Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome
Mutations in CGI-58, the gene encoding a new protein of the esterase/lipase/thioesterase subfamily, in Chanarin-Dorfman syndrome
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DOI：
10.1086/324121
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发表时间：
2001-11-01
影响因子：
9.8
通讯作者：
Fischer, J
中科院分区：
文献类型：
--
作者：
Lefevre, C;Jobard, F;Fischer, J
钱纳林 - 多尔夫曼综合征（CDS）是一种罕见的常染色体隐性遗传性非大疱性先天性鱼鳞病样红皮病（NCIE），其特征是在大多数组织中存在细胞内脂滴。我们之前在6个家族中将一部分NCIE的基因定位到3号染色体（命名为“NCIE2基因座”）。在这6个家族中的5个家族发现了脂滴，提示为CDS诊断。另外根据确诊的CDS选择的4个家族也显示与NCIE2基因座连锁。对这些都来自地中海盆地的家族进行连锁不平衡分析，使我们能够将NCIE2基因座精确到约1.3 - Mb的区域。对该区间的候选基因进行了筛选，在来自这9个家族的13名患者中发现了最近鉴定的CGI - 58基因的8种不同突变。基因变异的类型包括插入、缺失、剪接位点和点突变。CGI - 58蛋白属于一个以α/β水解酶折叠为特征的大的蛋白质家族。CGI - 58包含三个序列基序，它们对应于酯酶/脂肪酶/硫酯酶亚家族中发现的催化三联体。有趣的是，CGI - 58与酯酶/脂肪酶/硫酯酶亚家族的其他成员不同，其假定的催化三联体中含有一个天冬酰胺，而不是通常的丝氨酸残基。
Chanarin-Dorfman syndrome (CDS) is a rare autosomal recessive form of nonbullous congenital ichthyosiform erythroderma (NCIE) that is characterized by the presence of intracellular lipid droplets in most tissues. We previously localized a gene for a subset of NCIE to chromosome 3 (designated "the NCIE2 locus"), in six families. Lipid droplets were found in five of these six families, suggesting a diagnosis of CDS. Four additional families selected on the basis of a confirmed diagnosis of CDS also showed linkage to the NCIE2 locus. Linkage-disequilibrium analysis of these families, all from the Mediterranean basin, allowed us to refine the NCIE2 locus to an similar to1.3-Mb region. Candidate genes from the interval were screened, and eight distinct mutations in the recently identified CGI-58 gene were found in 13 patients from these nine families. The spectrum of gene variants included insertion, deletion, splice-site, and point mutations. The CGI-58 protein belongs to a large family of proteins characterized by an alpha/beta hydrolase fold. CGI-58 contains three sequence motifs that correspond to a catalytic triad found in the esterase/lipase/thioesterase subfamily. Interestingly, CGI-58 differs from other members of the esterase/lipase/thioesterase subfamily in that its putative catalytic triad contains an asparagine in place of the usual serine residue.