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

  • P. E. JIRA (a1), R. J. A. WANDERS (a2) (a3), J. A. M. SMEITINK (a1), J. DE JONG (a4), R. A. WEVERS (a4), W. OOSTHEIM (a2), J. H. A. M. TUERLINGS (a5), R. C. M. HENNEKAM (a3) (a6), R. C. A. SENGERS (a1) and H. R. WATERHAM (a3)...

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.

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Corresponding author

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: h.r.waterham@amc.uva.nl

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

  • P. E. JIRA (a1), R. J. A. WANDERS (a2) (a3), J. A. M. SMEITINK (a1), J. DE JONG (a4), R. A. WEVERS (a4), W. OOSTHEIM (a2), J. H. A. M. TUERLINGS (a5), R. C. M. HENNEKAM (a3) (a6), R. C. A. SENGERS (a1) and H. R. WATERHAM (a3)...

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