Point mutation of Arg440 to His in cytochrome P450c17 causes severe 17 alpha-hydroxylase deficiency.
Genetic disorders in the gene encoding P450c17 cause 17 alpha-hydroxylase deficiency. The consequent defects in the synthesis of cortisol and sex steroids cause sexual infantilism and a female phenotype in both genetic sexes as well as mineralocorticoid excess and hypertension. A 15-yr-old patient from Germany was seen for absent pubertal development and mild hypertension with hypokalemia, high concentrations of 17-deoxysteroids, and hypergonadotropic hypogonadism. Analysis of her P450c17 gene by polymerase chain reaction amplification and direct sequencing showed mutation of codon 440 from CGC (Arg) to CAC (His). Expression of a vector encoding this mutated form of P450c17 in transfected nonsteroidogenic COS-1 cells showed that the mutant P450c17 protein was produced, but it lacked both 17 alpha-hydroxylase and 17,20-lyase activities. To date, 15 different P450c17 mutations have been described in 23 patients with 17 alpha-hydroxylase deficiency, indicating that mutations in this gene are due to random events.
Department of Pediatrics, University of California, San Francisco 94143.
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Fardella
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Homoki
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Miller
D000293:Adolescent; D000312:Adrenal Hyperplasia, Congenital; D001120:Arginine / Q000235:genetics*; D001483:Base Sequence; D002460:Cell Line; D005260:Female; D005858:Germany; D006639:Histidine / Q000235:genetics*; D006801:Humans; D006973:Hypertension / Q000209:etiology; D007008:Hypokalemia / Q000209:etiology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
D006639:Histidine; D001120:Arginine; D013254:Steroid 17-alpha-Hydroxylase