A missense mutation in the human cytochrome b5 gene causes 46,XY disorder of sex development due to true isolated 17,20 lyase deficiency
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CONTEXT: Isolated 17,20 lyase deficiency is commonly defined by apparently normal 17α-hydroxylase activity but severely reduced 17,20 lyase activity of the bifunctional enzyme cytochrome P450 (CYP) enzyme 17A1 (CYP17A1), resulting in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. Cytochrome b5 (CYB5A) is thought to selectively enhance 17,20 lyase activity by facilitating the allosteric interaction of CYP17A1 with its electron donor P450 oxidoreductase (POR). OBJECTIVE: We investigated a large consanguineous family including three siblings with 46,XY disorder of sex development (DSD) presenting with isolated 17,20 lyase deficiency. DESIGN: We investigated the clinical and biochemical phenotype, conducted genetic analyses, and functionally characterized the identified CYB5A mutation in cell-based CYP17A1 coexpression assays. RESULTS: All three siblings presented with 46,XY DSD, sex steroid deficiency, normal mineralocorticoids and glucocorticoids, and a urine steroid metabolome suggestive of isolated 17,20 lyase deficiency. CYP17A1 and POR sequences were normal, but we detected a homozygous CYB5A missense mutation (g.28,400A→T; p.H44L). Functional in vitro analysis revealed normal CYP17A1 17α-hydroxylase activity but severely impaired 17,20 lyase activity. In silico analysis suggested the disruption of CYB5A heme binding by p.H44L. CONCLUSION: We have identified the first human CYB5A missense mutation as the cause of isolated 17,20 lyase deficiency in three individuals with 46,XY DSD. Detailed review of previously reported cases with apparently isolated 17,20 lyase deficiency due to mutant CYP17A1 and POR reveals impaired 17α-hydroxylase activity as assessed by steroid metabolome analysis and short cosyntropin testing. This suggests that truly isolated 17,20 lyase deficiency is observed only in individuals with inactivating CYB5A mutations.
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The principal action of cytochrome b5 is reduction of methemoglobin, and b5 deficiency causes DSD with methemoglobinemia.
“but the principal action of b5 is the reduction of methemoglobin ( 10 ), and b5 deficiency causes DSD with methemoglobinemia ( 11 , 12 ).”
From Disordered Electron Transfer: New Forms of Defective Steroidogenesis and Mitochondriopathy (2025) · cites this paper as [12]
A small number of reports have described b5 deficiency in patients with apparent isolated 17,20-lyase deficiency, sometimes associated with methemoglobinemia.
“Since then, a small number of reports have described b5 deficiency in patients with apparent isolated 17,20-lyase deficiency, sometimes associated with methemoglobinemia ( 11 , 12 , 54 ).”
From Disordered Electron Transfer: New Forms of Defective Steroidogenesis and Mitochondriopathy (2025) · cites this paper as [12]
Urine steroid profiling in CYP17A1 deficiency shows substantial reduction of all androgen metabolites, and diagnostic ratios indicate largely abolished 17,20-lyase activity.
“Urine steroid profiling (Fig. 2B) shows a substantial reduction of all androgen metabolites, and diagnostic ratios (Table 2) indicate largely abolished 17,20-lyase activity (15, 18).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [15]
Urine steroid profiling in milder CYP17A1 deficiency suggests attenuation of 17α-hydroxylase activity, assessed by ratio of mineralocorticoid over glucocorticoid metabolites, which is the most important diagnostic ratio for this disorder.
“Similarly, urine steroid profiling in these milder cases suggests attenuation of 17α-hydroxylase activity, assessed by the ratio of mineralocorticoid over glucocorticoid metabolites (15, 19), which is the most important diagnostic ratio for this disorder (Table 2).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [15]
In milder CYP17A1 deficiency, stimulated cortisol levels do not rise sufficiently, indicating glucocorticoid deficiency.
“Although milder forms of CYP17A1 deficiency have been reported, where only sex steroid production seems to be present (so-called “isolated 17,20-lyase deficiency”), stimulated cortisol levels do not rise sufficiently in these patients, indicating glucocorticoid deficiency (15, 37).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [15]
Diagnosis of SRD5A2 deficiency from urine steroid profiling is straightforward, with most robust information provided by diagnostic ratios of 5α-reduced over 5β-reduced glucocorticoid and mineralocorticoid metabolites.
“The diagnosis from urine steroid profiling is straightforward [Fig. 4 (15, 61, 62)], with most robust information provided by diagnostic ratios of 5α-reduced over 5β-reduced glucocorticoid and mineralocorticoid metabolites (Table 2) (61)”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [15]
Urine steroid profiling data in three siblings with CYB5A deficiency show increased excretion rates of the 17OHPreg metabolite 5PT, with reduced androgen excretion but normal glucocorticoids and mineralocorticoids.
“Urine steroid profiling data are available in three siblings (15): excretion rates of the 17OHPreg metabolite 5PT are increased, with reduced androgen excretion but normal glucocorticoids and mineralocorticoids (Fig. 4).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [15]
In contrast to 17,20-lyase deficiency in the context of CYP17A1 deficiency, which always comes with a degree of impairment of CYP17A1 17α-hydroxylase activity, CYB5A deficiency represents "true" isolated 17,20-lyase deficiency.
“In contrast to 17,20-lyase deficiency in the context of CYP17A1 deficiency (see “CAH due to CYP21A2 deficiency” above), which always comes with a degree of impairment of CYP17A1 17α-hydroxylase activity, CYB5A deficiency represents “true” isolated 17,20-lyase deficiency (15, 70);”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [15]
Serum sex steroids DHEA(S), A4, and T as well as 17β-estradiol are undetectable at baseline and after cosyntropin or hCG stimulation in CYB5A deficiency.
“Serum sex steroids DHEA(S), A4, and T as well as 17β-estradiol are undetectable at baseline and after cosyntropin or hCG stimulation (15, 70).”
From Steroid Metabolome Analysis in Disorders of Adrenal Steroid Biosynthesis and Metabolism (2019) · cites this paper as [15]
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- Authors
- Idkowiak, J., Randell, T., Dhir, V., Patel, P., Shackleton, C. H. L., Taylor, N. F., Krone, N., & Arlt, W.
- Affiliations
- University of Birmingham (GB)
- National Health Service (GB)
- University of London (GB)
- Corresponding author
- Arlt, Wiebke
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2012-03-01
- Volume
- 97
- Issue
- 3
- Pages
- E465-E475
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- PMC
- PMC3388247
- OpenAlex
- W2004011863
- Cited by
- 104
- References
- 39
- Citations by year
- 2026: 4 · 2025: 3 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 12 · 2020: 2 · 2019: 7 · 2018: 7 · 2017: 7 · 2016: 8 · 2015: 7 · 2014: 16 · 2013: 7 · 2012: 3
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion, cc-by-nc)
- Funders
- Wellcome Trust (0900567, GR079865MA)
- Medical Research Council (G1001964, 0900567)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Sexual Differentiation and Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- cytochrome b5, CYB5A, missense mutations, 46,XY disorders of sex development, CYP17A1, cytochrome P450 oxidoreductase, sex hormone deficiency, heme binding, consanguinity, steroid metabolome
- MeSH terms
- Adolescent, Adrenal Hyperplasia, Congenital, Child, Child, Preschool, Humans, Infant, Infant, Newborn, Steroid 17-alpha-Hydroxylase, Cytochromes b5, Mutation, Missense, Disorder of Sex Development, 46,XY
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