Novel P450c17 mutation H373D causing combined 17alpha-hydroxylase/17,20-lyase deficiency.

Abstract

CONTEXT:

Combined 17alpha-hydroxylase/17,20-lyase deficiency is a rare autosomal recessive form of congenital adrenal hyperplasia presenting with hypertension and sexual infantilism. This disorder is caused by defects in P450c17, encoded by the CYP17A1 gene.

OBJECTIVE:

We describe a 14-yr-old female with clinical and hormonal features of 17alpha-hydroxylase/17,20-lyase deficiency and identify and characterize the activities of her CYP17A1 mutations.

METHODS:

The coding regions of the CYP17A1 gene were amplified by PCR and sequenced. Mutations were recreated in P450c17 cDNA expression vectors; activities in transfected COS-1 cells were assayed by conversion of radiolabeled precursor steroids. One mutant was also expressed in Escherichia coli, and the reduced adsorption spectrum was measured.

RESULTS:

The patient carried the previously described mutation R96W and the novel missense mutation H373D. Neither mutant had detectable activity when expressed in COS-1 cells. Membrane preparations from E. coli expressing the H373D mutant vector produced an absorption peak at 420 nm, whereas the wild-type produced a peak at 450 nm, suggesting that the H373D mutation interferes with protein folding.

CONCLUSION:

The novel P450c17 mutation H373D abolished enzyme activity because of protein misfolding. These data indicate an important role for this residue in P450c17 activity.

• Authors: Taninee Sahakitrungruang, Meng Kian Tee, Phyllis W Speiser, Walter L Miller
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 94 Issue 8 Pg. 3089-92 (Aug 2009) ISSN: 1945-7197 [Electronic] United States
• PMID: 19470621 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Steroid 17-alpha-Hydroxylase

Topics

• Adolescent
• Adrenal Hyperplasia, Congenital (genetics)
• Female
• Humans
• Mutation
• Steroid 17-alpha-Hydroxylase (chemistry, genetics)