Steroid 17-hydroxylase and 17,20-lyase deficiencies, genetic and pharmacologic

Abstract

Steroid 17-hydroxylase 17,20-lyase (cytochrome P450c17, P450 17A1, CYP17A1) catalyzes two major reactions: steroid 17-hydroxylation followed by the 17,20-lyase reactions. The most severe mutations in the cognate CYP17A1 gene abrogate all activities and cause combined 17-hydroxylase/17,20-lyase deficiency (17OHD), a biochemical phenotype that is replicated by treatment with the potent CYP17A1 inhibitor abiraterone acetate. The adrenals of patients with 17OHD synthesize 11-deoxycorticosterone (DOC) and corticosterone but no 19-carbon steroids, similar to the rodent adrenal, and DOC causes hypertension and hypokalemia. Loss of 17,20-lyase activity precludes sex steroid synthesis and leads to sexual infantilism. Rare missense CYP17A1 mutations minimally disrupt 17-hydroxylase activity but cause isolated 17,20-lyase deficiency (ILD), Mutations in the POR gene encoding the required cofactor protein cytochrome P450-oxidoreductase causes a spectrum of disease from ILD to 17OHD combined with 21-hydroxylase and aromatase deficiencies, sometimes including skeletal malformations. Mutations in the CYB5A gene encoding a second cofactor protein cytochrome b₅ also selectively disrupt 17,20-lyase activity and cause the purest form of ILD. The clinical manifestations of these conditions are best understood in the context of the biochemistry of CYP17A1.

Keywords: 17-Hydroxylase/17,20-lyase; 46XY DSD; Androgen; Hypertension; Infertility; Mineralocorticoid; Primary amenorrhea.

Figure 1

Major pathways of adrenal steroid biosynthesis. Panel A shows the pathways in the normal human adrenal, and panel B shows altered pathways in 17OHD. Dashed arrows show minor or reduced pathways, and size of text indicates relative abundance for cortisol, aldosterone, androgens and estrogens, corticosterone, and DOC (11-deoxycorticosterone).

Figure 2

Cartoon of CYP17A1 gene showing the location of common mutations and mutations causing isolated 17,20-lyase deficiency. Exons are shown as numbered rectangles connected by introns as solid horizontal line and are approximately drawn to scale. Mutations found in isolated 17,20-lyase deficiency are shown below the gene cartoon.

Figure 3

Steroid-binding pocket in human CYP17A1. Images demonstrate proximity of hydrogen atoms at C-16, C-17, and C-21 of progesterone to heme ring (A) and hydrogen bonding (dots) of A-ring oxygen to side-chain of N202 in 17-hydroxypregnenolone (B) or 17-hydroxyprogesterone (C). Images were generated from the X-ray crystal structures of CYP17A1 mutation A105L with bound steroids (pdbid numbers 4NKX, 4NKY, 4NKZ) with program PyMol.