Waterham H R, Wijburg F A, Hennekam R C, Vreken P, Poll-The B T, Dorland L, Duran M, Jira P E, Smeitink J A, Wevers R A, Wanders R J
Departments of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, The Netherlands.
Am J Hum Genet. 1998 Aug;63(2):329-38. doi: 10.1086/301982.
Smith-Lemli-Opitz syndrome is a frequently occurring autosomal recessive developmental disorder characterized by facial dysmorphisms, mental retardation, and multiple congenital anomalies. Biochemically, the disorder is caused by deficient activity of 7-dehydrocholesterol reductase, which catalyzes the final step in the cholesterol-biosynthesis pathway-that is, the reduction of the Delta7 double bond of 7-dehydrocholesterol to produce cholesterol. We identified a partial transcript coding for human 7-dehydrocholesterol reductase by searching the database of expressed sequence tags with the amino acid sequence for the Arabidopsis thaliana sterol Delta7-reductase and isolated the remaining 5' sequence by the "rapid amplification of cDNA ends" method, or 5'-RACE. The cDNA has an open reading frame of 1,425 bp coding for a polypeptide of 475 amino acids with a calculated molecular weight of 54.5 kD. Heterologous expression of the cDNA in the yeast Saccharomyces cerevisiae confirmed that it codes for 7-dehydrocholesterol reductase. Chromosomal mapping experiments localized the gene to chromosome 11q13. Sequence analysis of fibroblast 7-dehydrocholesterol reductase cDNA from three patients with Smith-Lemli-Opitz syndrome revealed distinct mutations, including a 134-bp insertion and three different point mutations, each of which was heterozygous in cDNA from the respective parents. Our data demonstrate that Smith-Lemli-Opitz syndrome is caused by mutations in the gene coding for 7-dehydrocholesterol reductase.
史密斯-利姆利-奥皮茨综合征是一种常见的常染色体隐性发育障碍，其特征为面部畸形、智力迟钝和多种先天性异常。从生物化学角度来看，该疾病是由7-脱氢胆固醇还原酶活性不足引起的，这种酶催化胆固醇生物合成途径的最后一步，即将7-脱氢胆固醇的Δ7双键还原以生成胆固醇。我们通过用拟南芥甾醇Δ7-还原酶的氨基酸序列搜索表达序列标签数据库，鉴定出了编码人7-脱氢胆固醇还原酶的部分转录本，并通过“cDNA末端快速扩增”方法（即5'-RACE）分离出了其余的5'序列。该cDNA有一个1425 bp的开放阅读框，编码一个由475个氨基酸组成的多肽，计算分子量为54.5 kD。该cDNA在酿酒酵母中的异源表达证实了它编码7-脱氢胆固醇还原酶。染色体定位实验将该基因定位于11号染色体q13区域。对三名史密斯-利姆利-奥皮茨综合征患者的成纤维细胞7-脱氢胆固醇还原酶cDNA进行序列分析，发现了不同的突变，包括一个134 bp的插入和三个不同的点突变，每个突变在各自父母的cDNA中均为杂合状态。我们的数据表明，史密斯-利姆利-奥皮茨综合征是由编码7-脱氢胆固醇还原酶的基因突变引起的。
