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Free Content Novel mutations in the 7-dehydrocholesterol reductase gene of 13 patients with Smith–Lemli–Opitz syndrome

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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.
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Document Type: Research Article

Affiliations: 1: Department of Pediatrics, University Medical Centre Nijmegen, Nijmegen, The Netherlands 2: Department of Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands 3: Laboratory of Pediatrics and Neurology, University Medical Centre Nijmegen, Nijmegen, The Netherlands 4: Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands 5: Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

Publication date: May 1, 2001

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