title: A novel mutation of the human 7-dehydrocholesterol reductase gene reduces enzyme activity in patients with holoprosencephaly.
abstract: Defects in cholesterol biosynthesis genes are recognized as a leading cause for holoprosencephaly (HPE). Previous reports suggest that mutations of human 7-dehydrocholesterol reductase (Dhcr7), which catalyzes the final step of cholesterol biosynthesis, may cause HPE [Clin. Genet. 53 (1998) 155]. To determine whether Dhcr7 mutations are involved in HPE pathogenesis, we analyzed the sequence of exon 9, which contains both a catalytic domain and a mutational hot spot. We examined 36 prematurely terminated fetuses with HPE at their gestation ages in the range from 21 to 33 weeks by single strand conformation polymorphism analysis and DNA sequencing. A novel missense mutation was identified: G344D. Dhcr7 enzyme assays using overexpressed recombinant mutant proteins revealed altered enzyme activity. Mutant G344D harbored less than 50% of enzyme activity compared with the control. Two previously reported mutations, R404C and G410S, abolished enzyme activity. These results suggest that mutation of the Dhcr7 gene is involved in HPE pathogenesis.
authors.affiliation: Department of Biological Sciences and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea. yshim@konkuk.ac.kr
authors.forename: Yhong-Hee
authors.initials: YH
authors.lastname: Shim
authors.forename: Soo-Han
authors.initials: SH
authors.lastname: Bae
authors.forename: Jai-Hyun
authors.initials: JH
authors.lastname: Kim
authors.forename: Kyu-Rae
authors.initials: KR
authors.lastname: Kim
authors.forename: Chong Jai
authors.initials: CJ
authors.lastname: Kim
authors.forename: Young-Ki
authors.initials: YK
authors.lastname: Paik
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D015153:Blotting, Western; D003062:Codon / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005091:Exons / Q000235:genetics; D005333:Fetus; D016142:Holoprosencephaly / Q000201:enzymology* / Q000235:genetics*; D006801:Humans; D008861:Microsomes / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015003:Yeasts / Q000378:metabolism
chemical_list: D003062:Codon; D017931:DNA Primers; D011994:Recombinant Proteins; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase