Human Molecular Genetics, 2000, Vol. 9, No. 9 1385-1391
© 2000 Oxford University Press
Spectrum of 
7-dehydrocholesterol reductase mutations in patients with the Smith–Lemli–Opitz (RSH) syndrome
Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, STR 541, 114 Doughty Street, Charleston, SC 29403, USA, 1Sachs’ Children’s Hospital, Department of Pediatrics, Karolinska Institute, Stockholm, Sweden, 2Coordinated Care Service, Department of Pediatrics and 3Division of Genetics and Metabolism, Department of Medicine, Children’s Hospital, Boston, MA, USA and 4Department of Veterans Affairs Medical Center, New Jersey Healthcare System, East Orange, NJ and University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, NJ, USA
The Smith–Lemli–Opitz syndrome (SLOS; also known as the RSH syndrome) is an autosomal recessive genetic disorder, leading to characteristic multi-organ developmental abnormalities, dysmorphic facies, limb malformations and mental retardation. Mutations in the gene for 
7-dehydrocholesterol reductase (7-reductase), which catalyzes the last step in cholesterol biosynthesis, cause the disease. We screened 32 patients with SLOS, 28 from the USA and four from Sweden. Twenty-two different nucleotide changes, predicted to be disease-causing mutations, were identified; 20 missense mutations, one nonsense mutation and one splice-site mutation involving the exon 9 acceptor site (IVS8 –1G
C) were detected. All probands were heterozygous for mutations. Twelve of these mutations have not been reported previously, including missense mutations L148R, F168I, D175H, P179L, P243R, F284L, N287K, F302L, R404S, Y462H, R469P and one nonsense mutation E37X. Coupled with previously reported mutations, these findings bring the total of different 7-reductase mutations to 36. These are distributed throughout the coding sequence of the 7-reductase gene except exons 3 and 5, with a clustering in exon 9. Three mutations account for 54% of those observed in our cohort, the splice acceptor site mutation IVS8 –1GC (22/64 alleles, 34%), T93M (8/64, 12.5%) and V326L (5/64, 7.8%). Severity of SLOS was negatively correlated with both plasma cholesterol and relative plasma cholesterol, but not with 7-dehydrocholesterol, the immediate precursor, confirming previous observations. However, no correlation was observed between mutations and phenotype, suggesting that the degree of severity may be affected by other factors. We estimate that between 33 and 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol. Thus, factors other than plasma cholesterol are additionally involved in determining severity.
+ To whom correspondence should be addressed. Tel: +1 843 953 0870; Fax: +1 843 953 6480; Email: patelsb@musc.edu
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