Mutations in the human sterol Δ7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome
Mutations in the human sterol Δ7-reductase gene at 11q12-13 cause Smith-Lemli-Opitz syndrome
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DOI：
10.1086/301936
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发表时间：
1998-07-01
影响因子：
9.8
通讯作者：
Porter, FD
中科院分区：
文献类型：
--
作者：
Wassif, CA;Maslen, C;Porter, FD
Smith-Lemli-Opitz综合征（SLOS，又称“RSH综合征”[MIM 270400]）是一种因胆固醇生物合成缺陷引起的常染色体隐性多重畸形综合征。患有sls的儿童血清7-脱氢胆固醇（7-DHC）水平升高，通常血清胆固醇水平较低。基于这一生化异常，有人提出人类甾醇δ(7)-还原酶（7- dhc reductase; e.c 1.3.1.21）基因突变导致SLOS。然而，人们也可能认为编码一种蛋白质的基因存在缺陷，这种蛋白质是固醇δ(7)-还原酶表达或正常功能所必需的。我们根据拟南芥中甾醇δ(7)-还原酶的同源性克隆了人甾醇δ(7)-还原酶（DHCR7）的cDNA，并通过在sls成纤维细胞中的表达证实了该人基因产物的酶促功能。转染人甾醇δ(7)还原酶cDNA的sls成纤维细胞显示，与单独转染该载体的sls成纤维细胞相比，7- dhc水平显著降低。通过辐射杂交定位，我们发现DHCR7基因编码在染色体11q12-13上。为了确定该基因缺陷导致SLOS，我们对来自SLOS患者的cDNA克隆进行了测序。在三个不相关的病人中，我们发现了四个不同的突变等位基因。我们的研究结果表明，我们已经鉴定的cDNA编码人类甾醇δ(7)-还原酶，DHCR7的突变至少是导致部分sls病例的原因。
The Smith-Lemli-Opitz syndrome (SLOS; also known as "RSH syndrome" [MIM 270400]) is an autosomal recessive multiple malformation syndrome due to a defect in cholesterol biosynthesis. Children with SLOS have elevated serum 7-dehydrocholesterol (7-DHC) levels and typically have low serum cholesterol levels. On the basis of this biochemical abnormality, it has been proposed that mutations in the human sterol Delta(7)-reductase (7-DHC reductase; E.C.1.3.1.21) gene cause SLOS. However, one could also propose a defect in a gene that encodes a protein necessary for either the expression or normal function of sterol Delta(7)-reductase. We cloned cDNA encoding a human sterol Delta(7)-reductase (DHCR7) on the basis of its homology with the sterol Delta(7)-reductase from Arabidopsis thaliana, and we confirmed the enzymatic function of the human gene product by expression in SLOS fibroblasts. SLOS fibroblasts transfected with human sterol Delta(7)-reductase cDNA showed a significant reduction in 7-DHC levels, compared with those in SLOS fibroblasts transfected with the vector alone. Using radiation-hybrid mapping, we show that the DHCR7 gene is encoded at chromosome 11q12-13. To establish that defects in this gene cause SLOS, we sequenced cDNA clones from SLOS patients. In three unrelated patients we have identified four different mutant alleles. Our results demonstrate both that the cDNA that we have identified encodes the human sterol Delta(7)-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS.