title: Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith--Lemli--Opitz syndrome.
abstract: Smith--Lemli--Opitz syndrome (SLOS) is caused by mutations in the DHCR7 gene leading to deficient activity of 7-dehydrocholesterol reductase (DHCR7; EC 1.3.1.21), the final enzyme of the cholesterol biosynthetic pathway, resulting in low cholesterol and high concentrations of its direct precursor 7-dehydrocholesterol in plasma and tissues. We here report mutations identified in the DHCR7 gene of 13 children diagnosed with SLOS by clinical and biochemical criteria. We found a high frequency of the previously described IVS8--1 G > C splice acceptor site mutation (two homozygotes, eight compound heterozygotes). In addition, 13 missense mutations and one splice acceptor mutation were detected in eleven patients with a mild to moderate SLOS-phenotype. The mutations include three novel missense mutations (W182L, C183Y, F255L) and one novel splice acceptor site mutation (IVS8--1 G > T). Two patients, homozygous for the IVS8--1 G > C mutation, presented with a severe clinical phenotype and died shortly after birth. Seven patients with a mild to moderate SLOS-phenotype disclosed compound heterozygosity of the IVS8--1 G > C mutation in combination with different novel and known missense mutations.
authors: Department of Pediatrics, University Medical Center Nijmegen, The Netherlands.
authors: P E
authors: PE
authors: Jira
authors: R J
authors: RJ
authors: Wanders
authors: J A
authors: JA
authors: Smeitink
authors: J
authors: J
authors: De Jong
authors: R A
authors: RA
authors: Wevers
authors: W
authors: W
authors: Oostheim
authors: J H
authors: JH
authors: Tuerlings
authors: R C
authors: RC
authors: Hennekam
authors: R C
authors: RC
authors: Sengers
authors: H R
authors: HR
authors: Waterham
mesh_terms: D002648:Child; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D017353:Gene Deletion; D005808:Genes, Recessive; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007621:Karyotyping; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010088:Oxidoreductases / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors; D010641:Phenotype; D012326:RNA Splicing; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D010088:Oxidoreductases; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase