Mutational Spectrum in the Δ7-Sterol Reductase Gene and Genotype-Phenotype Correlation in 84 Patients with Smith-Lemli-Opitz Syndrome

摘要: Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive malformation syndrome, ranges in clinical severity from mild dysmorphism and moderate mental retardation to severe congenital intrauterine lethality. Mutations the gene for Δ7-sterol reductase (DHCR7), which catalyzes final step cholesterol biosynthesis endoplasmic reticulum (ER), cause SLOS. We have determined, 84 patients with clinically biochemically characterized SLOS (detection rate 96%), mutational spectrum DHCR7 gene. Forty different mutations, some frequent, were identified. On basis of mutation type expression studies HEK293-derived cell line tsA-201, we grouped mutations into four classes: nonsense splice-site resulting putative null alleles, missense transmembrane domains (TM), 4th cytoplasmic loop (4L), C-terminal ER domain (CT). All but one tested reduced protein stability. Concentrations precursor 7-dehydrocholesterol scores correlated classes. The mildest phenotypes associated TM CT most types 0 4L mutations. Most homozygotes alleles had SLOS; patient a phenotype. Homozygosity appears compatible life, suggesting that may be synthesized absence this enzyme or exogenous sources can used.