Mutations in the human DHCR7 gene

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive metabolic d isorder characterized by variable congenital malformations, facial dysmorph ism, and mental retardation. Mutations in the DHCR7 gene have been identifi ed in SLOS patients. This gene encodes for the enzyme Delta7-sterol reducta se which catalyses the last step of cholesterol biosynthesis. Among the 73 different mutations observed so far, including 10 novel mutations reported in this review, the majority are missense mutations (65) which cluster in t hree domains of the protein: in the transmembrane domain (TM mutations), in the fourth cytoplasmic loop (4L mutations), and at the C-terminus (CT muta tions). Two nonsense mutations, one splice site mutation, two single nucleo tide insertions, and three deletions which likely all represent null mutati ons were also described. Expression studies have demonstrated a decreased p rotein stability for all analyzed missense mutations. By comparing clinical severity scores, biochemical data, and mutations in SLOS patients a genoty pe-phenotype correlation has been established. The null and 4L mutations ar e associated with a severe clinical phenotype, and TM and CT mutations are associated with a mild clinical phenotype. DHCR7 mutational spectra in SLOS patients of British, German, Italian, and Polish origin demonstrate signif icant geographic frequency differences of common DHCR7 mutations. Hum Mutat 17:172-182, 2001. (C) 2001 Wiley Liss, Inc.