Abstract |
P450 oxidoreductase (POR) is the obligatory flavoprotein intermediate that transfers electrons from reduced nicotinamide adenine dinucleotide phosphate ( NADPH) to all microsomal cytochrome P450 enzymes. Although mouse Por gene ablation causes embryonic lethality, POR missense mutations cause disordered steroidogenesis, ambiguous genitalia, and Antley-Bixler syndrome (ABS), which has also been attributed to fibroblast growth factor receptor 2 (FGFR2) mutations. We sequenced the POR gene and FGFR2 exons 8 and 10 in 32 individuals with ABS and/or hormonal findings that suggested POR deficiency. POR and FGFR2 mutations segregated completely. Fifteen patients carried POR mutations on both alleles, 4 carried mutations on only one allele, 10 carried FGFR2 or FGFR3 mutations, and 3 patients carried no mutations. The 34 affected POR alleles included 10 with A287P (all from whites) and 7 with R457H (four Japanese, one African, two whites); 17 of the 34 alleles carried 16 "private" mutations, including 9 missense and 7 frameshift mutations. These 11 missense mutations, plus 10 others found in databases or reported elsewhere, were recreated by site-directed mutagenesis and were assessed by four assays: reduction of cytochrome c, oxidation of NADPH, support of 17alpha-hydroxylase activity, and support of 17,20 lyase using human P450c17. Assays that were based on cytochrome c, which is not a physiologic substrate for POR, correlated poorly with clinical phenotype, but assays that were based on POR's support of catalysis by P450c17--the enzyme most closely associated with the hormonal phenotype--provided an excellent genotype/phenotype correlation. Our large survey of patients with ABS shows that individuals with an ABS-like phenotype and normal steroidogenesis have FGFR mutations, whereas those with ambiguous genitalia and disordered steroidogenesis should be recognized as having a distinct new disease: POR deficiency.
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Authors | Ningwu Huang, Amit V Pandey, Vishal Agrawal, William Reardon, Pablo D Lapunzina, David Mowat, Ethylin Wang Jabs, Guy Van Vliet, Joseph Sack, Christa E Flück, Walter L Miller |
Journal | American journal of human genetics
(Am J Hum Genet)
Vol. 76
Issue 5
Pg. 729-49
(May 2005)
ISSN: 0002-9297 [Print] United States |
PMID | 15793702
(Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Receptors, Fibroblast Growth Factor
- Steroids
- NADPH-Ferrihemoprotein Reductase
- FGFR2 protein, human
- Receptor Protein-Tyrosine Kinases
- Receptor, Fibroblast Growth Factor, Type 2
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Topics |
- Abnormalities, Multiple
(genetics)
- Amino Acid Sequence
- Craniosynostoses
(genetics)
- Female
- Genetic Variation
- Genitalia
(abnormalities)
- Humans
- Infant
- Infant, Newborn
- Male
- Models, Molecular
- Molecular Sequence Data
- Mutation
- NADPH-Ferrihemoprotein Reductase
(genetics)
- Receptor Protein-Tyrosine Kinases
(genetics)
- Receptor, Fibroblast Growth Factor, Type 2
- Receptors, Fibroblast Growth Factor
(genetics)
- Sequence Alignment
- Steroids
(biosynthesis)
- Syndrome
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