Mutations in the 3beta-hydroxysterol Delta24-reductase gene cause desmosterolosis, an autosomal recessive disorder of cholesterol biosynthesis
| Autor: | Hans R. Waterham, Richard I. Kelley, G. J. Romeijn, Janet Koster, Hans C. Andersson, Peter Vreken, David R. FitzPatrick, Ronald J.A. Wanders, Raoul C.M. Hennekam |
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| Přispěvatelé: | Other departments, AGEM - Inborn errors of metabolism, Laboratory Genetic Metabolic Diseases |
| Jazyk: | angličtina |
| Rok vydání: | 2001 |
| Předmět: |
Male
Oxidoreductases Acting on CH-CH Group Donors DNA Mutational Analysis Molecular Sequence Data Genes Recessive Nerve Tissue Proteins Saccharomyces cerevisiae Biology Reductase medicine.disease_cause Lipid Metabolism Inborn Errors chemistry.chemical_compound Desmosterol Genetics medicine Animals Humans Genetics(clinical) Amino Acid Sequence Cloning Molecular Genetics (clinical) Flavin adenine dinucleotide Mutation Infant Newborn Lathosterolosis Articles Plants medicine.disease Molecular biology Sterol Desmosterolosis Cholesterol Phenotype chemistry Biochemistry Child Preschool Flavin-Adenine Dinucleotide Female Heterologous expression Oxidoreductases Sequence Alignment NADP |
| Zdroj: | American journal of human genetics, 69(4), 685-694. Cell Press |
| ISSN: | 0002-9297 |
| Popis: | Desmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies. Patients with desmosterolosis have elevated levels of the cholesterol precursor desmosterol, in plasma, tissue, and cultured cells; this abnormality suggests a deficiency of the enzyme 3beta-hydroxysterol Delta24-reductase (DHCR24), which, in cholesterol biosynthesis, catalyzes the reduction of the Delta24 double bond of sterol intermediates. We identified the human DHCR24 cDNA, by the similarity between the encoded protein and a recently characterized plant enzyme--DWF1/DIM, from Arabidopsis thaliana--catalyzing a different but partially similar reaction in steroid/sterol biosynthesis in plants. Heterologous expression, in the yeast Saccharomyces cerevisiae, of the DHCR24 cDNA, followed by enzyme-activity measurements, confirmed that it encodes DHCR24. The encoded DHCR24 protein has a calculated molecular weight of 60.1 kD, contains a potential N-terminal secretory-signal sequence as well as at least one putative transmembrane helix, and is a member of a recently defined family of flavin adenine dinucleotide (FAD)-dependent oxidoreductases. Conversion of desmosterol to cholesterol by DHCR24 in vitro is strictly dependent on reduced nicotinamide adenine dinucleotide phosphate and is increased twofold by the addition of FAD to the assay. The corresponding gene, DHCR24, was identified by database searching, spans approximately 46.4 kb, is localized to chromosome 1p31.1-p33, and comprises nine exons and eight introns. Sequence analysis of DHCR24 in two patients with desmosterolosis revealed four different missense mutations, which were shown, by functional expression, in yeast, of the patient alleles, to be disease causing. Our data demonstrate that desmosterolosis is a cholesterol-biosynthesis disorder caused by mutations in DHCR24. |
| Databáze: | OpenAIRE |
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