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

J Clin Endocrinol Metab. 1992 Mar;74(3):667-72. 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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


  • Oligodeoxyribonucleotides
  • Threonine
  • DNA
  • Cytochrome P-450 Enzyme System
  • Arginine
  • Proline
  • Steroid 17-alpha-Hydroxylase
  • Aldehyde-Lyases