rs104894142 — CYP17A1 R362C (Arg362Cys)

CYP17A1 R362C — When the Steroid Factory Stalls

CYP17A1 encodes 17α-hydroxylase/17,20-lyase¹¹ 17α-hydroxylase/17,20-lyase
a single dual-function cytochrome P450 enzyme that catalyzes two sequential reactions at the heart of steroid hormone production in the adrenal glands and gonads: first adding a hydroxyl group at carbon-17, then cleaving the side chain to generate androgens and cortisol precursors. Without this enzyme, the steroid biosynthesis pathway cannot produce cortisol, androgens, or estrogens. Instead, steroid precursors accumulate and spill into the mineralocorticoid pathway — flooding the body with compounds that mimic aldosterone, driving up blood pressure and suppressing potassium.

The R362C variant (c.1084C>T on the coding strand; G>A on the genomic plus strand) replaces arginine at position 362 with cysteine in the enzyme's oxygen-binding domain. Unlike some CYP17A1 mutations that selectively impair only one of the two enzymatic activities, R362C abolishes both — it is a complete null allele. Carriers of two copies develop combined 17α-hydroxylase/17,20-lyase deficiency²² combined 17α-hydroxylase/17,20-lyase deficiency
classified as a rare form of congenital adrenal hyperplasia (CAH); total worldwide prevalence approximately 1 per 50,000 births, while one-copy carriers (heterozygotes) are unaffected clinically but carry the mutation to the next generation.

R362C is notably concentrated in Brazil, where it accounts for approximately 32% of all mutant CYP17A1 alleles in affected patients — a founder effect³³ founder effect
A mutation that becomes common in a population descended from a small ancestral group that happened to carry it; in Brazil, R362C traces to Portuguese founders traced to Portuguese ancestry. Cases have also been reported in India and other populations.

The Mechanism

The Arg362 residue sits in the enzyme's I-helix, adjacent to the heme-binding domain that coordinates molecular oxygen for catalysis. Replacing the positively charged, bulky arginine with a small, sulfur-containing cysteine disrupts the local protein geometry around the active site. Functional studies in COS-7 cells and yeast microsomes confirm that the R362C protein retains essentially no 17α-hydroxylase or 17,20-lyase activity — both reaction steps are completely abolished⁴⁴ completely abolished
Costa-Santos et al. 2004 (PMID 14715827): enzyme activity measured as zero in heterologous expression systems for both hydroxylation of progesterone and lyase cleavage of 17-hydroxyprogesterone.

The downstream consequences follow directly from the enzyme block. Without 17α-hydroxylase, pregnenolone and progesterone cannot enter the cortisol or sex hormone branches of the pathway. They accumulate and are converted instead to 11-deoxycorticosterone (DOC) and corticosterone — potent mineralocorticoids that raise blood pressure and suppress potassium. Elevated ACTH (due to absent cortisol feedback) drives this shunting chronically, producing hypertension and hypokalemia that can persist for years before diagnosis. Simultaneously, the absence of sex steroids means puberty fails to proceed normally in both 46,XX and 46,XY individuals.

The Evidence

The evidence base for R362C rests on case series and functional studies — as with all rare Mendelian disorders, large randomized trials are not feasible.

Costa-Santos et al. 2004⁵⁵ Costa-Santos et al. 2004
24 subjects from 19 Brazilian families with confirmed 17-hydroxylase deficiency; R362C accounted for 32% of mutant alleles across 13 affected individuals; confirmed complete enzyme loss in cell-based functional assays for both activities established R362C as a major pathogenic allele and characterized its functional consequence biochemically.

Belgini et al. 2010⁶⁶ Belgini et al. 2010
6 additional Brazilian patients from 3 inbred families; 3 homozygous for R362C; ACTH >104 ng/mL, progesterone >4.4 ng/mL, potassium <2.8 mEq/L in all six demonstrated the reproducible biochemical profile across independent families and confirmed that R362C homozygotes present identically to W406R homozygotes — both are complete loss-of-function alleles.

Regarding fertility outcomes, Pan et al. 2023⁷⁷ Pan et al. 2023
5 women with 17-OHD undergoing ART; elevated endogenous progesterone blocks endometrial receptivity; freeze-all embryo transfer with hormonal optimization achieved live births in 4 of 5 women and Xu et al. 2022⁸⁸ Xu et al. 2022
13 patients with variable CYP17A1 mutations; 2 women with partial deficiency achieved pregnancy via ovulation induction and IVF-ET with glucocorticoid suppression confirm that with appropriate hormonal management, affected women can achieve live birth through assisted reproduction.

Practical Actions

For individuals homozygous for R362C, lifelong hormone replacement addresses all three consequences of enzyme absence: glucocorticoid replacement suppresses the ACTH-driven mineralocorticoid excess (resolving hypertension and hypokalemia), and sex hormone replacement initiates or maintains puberty and secondary sexual development. Fertility in affected women requires specialist reproductive endocrinology care, as chronically elevated endogenous progesterone impairs endometrial receptivity — but live birth via IVF is achievable with the right protocol.

For heterozygous carriers, the clinical impact is absent, but the recurrence risk is substantial: two carriers have a 1-in-4 chance of an affected child. Genetic counseling and partner testing are the key actions.

Interactions

R362C is one of several pathogenic CYP17A1 variants affecting the same enzymatic function. W406R (rs104894143)⁹⁹ W406R (rs104894143)
The most common CYP17A1 null allele in Brazilian patients, accounting for ~50% of mutant alleles; same complete loss-of-function phenotype as R362C is a distinct mutation at a different codon producing an identical biochemical outcome. Compound heterozygotes carrying one R362C allele and one W406R allele develop the same full clinical syndrome as homozygotes for either mutation — both alleles are functionally null, so the combined effect equals complete deficiency.

[rs104894138 (Arg96Trp) | A third rare CYP17A1 pathogenic variant at codon 96, also causing 17α-hydroxylase/17,20-lyase deficiency] is another null allele in the same gene. Any compound heterozygote pairing of these three alleles produces complete deficiency. Screening for all three simultaneously is standard in molecular diagnostics for suspected 17-hydroxylase deficiency.