|Mutational spectrum in the Delta7-sterol reductase gene and genotype-phenotype correlation in 84 patients with Smith-Lemli-Opitz syndrome.|
|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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|Type: Journal Article; Research Support, Non-U.S. Gov't|
|Title: American journal of human genetics Volume: 66 ISSN: 0002-9297 ISO Abbreviation: Am. J. Hum. Genet. Publication Date: 2000 Feb|
|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|
|Languages: eng Pagination: 402-12 Citation Subset: IM|
|Institute of Medical Biology and Human Genetics, Schoepfstrasse 41, 6020 Innsbruck, Austria.|
|APA/MLA Format Download EndNote Download BibTex|
Age of Onset
Cholesterol / analogs & derivatives, blood
Codon, Nonsense / genetics
DNA Mutational Analysis
Exons / genetics
Gene Frequency / genetics
Introns / genetics
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*
|0/Codon, Nonsense; 57-88-5/Cholesterol; EC 1.-/Oxidoreductases; EC 220.127.116.11/lathosterol 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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