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    • br The human CYP A gene is located on

    2024-03-28


    The human CYP17A1 gene is located on chromosome 10q24.3 (1) and spans 6.6 kb, which contain eight exons (2) and 1.6 kb of coding region. From this gene, the same 2.1-kb mRNA species is transcribed in both the adrenals and gonads (3), which yields a 57-kDa microsomal cytochrome P450c17 enzyme (CYP17A1). The CYP17A1 enzyme catalyzes both steroid 17-hydroxylase and 17,20-lyase activities (4), and both activities require one equivalent of molecular oxygen and two electrons from nicotinamide autophagy inhibitor dinucleotide phosphate (reduced form, NADPH). The electron transfer flavoprotein, cytochrome P450 oxidoreductase (POR), serves as a conduit for the electron transfer from NADPH to CYP17A1, but other flavoproteins can substitute for POR, at least for the 17-hydroxylase activity (5). The 17,20-lyase activity is particularly vulnerable to the abundance and structure of the electron transfer complex (6). In addition, optimal 17,20-lyase reaction requires the cofactor protein cytochrome b5 (b5); b5 stimulates the maximal rate of the reaction in the steady state over 10-fold 7, 8, 9, 10. Nearly 100 disease-causing mutations 17-hydroxylase/17,20-lyase deficiency (17OHD, OMIM 202110) have been described. All forms of CYP17A1 deficiency are extremely rare, and in most populations without founder mutations, 17OHD accounts for <1% of all cases of congenital adrenal hyperplasia (CAH). Although 17OHD patients are found worldwide, the disease is particularly abundant in Brazil owing to two founder mutations, R362C and W406R. Other mutations are found repeatedly, such as Y329 mutations and a deletion of residues 487–489, particularly in Asia. Mutations are found throughout the gene, with the largest number in the C-terminus, up to the last 14 amino acids. The majority of these changes are missense or nonsense single base pair substitutions, and residues prone to mutation of one or more base change include R96, R239, Y329, R362, H373, R347, R416, R440, D487, and R496. A few small deletions and duplications have been described, and large deletions account for a very few cases. In some cases, no CYP17A1 mutations have been located, despite clinical and hormonal evidence for 17-hydroxylase deficiency (11). Table 1 lists some of the more common CYP17A1 mutations causing combined 17OHD.
    Defects in steroidogenesis CYP17A1 is the major qualitative regulator of steroidogenesis (12), meaning that CYP17A1 activities determine which steroid products derive from a given cell. CYP17A1 is absent in the zona glomerulosa of the adrenal and the corpora lutea of the ovary, and its expression in the placenta is low. In the adrenal zona glomerulosa, the enzyme steroid 21-hydroxylase (cytochrome P450c21, CYP21A2) converts P to 11-deoxycorticosterone (DOC). Ordinarily, the coexpression of aldosterone synthase (cytochrome P450c11AS, CYP11B2) completes the synthesis of aldosterone from DOC via three sequential oxygenations, one at C-11 and two at C-18. In the placenta and corpora lutea, the steroid hydroxylases are essentially absent, and steroidogenesis stops at P. In 17OHD and isolated 17,20-lyase deficiency, steroidogenesis mirrors the normal steroid biosynthesis in these tissues, and the physiology derives from androgen deficiency and varying degrees of mineralocorticoid excess (Fig. 1).
    Fertility The decreased enzymatic activity from CYP17A1 is associated with hypergonadotropic hypogonadism and infertility. Decreased production of gonadal steroids is seen in individuals with 17OHD and can cause impaired spermatogenesis and folliculogenesis 32, 33, 34, 35. In females, folliculogenesis is arrested with only primary and secondary oocytes seen on ovarian pathology 36, 37, 38. In males, pathologic evaluation reveals testicular atrophy with interstitial cell hyperplasia and arrested spermatogenesis (39). Although generally thought to be anovulatory, there are case reports of females with 17OHD who underwent spontaneous menarche with cyclic menses. Miura and colleagues reported regular menstruation in four females with homozygous deletions of phenylalanine codon at either amino acid position 53 or 54 (delF53/54) in exon 1 of the CYP17A1 gene (40). Despite a history of regular menses, one of the four females with this deletion had an episode of prolonged menstrual bleeding and underwent total hysterectomy with ovarian biopsy, which revealed an absence of corpora lutea and follicles. The delF53/54 enzyme retains partial activity, consistent with the intermediate phenotype. Similarly, Yanase et al. reported regular menstruation in a female with delF53/54 and 17,20 lyase activity that was only 5% that of normal (41). Singhellakis et al. reported spontaneous sexual development and menarche in a female with 17-hydroxylase deficiency, but diagnostic testing did not include sequencing of the CYP17A1 gene or any measures of 17-hydroxylase or 17,20-lyase enzymatic activities (42).