Annals of Human Genetics



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


P. E. JIRA a1, R. J. A. WANDERS a2a5, J. A. M. SMEITINK a1, J. DE JONG a3, R. A. WEVERS a3, W. OOSTHEIM a2, J. H. A. M. TUERLINGS a4, R. C. M. HENNEKAM a5a6, R. C. A. SENGERS a1 and H. R. WATERHAM a5c1
a1 Department of Pediatrics, University Medical Centre Nijmegen, Nijmegen, The Netherlands
a2 Department of Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
a3 Laboratory of Pediatrics and Neurology, University Medical Centre Nijmegen, Nijmegen, The Netherlands
a4 Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands
a5 Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
a6 Department of Medical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands

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.

(Received November 16 00)
(Accepted February 19 01)


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