Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith–Lemli–Opitz syndrome
Smith–Lemli–Opitz syndrome (SLOS) is caused by mutations in the DHCR7 gene leading to deficient activity of 7-dehydrocholesterol reductase (DHCR7; EC 126.96.36.199), 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.(Received November 16 00)
(Accepted February 19 01)
c1 Correspondence: Dr. H. R. Waterham, Laboratory for Genetic Metabolic Diseases (F0–224), Department of Pediatrics, Emma Children's Hospital, Academic Medical Centre, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Fax: +31–20–6962596. E-mail: firstname.lastname@example.org