Michael Waterman
Faculty Member
Last active: 2/12/2015

Compound heterozygous mutations (Arg 239----stop, Pro 342----Thr) in the CYP17 (P45017 alpha) gene lead to ambiguous external genitalia in a male patient with partial combined 17 alpha-hydroxylase/17,20-lyase deficiency.

Ahlgren R, Yanase T, Simpson ER, Winter JS, Waterman MR
J Clin Endocrinol Metab. 1992 74 (3): 667-72

PMID: 1740503 · DOI:10.1210/jcem.74.3.1740503

17 alpha-Hydroxylase deficiency is characterized by defects in either or both the 17 alpha-hydroxylase/17,20-lyase activities. We have, for the first time, elucidated the molecular basis of the deficiency in a male pseudohermaphrodite with ambiguous external genitalia resulting from partial combined deficiency of both activities. The patient is found to be a compound heterozygote, carrying two different inherited mutant alleles in the cytochrome P45017 alpha (CYP17) gene. One allele, from his mother, contains a stop codon (TGA) in place of arginine (CGA) at amino acid position 239 in exon 4. Because this occurs at the N-terminal side of the heme binding sequence, the putative resultant truncated protein is nonfunctional. The second allele, from his father, contains a missense mutation encoding the substitution of proline (CCA) by threonine (ACA) at position 342 in exon 6. Reconstruction of this mutation by site-directed mutagenesis into human P45017 alpha cDNA followed by expression in COS 1 cells leads to the same amount of immunodetectable P45017 alpha protein as found with expression of the normal P45017 alpha cDNA, although both the 17 alpha-hydroxylase and 17,20-lyase activities are found to be reduced to 40-45% of those of the normal enzyme. The presence of ambiguous external genitalia in this 46 XY individual indicates that greater than 20% of the total normal 17,20-lyase activity is required for complete virilization in the male.

MeSH Terms (26)

Adrenal Hyperplasia, Congenital Aldehyde-Lyases Alleles Amino Acid Sequence Animals Arginine Base Sequence Blotting, Southern Cell Line Child Cytochrome P-450 Enzyme System Disorders of Sex Development DNA Heterozygote Humans Leukocytes Male Molecular Sequence Data Mutation Oligodeoxyribonucleotides Polymerase Chain Reaction Proline Restriction Mapping Steroid 17-alpha-Hydroxylase Threonine Transfection

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