A novel CYP17A1 deletion causes a functional knockout of the steroid enzyme 17-hydroxylase and 17,20-lyase in a Turkish family and illustrates the precise role of the CYP17A1 gene

Abstract

A novel homozygous long-range deletion of the CYP17A1 gene abolished protein expression and caused the severest form of 17-hydroxylase deficiency in one kindred of a Turkish family. The affected subjects presented with 46,XY sex reversal and 46,XX lack of pubertal development as well as severe hypertension.

Keywords: 17α-hydroxylase/17,20-lyase deficiency; hypertension; pubertal development; sexual development; steroidogenesis.

Figure 1

Steroid profiling and genetic work-up of the family with a novel CYP17A1 deletion. (A) Family tree showing karyotype, genotype (2×, 3×, and 5× – number of healthy individuals; wt, wild type; del, deletion), and phenotype. (B) Gas chromatography/mass spectrometry profile of 24-h urine from a control and patient IV.4. Arrows indicate corticosterone metabolites THA, THB, and 5a-THB (in bold), which are elevated in CYP17 deficiency. Note also overall low androgens. Andro, androsterone; Etio, etiocholanolone; DHA, dehydroepiandrosterone; 11-oxo-etio, 11-oxo-etiocholanolone; 11β-OH-andro, 11β-hydroxyandrosterone; 17-HP, 17hydroxypregnanolone; 11β-OH-etio, 11β-hydroxyetiocholanolone; PD, pregnanediol; PT, pregnanetriol; 5-AT, 5-androstene-3β, 16α, 17β-triol; THS, tetrahydrodeoxycortisol; THDOC, tetrahydrodeoxycorticosterone; PTone, 11-oxo-pregnanetriol (or pregnanetriolone); MP(ISTD), medroxyprogesterone (recovery standard); THE, tetrahydrocortisone; THA, tetrahydro11-dehydrocorticosterone; THB, tetrahydrocorticosterone; 5a-THB, 5α-tetrahydrocorticosterone; THF, tetrahydrocortisol; 5a-THF, 5α-tetrahydrocortisol; SS(ISTD), stigmasterol (standard for derivatization and chromatography); 20β-DHF, 20β-dihydrocortisol; 20α-DHF, 20α-dihydrocortisol. (C) Genetic analysis of the identified deletion. The analytic strategy and location of the identified deletion is shown in a diagram showing the CYP17A1 gene. PCR products of the long amplification PCR are depicted. The lower band corresponds to double deletion and the upper band to the wild-type situation. All patients are homozygous for the deletion, the parents are heterozygous whereas one sibling is genetically wild-type on both alleles (wt, wild type; del, deletion). The original sequence (reverse) of the CYP17A1 gene with the 2-deletion breakpoints and the conserved IVS2 sequence detected in the parents and the three affected siblings are also shown.