Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene.
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.
Departments of Clinical Chemistry and Pediatrics, Academic Medical Center, University of Amsterdam, The Netherlands. h.r.waterham@amc.uva.nl
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Waterham
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Wijburg
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Hennekam
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Vreken
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Poll-The
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Dorland
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Duran
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Jira
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Smeitink
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Wevers
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Wanders
D000595:Amino Acid Sequence; D017360:Arabidopsis / Q000201:enzymology / Q000235:genetics; D001483:Base Sequence; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009679:Nuclear Family; D016366:Open Reading Frames; D010088:Oxidoreductases / Q000737:chemistry / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000201:enzymology / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012867:Skin / Q000201:enzymology; D019082:Smith-Lemli-Opitz Syndrome / Q000201:enzymology* / Q000235:genetics*; D000097682:Lamin B Receptor
D002784:Cholesterol; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor; C033144:lathosterol delta-5-dehydrogenase; C022673:delta 24-sterol reductase; C019995:7-dehydrocholesterol reductase