Smith-Lemli-Opitz syndrome is caused by mutations in the 7-dehydrocholesterol reductase gene

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.

Publication types

  • Case Reports

MeSH terms

  • Amino Acid Sequence
  • Arabidopsis / enzymology
  • Arabidopsis / genetics
  • Base Sequence
  • Cells, Cultured
  • Cholesterol / metabolism
  • Chromosome Mapping
  • Chromosomes, Human, Pair 11*
  • Female
  • Fibroblasts / enzymology
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutagenesis, Site-Directed
  • Nuclear Family
  • Open Reading Frames
  • Oxidoreductases / chemistry
  • Oxidoreductases / genetics*
  • Oxidoreductases Acting on CH-CH Group Donors*
  • Receptors, Cytoplasmic and Nuclear / chemistry
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Sequence Alignment
  • Sequence Homology, Amino Acid
  • Skin / enzymology
  • Smith-Lemli-Opitz Syndrome / enzymology*
  • Smith-Lemli-Opitz Syndrome / genetics*


  • Receptors, Cytoplasmic and Nuclear
  • lamin B receptor
  • lathosterol delta-5-dehydrogenase
  • Cholesterol
  • Oxidoreductases
  • Oxidoreductases Acting on CH-CH Group Donors
  • delta 24-sterol reductase
  • 7-dehydrocholesterol reductase

Associated data

  • GENBANK/AF067127