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

Published online by Cambridge University Press:  26 June 2001

P. E. JIRA
Affiliation:
Department of Pediatrics, University Medical Centre Nijmegen, Nijmegen, The Netherlands
R. J. A. WANDERS
Affiliation:
Department of Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
J. A. M. SMEITINK
Affiliation:
Department of Pediatrics, University Medical Centre Nijmegen, Nijmegen, The Netherlands
J. DE JONG
Affiliation:
Laboratory of Pediatrics and Neurology, University Medical Centre Nijmegen, Nijmegen, The Netherlands
R. A. WEVERS
Affiliation:
Laboratory of Pediatrics and Neurology, University Medical Centre Nijmegen, Nijmegen, The Netherlands
W. OOSTHEIM
Affiliation:
Department of Clinical Chemistry, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
J. H. A. M. TUERLINGS
Affiliation:
Department of Human Genetics, University Medical Centre Nijmegen, Nijmegen, The Netherlands
R. C. M. HENNEKAM
Affiliation:
Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands Department of Medical Genetics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
R. C. A. SENGERS
Affiliation:
Department of Pediatrics, University Medical Centre Nijmegen, Nijmegen, The Netherlands
H. R. WATERHAM
Affiliation:
Department of Pediatrics, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
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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.

Type
Research Article
Copyright
© University College London 2001

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