肤病，临床上以多发性角化性丘疹为特征，组织学上以表皮细胞间的粘着力丧失（棘层松解）和异常角化为特征。相关的神经精神特征，包括精神障碍、精神分裂症、双相情感障碍和癫痫也有报道。DD的原因最近被证明是突变的ATP 2A 2基因在12q24.1，它编码的肌质内质网钙ATP酶2型（SERCA 2），在这里，我们表明，而两个常见的异构体SERCA 2的表达在培养的角质形成细胞和成纤维细胞的细胞质中，在成人皮肤切片中，只有较长的异构体，SERCA 2b，在表皮结构中大量表达。在欧洲DD患者中使用单链构象多态性和/或直接测序的扩展突变分析确定了47个家族中的40种不同的患者特异性突变。大多数（23/40）可能导致无义介导的RNA衰变。其余17个是分布在整个蛋白质中的错义突变，与非典型临床特征显著相关。最密切的关联是与家族性出血变异，其中所有四个家庭测试有一个错义突变。其中三个家族（一个苏格兰家族和两个无关的意大利家族）在M5跨膜结构域中表现出相同的N767 S置换，第四个来自瑞典的家族在M3跨膜结构域中具有C268 F置换。神经精神病学特征似乎与特定类型的突变无关，可能是ATP 2A 2表达缺陷的内在但不一致的影响。
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 dearest 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.