Mutational Spectrum in the Δ7-Sterol Reductase Gene and Genotype-Phenotype Correlation in 84 Patients with Smith-Lemli-Opitz Syndrome
| Autor: | Hartmut Glossmann, Georg F. Hoffmann, Peter Clayton, Richard I. Kelley, F. F. Moebius, Barbara U. Fitzky, Udo Seedorf, G. Gillessen-Kaesbach, Martina Witsch-Baumgartner, M. Ogorelkova, H. G. Kraft, Gerd Utermann |
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| Rok vydání: | 2000 |
| Předmět: |
Adult
Male Oxidoreductases Acting on CH-CH Group Donors congenital hereditary and neonatal diseases and abnormalities 7-Dehydrocholesterol reductase Adolescent Genotype DNA Mutational Analysis Mutation Missense Reductase Biology Cell Line Gene Frequency Genetics medicine Humans Missense mutation Genetics(clinical) Age of Onset Child Gene Polymorphism Single-Stranded Conformational Genetics (clinical) Infant Newborn delta 7 (Δ7)-sterol reductase Infant Exons Articles medicine.disease Phenotype Null allele Introns Smith-Lemli-Opitz Syndrome Cholesterol Codon Nonsense Smith–Lemli–Opitz syndrome Child Preschool Mutation Linear Models Female Oxidoreductases |
| Zdroj: | The American Journal of Human Genetics. 66:402-412 |
| ISSN: | 0002-9297 |
| Popis: | SummarySmith-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 Δ7-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. |
| Databáze: | OpenAIRE |
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