Dhitavat Jittima, Dode Leonard, Leslie Natalie, Sakuntabhai Anavaj, Lorette Gérard, Hovnanian Alain
The Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.
J Invest Dermatol. 2003 Sep;121(3):486-9. doi: 10.1046/j.1523-1747.2003.12410.x.
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.
毛囊角化病是一种常染色体显性遗传的皮肤疾病，其特征为表皮细胞间黏附丧失和异常角化。编码肌浆网/内质网Ca2+ATP酶（SERCA）2的ATP2A2已被确定为毛囊角化病中的缺陷基因。先前报道的所有突变均发生在ATP2A2编码SERCA2a和SERCA2b同工型的区域。这些同工型由外显子20的可变剪接产生，其中SERCA2b是在表皮中表达的主要同工型。在本报告中，我们研究了一个患有毛囊角化病的家族，并在ATP2A2外显子20的一个区域中鉴定出一个缺失（2993delTG），该缺失是SERCA2b特有的。这种杂合突变预测在SERCA2b的第11个跨膜结构域中会出现移码并带有一个提前终止密码子（PTC+32aa）。在受测家族成员中，它与疾病表型共分离，功能分析表明，与野生型SERCA2b相比，突变蛋白的表达大幅减少。我们的结果表明，突变等位基因通过SERCA2b同工型的功能丧失导致疾病表型。这一发现表明，SERCA2b在表皮生物学中起关键作用，其缺陷足以导致毛囊角化病。
