Mutations in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase isoform cause Darier's disease
Mutations in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase isoform cause Darier's disease
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DOI：
10.1046/j.1523-1747.2003.12410.x
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发表时间：
2003-09-01
影响因子：
6.5
通讯作者：
Hovnanian, A
中科院分区：
文献类型：
--
作者：
Dhitavat, J;Dode, L;Hovnanian, A
Darier病是一种常染色体显性遗传的皮肤病，其特征在于表皮细胞之间的粘附力丧失和异常角化。ATP 2A 2编码肌质/内质网Ca ~（2+）ATP酶（SERCA）2，已被鉴定为Darier病的缺陷基因。先前报道的所有突变都发生在编码SERCA 2a和SERCA 2b亚型的ATP 2A 2区域。这些亚型由外显子20的选择性剪接产生，其中SERCA 2b是表皮中表达的主要亚型。在这份报告中，我们研究了一个家庭受影响的Darier病，并确定了一个缺失（2993 delTG）在一个区域的外显子20的ATP 2A 2，这是特定的SERCA 2b。这种杂合突变预测了在SERCA 2b的第十一跨膜结构域中具有提前终止密码子（PTC+32aa）的移码。它与测试的家族成员中的疾病表型分离，并且功能分析显示与野生型SERCA 2b相比突变蛋白的表达急剧减少。我们的结果表明，突变的等位基因通过SERCA 2b亚型功能的丧失导致疾病表型。这一发现表明SERCA 2b在表皮生物学中起着关键作用，其缺陷足以导致Darier病。
Darier's disease is an autosomal dominantly inherited skin disorder, characterized by loss of adhesion between epidermal cells and abnormal keratinization. ATP2A2 encoding the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) 2 has been identified as the defective gene in Darier's disease. All mutations previously reported occur in the region of ATP2A2 encoding both SERCA2a and SERCA2b isoforms. These isoforms result from alternative splicing of exon 20, with SERCA2b being the major isoform expressed in the epidermis. In this report, we studied a family affected with Darier's disease and identified a deletion (2993delTG) in a region of exon 20 of ATP2A2, which is specific for SERCA2b. This heterozygous mutation predicts a frameshift with a premature termination codon (PTC+32aa) in the eleventh transmembrane domain of SERCA2b. It segregates with the disease phenotype in the family members tested, and functional analysis shows a drastic reduction of the expression of the mutated protein in comparison with the wild-type SERCA2b. Our result suggests that the mutated allele causes the disease phenotype through loss of function of SERCA2b isoform. This finding indicates that SERCA2b plays a key role in the biology of the epidermis, and its defects are sufficient to cause Darier's disease.