Wassif C A, Maslen C, Kachilele-Linjewile S, Lin D, Linck L M, Connor W E, Steiner R D, Porter F D
Unit on Molecular Dysmorphology, Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1830, USA.
Am J Hum Genet. 1998 Jul;63(1):55-62. doi: 10.1086/301936.
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 Delta7-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 Delta7-reductase. We cloned cDNA encoding a human sterol Delta7-reductase (DHCR7) on the basis of its homology with the sterol Delta7-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 Delta7-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 Delta7-reductase and that mutations in DHCR7 are responsible for at least some cases of SLOS.
史密斯-利姆利-奥皮茨综合征（SLOS；也称为“RSH综合征”[MIM 270400]）是一种常染色体隐性遗传的多发畸形综合征，由胆固醇生物合成缺陷引起。患有SLOS的儿童血清7-脱氢胆固醇（7-DHC）水平升高，血清胆固醇水平通常较低。基于这种生化异常，有人提出人类固醇Δ7-还原酶（7-DHC还原酶；E.C.1.3.1.21）基因的突变会导致SLOS。然而，也有人可能会提出，在一个编码对于固醇Δ7-还原酶的表达或正常功能所必需的蛋白质的基因中存在缺陷。我们基于与拟南芥固醇Δ7-还原酶的同源性克隆了编码人类固醇Δ7-还原酶（DHCR7）的cDNA，并通过在SLOS成纤维细胞中的表达证实了人类基因产物的酶功能。与仅用载体转染的SLOS成纤维细胞相比，用人固醇Δ7-还原酶cDNA转染的SLOS成纤维细胞显示7-DHC水平显著降低。通过辐射杂种作图，我们表明DHCR7基因定位于11号染色体q12 - 13区域。为了确定该基因的缺陷会导致SLOS，我们对SLOS患者的cDNA克隆进行了测序。在三名无亲缘关系的患者中，我们鉴定出了四个不同的突变等位基因。我们的结果既证明了我们鉴定出的cDNA编码人类固醇Δ7-还原酶，也证明了DHCR7基因的突变至少在某些SLOS病例中起作用。
