Mutational spectrum in the Delta 7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome

Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive malformation synd rome, ranges in clinical severity from mild dysmorphism and moderate mental retardation to severe congenital malformation and intrauterine lethality. Mutations in the gene for Delta 7-sterol reductase (DHCR7), which catalyzes the final step in cholesterol biosynthesis in the endoplasmic reticulum (E R), cause SLOS. We have determined, in 84 patients with clinically and bioc hemically characterized SLOS (detection rate 96%), the mutational spectrum in the DHCR7 gene. Forty different SLOS mutations, some frequent, were iden tified. On the basis of mutation type and expression studies in the HEK293- derived cell line tsA-201, we grouped mutations into four classes: nonsense and splice-site mutations resulting in putative null alleles, missense mut ations in the transmembrane domains (TM), mutations in the 4th cytoplasmic loop (4L), and mutations in the C-terminal ER domain (CT). All but one of t he tested missense mutations reduced protein stability Concentrations of th e cholesterol precursor 7-dehydrocholesterol and clinical severity scores c orrelated with mutation classes. The mildest clinical phenotypes were assoc iated with TM and CT mutations, and the most severe types were associated w ith 0 and 4L mutations. Most homozygotes for null alleles had severe SLOS; one patient had a moderate phenotype. Homozygosity for 0 mutations in DHCR7 appears compatible with life, suggesting that cholesterol may be synthesiz ed in the absence of this enzyme or that exogenous sources of cholesterol c an be used.