Mutations in the human DHCR7 gene

Abstract

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive metabolic disorder characterized by variable congenital malformations, facial dysmorphism, and mental retardation. Mutations in the DHCR7 gene have been identified in SLOS patients. This gene encodes for the enzyme Delta7-sterol reductase 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 three domains of the protein: in the transmembrane domain (TM mutations), in the fourth cytoplasmic loop (4L mutations), and at the C-terminus (CT mutations). Two nonsense mutations, one splice site mutation, two single nucleotide insertions, and three deletions which likely all represent null mutations were also described. Expression studies have demonstrated a decreased protein stability for all analyzed missense mutations. By comparing clinical severity scores, biochemical data, and mutations in SLOS patients a genotype-phenotype correlation has been established. The null and 4L mutations are 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 significant geographic frequency differences of common DHCR7 mutations.

Probing lipid-protein adduction with alkynyl surrogates: application to Smith-Lemli-Opitz syndrome

“…In SLOS, mutations in the gene encoding Dhcr7 result in an inactive enzyme and an accumulation of 7-DHC ( 36 ). Here, we tested whether increased 7-DHC and the presence of 7-DHC-derived oxysterols would lead to increased lipidation of a cellular proteome.…”

Maternal ABCA1 genotype is associated with severity of Smith–Lemli–Opitz syndrome and with viability of patients homozygous for null mutations

“…13,31,33,34 Variations in DHCR7 and maternal ApoE explain 29 and 12%, respectively, of the variance of cholesterol (logarithmised) in SLOS patients. Hence, it is probable that additional factors contribute to the variability of SLOS phenotype.…”

Clinical utility gene card for: Smith-Lemli-Opitz Syndrome [SLOS]

“…Characterisation of the mutational spectrum of the DHCR7 gene was possible after studying 4100 SLOS patients (Witsch-Baumgartner M et al 4,5 Correa-Cerro et al 6 ). Until now 4100 different mutations: nonsense (eg, p.Trp151*), deletions (eg, c.720-735del and c.385-412IVS5 þ 1-5del, HGVS: c.385_412 þ 5del), splice site mutations (eg, c.964-1G4C) and missense mutations have been described.…”

“…They are located in or near the transmembrane domains, in the fourth cytoplasmic loop or in the C terminal region of the DHCR7 protein. 4 More than 95% SLOS patients are homozygous or compound heterozygous for DHCR7 point mutations.…”