Document Detail

Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.
MedLine Citation:
PMID:  10677299     Owner:  NLM     Status:  MEDLINE    
Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive malformation syndrome, ranges in clinical severity from mild dysmorphism and moderate mental retardation to severe congenital malformation and intrauterine lethality. Mutations in the gene for Delta7-sterol reductase (DHCR7), which catalyzes the final step in cholesterol biosynthesis in the endoplasmic reticulum (ER), cause SLOS. We have determined, in 84 patients with clinically and biochemically characterized SLOS (detection rate 96%), the mutational spectrum in the DHCR7 gene. Forty different SLOS mutations, some frequent, were identified. On the basis of mutation type and expression studies in the HEK293-derived cell line tsA-201, we grouped mutations into four classes: nonsense and splice-site mutations resulting in putative null alleles, missense mutations in the transmembrane domains (TM), mutations in the 4th cytoplasmic loop (4L), and mutations in the C-terminal ER domain (CT). All but one of the tested missense mutations reduced protein stability. Concentrations of the cholesterol precursor 7-dehydrocholesterol and clinical severity scores correlated with mutation classes. The mildest clinical phenotypes were associated with TM and CT mutations, and the most severe types were associated with 0 and 4L mutations. Most homozygotes for null alleles had severe SLOS; one patient had a moderate phenotype. Homozygosity for 0 mutations in DHCR7 appears compatible with life, suggesting that cholesterol may be synthesized in the absence of this enzyme or that exogenous sources of cholesterol can be used.
M Witsch-Baumgartner; B U Fitzky; M Ogorelkova; H G Kraft; F F Moebius; H Glossmann; U Seedorf; G Gillessen-Kaesbach; G F Hoffmann; P Clayton; R I Kelley; G Utermann
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  American journal of human genetics     Volume:  66     ISSN:  0002-9297     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2000 Feb 
Date Detail:
Created Date:  2000-03-30     Completed Date:  2000-03-30     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  402-12     Citation Subset:  IM    
Institute of Medical Biology and Human Genetics, Schoepfstrasse 41, 6020 Innsbruck, Austria.
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MeSH Terms
Age of Onset
Cell Line
Child, Preschool
Cholesterol / analogs & derivatives,  blood
Codon, Nonsense / genetics
DNA Mutational Analysis
Exons / genetics
Gene Frequency / genetics
Infant, Newborn
Introns / genetics
Linear Models
Mutation / genetics*
Mutation, Missense / genetics
Oxidoreductases / deficiency,  genetics*
Oxidoreductases Acting on CH-CH Group Donors*
Polymorphism, Single-Stranded Conformational
Smith-Lemli-Opitz Syndrome / blood,  enzymology*,  epidemiology,  genetics*
Reg. No./Substance:
0/Codon, Nonsense; 57-88-5/Cholesterol; EC 1.-/Oxidoreductases; EC delta-5-dehydrogenase; EC 1.3.-/Oxidoreductases Acting on CH-CH Group Donors

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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