rs28934880 — HSD3B2 Ala10Glu

Missense variant abolishing 3β-hydroxysteroid dehydrogenase type 2 activity; homozygotes develop salt-wasting congenital adrenal hyperplasia, heterozygous carriers are clinically normal but can pass the allele to offspring

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HSD3B2 Ala10Glu — A Founder Variant That Eliminates Steroidogenesis

3β-hydroxysteroid dehydrogenase type 211 3β-hydroxysteroid dehydrogenase type 2
encoded by HSD3B2; the rate-limiting enzyme for converting Δ5-precursors (pregnenolone, 17-OH-pregnenolone, DHEA) into the active Δ4-steroids (progesterone, 17-OH-progesterone, androstenedione) is indispensable for the biosynthesis of all major steroid hormones — mineralocorticoids (aldosterone), glucocorticoids (cortisol), and sex steroids (testosterone, estrogens). The enzyme is expressed in both the adrenal cortex and the gonads. Without it, the body cannot complete the conversion from cholesterol-derived precursors to functional steroids in either tissue.

The rs28934880 variant introduces a C-to-A transversion in exon 1 of HSD3B2, changing codon 10 from GCA (alanine) to GAA (glutamic acid). This single amino acid substitution — p.Ala10Glu — was first characterized in two French-Canadian families presenting with severe salt-wasting congenital adrenal hyperplasia (CAH), and evidence of a shared ancestral haplotype spanning 3.3 cM around the locus points to a founder event in that population. The variant is exceptionally rare globally (gnomAD genomes: 1 observation in 149,092 alleles).

The Mechanism

Alanine at position 10 is highly conserved across the entire 3βHSD gene family in vertebrates22 Alanine at position 10 is highly conserved across the entire 3βHSD gene family in vertebrates
Conservation at this site implies structural or catalytic importance across species. The residue sits in the enzyme's NAD-binding domain — the cofactor-binding pocket that the enzyme requires to carry out oxidation and isomerization of Δ5-steroids. Replacing the small, non-polar alanine with a bulkier, negatively charged glutamic acid at this site is expected to disrupt the geometry of the NAD-binding pocket and destabilize the protein's tertiary structure.

Functional studies in transfected Ad293 cells confirmed this prediction: the Ala10Glu mutant enzyme exhibited no detectable 3β-HSD activity33 the Ala10Glu mutant enzyme exhibited no detectable 3β-HSD activity
Intact-cell transfection assays quantify the enzyme's ability to convert substrate in a cellular environment; zero detectable activity means essentially no functional enzyme is produced or retained. This is a complete loss-of-function variant. When both copies of HSD3B2 carry this (or another severe) mutation, the adrenal cortex and gonads cannot produce glucocorticoids, mineralocorticoids, or sex steroids from their Δ5-steroid precursors. The consequent accumulation of DHEA and 17-OH-pregnenolone alongside deficiency of cortisol and aldosterone defines the biochemical signature of the disorder.

Because HSD3B1 (the type 1 isoenzyme, expressed in placenta and peripheral tissues) is encoded by a different gene and is not affected, partial peripheral conversion of androgens can still occur via HSD3B1 — explaining why some affected individuals show partial masculinization during puberty despite adrenal/gonadal deficiency.

The Evidence

The index case characterization comes from Alos et al. 2000 (J Clin Endocrinol Metab 85:1968–74)44 Alos et al. 2000 (J Clin Endocrinol Metab 85:1968–74)
A novel A10E homozygous mutation in HSD3B2 gene causing severe salt-wasting 3beta-hydroxysteroid dehydrogenase deficiency in 46,XX and 46,XY French-Canadians: evaluation of gonadal function after puberty. Two unrelated homozygous patients — one 46,XX, one 46,XY — both presented in infancy with salt-wasting CAH. The 46,XY patient achieved partial masculinization during puberty through peripheral HSD3B1 activity, but semen analysis at age 18.5 showed azoospermia; the 46,XX patient reached menarche and had progesterone secretion, demonstrating residual gonadal function via peripheral conversion.

A comprehensive 2019 review by Al Alawi, Nordenström and Falhammar (Endocrine 64:622–634)55 Al Alawi, Nordenström and Falhammar (Endocrine 64:622–634)
Clinical perspectives in congenital adrenal hyperplasia due to 3β-hydroxysteroid dehydrogenase type 2 deficiency synthesized data from all published HSD3B2 cases. A critical point for carriers: "the hormonal profile cannot distinguish heterozygous carriers from normal people" — molecular genetic testing is required to identify carrier status. The review documents that over 40 HSD3B2 mutations have been characterized, with null mutations (frameshift, nonsense) invariably causing salt-wasting, while missense mutations with residual activity (~10%) are associated with non-salt-wasting phenotypes.

Mermejo et al. 2005 (J Clin Endocrinol Metab 90:1287–93)66 Mermejo et al. 2005 (J Clin Endocrinol Metab 90:1287–93) established biochemical thresholds: ACTH-stimulated 17-OH-pregnenolone ≥201 nmol/L distinguishes genotype-confirmed HSD3B2-deficient patients from hormonal-only evaluations, helping reduce false-positive diagnoses. Importantly, their data showed heterozygous parents of affected children had intermediate but not clearly elevated hormone levels — again supporting that carriers do not have detectable clinical disease.

Male fertility in treated patients is not uniformly lost. Donadille et al. 2018 (Endocrine Connections 7:R255–R265)77 Donadille et al. 2018 (Endocrine Connections 7:R255–R265) reported a 24-year-old male homozygote with a different HSD3B2 deletion who maintained sperm concentrations of 57.6 million/mL under replacement therapy — the first report of adequate spermatogenesis in a clinically confirmed case, suggesting that early diagnosis and steroid replacement may preserve fertility in some males.

Practical Actions

For heterozygous carriers (AC genotype), no clinical management is required — adrenal and gonadal steroid production is entirely normal with one functional gene copy. The clinical relevance is reproductive: each pregnancy with another carrier carries a 25% probability of an affected child. Informing a reproductive endocrinologist or genetic counselor before conception allows informed decisions.

For homozygous individuals (AA genotype), this is a medical condition requiring specialist management. Long-term glucocorticoid replacement (hydrocortisone 10–15 mg/m²/day, divided three times daily) suppresses excess Δ5-androgens and replaces cortisol. Salt-wasting forms additionally require mineralocorticoid replacement (fludrocortisone 0.1 mg/day with sodium supplementation in infancy). Androgen management is typically more challenging than in 21-hydroxylase deficiency. Fertility preservation counseling should be initiated early in adulthood.

Interactions

Compound heterozygosity — one Ala10Glu allele plus a second distinct HSD3B2 pathogenic variant — produces the same phenotypic spectrum as homozygosity for either single variant, since both copies of HSD3B2 are nonfunctional. The severity depends on the residual activity of the second allele: a missense mutation with ~10% activity combined with the Ala10Glu null allele may produce a milder non-salt-wasting phenotype. Full genotype characterization of both alleles is essential for prognosis.

Genotype Interpretations

What each possible genotype means for this variant.

CC Non-Carrier Normal

Two copies of the reference allele; full HSD3B2 enzyme function

You have two copies of the common C allele at this position in HSD3B2. The Ala10Glu pathogenic variant is not present in your genome. This is by far the most common genotype globally; the disease-causing A allele appears in approximately 1 in 149,000 alleles in gnomAD genome data.

Your HSD3B2 gene carries the reference alanine at position 10 of the enzyme, leaving the NAD-binding domain intact. Steroid hormone biosynthesis — mineralocorticoids, glucocorticoids, and sex steroids — proceeds through the normal 3β-HSD type 2 pathway in both the adrenal cortex and gonads.

AC Carrier Carrier

Heterozygous carrier of the Ala10Glu pathogenic variant; clinically unaffected, but can pass the variant to children

3β-HSD type 2 deficiency is an autosomal recessive condition caused by biallelic loss-of-function mutations in HSD3B2. One functional copy of the gene is sufficient to maintain normal adrenal and gonadal steroidogenesis. The Ala10Glu mutation at codon 10 of the enzyme disrupts the NAD-binding domain and eliminates all detectable enzymatic activity in functional assays (Alos et al. 2000, PMID 10843183). Heterozygous carriers have one fully functional copy and show no biochemical or clinical evidence of steroid deficiency.

The inheritance math: if both parents are carriers of any pathogenic HSD3B2 variant, each child has a 1-in-4 (25%) chance of inheriting a defective allele from each parent, resulting in 3β-HSD deficiency. The 50% probability of inheriting carrier status and the 25% probability of inheriting two normal copies complete the Mendelian picture.

Because the condition is rare (fewer than 100 published cases worldwide), the probability that a random partner carries a second HSD3B2 pathogenic allele is very low. However, the Ala10Glu allele has a documented founder effect in the French-Canadian population, where population-specific carrier frequency may be higher than the global estimate.

Neonatal screening programs (newborn screening for CAH) do not specifically distinguish 3β-HSD deficiency from 21-hydroxylase deficiency on routine hormone panels without genetic follow-up. If an affected child is born, early molecular diagnosis of both HSD3B2 alleles enables accurate genotype-phenotype prognosis.

AA Homozygous — 3β-HSD Deficiency Homozygous

Two copies of the Ala10Glu pathogenic variant; consistent with 3β-hydroxysteroid dehydrogenase type 2 deficiency requiring specialist management

Classical 3β-HSD type 2 deficiency presents in newborns with adrenal insufficiency: hyponatremia, hyperkalemia, metabolic acidosis, and hypoglycemia (salt-wasting form). In 46,XY individuals, impaired testicular testosterone synthesis during fetal development causes incomplete masculinization; in 46,XX individuals, elevated adrenal DHEA concentrations cause variable virilization, though often mild at birth with the non-salt-wasting phenotype.

The Ala10Glu (A10E) allele specifically produces zero residual enzyme activity (Alos et al. 2000), making it one of the more severe HSD3B2 alleles. Homozygotes for this allele are expected to present with the classical salt-wasting phenotype rather than the milder non-salt-wasting or non-classical forms seen with missense mutations that retain ~10% activity.

Long-term management requires glucocorticoid replacement (hydrocortisone 10–15 mg/m²/day divided three times daily, adjusted by growth and suppression of Δ5-steroid precursors) and mineralocorticoid replacement in salt-wasting forms (fludrocortisone 0.1 mg/day with sodium chloride supplementation in infancy). Androgen suppression is typically more difficult than in 21-hydroxylase deficiency. Fertility is frequently impaired but not uniformly absent under optimal replacement therapy; spermatogenesis in one treated male with a severe HSD3B2 deletion was reportedly normal (Donadille et al. 2018).

If this finding is new (i.e., not already diagnosed), immediate evaluation by a pediatric endocrinologist or adult endocrinologist is indicated. Adrenal crisis is life-threatening and preventable with adequate replacement and stress dosing protocols.