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Why Boys Will Be Boys: Two Pathways of Fetal Testicular Androgen Biosynthesis Are Needed for Male Sexual Differentiation
Open accessAbstract
Human sexual determination is initiated by a cascade of genes that lead to the development of the fetal gonad. Whereas development of the female external genitalia does not require fetal ovarian hormones, male genital development requires the action of testicular testosterone and its more potent derivative dihydrotestosterone (DHT). The "classic" biosynthetic pathway from cholesterol to testosterone in the testis and the subsequent conversion of testosterone to DHT in genital skin is well established. Recently, an alternative pathway leading to DHT has been described in marsupials, but its potential importance to human development is unclear. AKR1C2 is an enzyme that participates in the alternative but not the classic pathway. Using a candidate gene approach, we identified AKR1C2 mutations with sex-limited recessive inheritance in four 46,XY individuals with disordered sexual development (DSD). Analysis of the inheritance of microsatellite markers excluded other candidate loci. Affected individuals had moderate to severe undervirilization at birth; when recreated by site-directed mutagenesis and expressed in bacteria, the mutant AKR1C2 had diminished but not absent catalytic activities. The 46,XY DSD individuals also carry a mutation causing aberrant splicing in AKR1C4, which encodes an enzyme with similar activity. This suggests a mode of inheritance where the severity of the developmental defect depends on the number of mutations in the two genes. An unrelated 46,XY DSD patient carried AKR1C2 mutations on both alleles, confirming the essential role of AKR1C2 and corroborating the hypothesis that both the classic and alternative pathways of testicular androgen biosynthesis are needed for normal human male sexual differentiation.
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In the citing paper
“These data demonstrate that both the canonical and backdoor pathways are essential for normal fetal masculinization.”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [15]
In the citing paper
“studies by Flück and colleagues [15] have shown that disordered sex development (DSD) will arise if the pathway is disrupted. In one individual with mutations in aldo-keto reductase type 1C2 (AKR1C2) and in another family with an added mutation in aldo-keto reductase type 1C4 (AKR1C4), there was failure of normal masculinization.”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [15]
In the citing paper
“Currently, the accepted model for masculinization is that circulating DHT, formed via the backdoor pathway in the fetal testis [15,16], is important for virilization alongside circulating testosterone.”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [15]
In the citing paper
“More recently, however, it has been reported that an alternative pathway to DHT formation exists that does not require testosterone as an intermediate. This alternative, “backdoor” pathway (Fig 1) was first described in the testes of pouch young marsupials [13], and a similar pathway has since been reported in the prepubertal mouse testis [14] and the fetal human testis [15].”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [15]
In the citing paper
“Masculinization of the external genitalia in humans is dependent on formation of 5α-dihydrotestosterone (DHT) through both the canonical androgenic pathway and an alternative (backdoor) pathway.”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [15]
In the citing paper
“However, the recent demonstration that the alternative, backdoor pathway to DHT synthesis is also required for normal human fetal male development [15,16] has shown that the process involves a complex interaction between different steroidogenic pathways.”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [15]
In the citing paper
“two 46,XY individuals who are known heterozygotes for a mutation in AKR1C2 show divergent phenotypes, with one showing a normal male phenotype and the other DSD [15]”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [15]
In the citing paper
“the normal process of masculinization in the human depends on two separate pathways of androgen synthesis, the canonical and backdoor pathways [15]”
From Alternative (backdoor) androgen production and masculinization in the human fetus (2019) · cites this paper as [15]
In the citing paper
“Recently several inherited mutations in the AKR1C2 and AKR1C4 genes have been identified in two Swiss families which were associated with disordered sexual dysgenesis (DSD).”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [103]
In the citing paper
“The mutants Ile79Val, His90Gln, Asn300Thr and His222Gln have been prepared in recombinant forms or over-expressed in COS-1 cells and showed reduced enzymatic activities [103].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [103]
In the citing paper
“The authors observed AKR1C2 and AKR1C4 expression in fetal testes thus they concluded that these enzymes are needed for fetal 5α-DHT synthesis via the backdoor pathway and normal development of the genitalia [103].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [103]
In the citing paper
“In addition to these AKR1C2 mutations these individuals also carried a mutation causing aberrant splicing of the AKR1C4 gene (Val29_Lys84del).”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [103]
In the citing paper
“In the first family identified with DSD, missense AKR1C2 muations: Ile79Val, His906Glu, and Asn300Thr were identified in the affected individuals.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [103]
In the citing paper
“So far SNPs in AKR1C1, AKR1C2 and AKR1C4 have been studied at the protein level and Phe46Tyr has been associated with disease [95–97, 99, 103, 104].”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [103]
In the citing paper
“In the second family recombination between AKR1C1 and AKR1C3 was detected and a missense AKR1C2 mutation His222Gln was identified.”
From Role of aldo-keto reductase family 1 (AKR1) enzymes in human steroid metabolism (2014) · cites this paper as [103]
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Metadata
- Authors
- Flück, C. E., Meyer-Böni, M., Pandey, A. V., Kempná, P., Miller, W. L., Schoenle, E. J., & Biason-Lauber, A.
- Affiliations
- University of Bern (CH)
- University of California, San Francisco (US)
- University Children's Hospital Zurich (CH)
- Corresponding author
- Flück, Christa E.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2011-08
- Volume
- 89
- Issue
- 2
- Pages
- 201-218
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3155178
- OpenAlex
- W2066296351
- Semantic Scholar
- 35d55145faae3af26a68bab9da7255b0b7db12d0
- Cited by
- 248
- References
- 74
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 11 · 2023: 14 · 2022: 22 · 2021: 26 · 2020: 21 · 2019: 17 · 2018: 16 · 2017: 19 · 2016: 18 · 2015: 16 · 2014: 25 · 2013: 13 · 2012: 12
- FWCI
- 6.88
- Type
- journal article
- Language
- en
- Update notices
- erratum (2011-08-12)
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (130710)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Sexual Differentiation and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Health Sciences › Medicine › Reproductive Medicine › Sperm and Testicular Function
- Keywords
- AKR1C2, AKR1C4, dihydrotestosterone, male sexual differentiation, 46,XY disorders of sex development, enzyme activity, aberrant splicing, candidate gene identification
- MeSH terms
- Amino Acid Sequence, Androgens, Base Sequence, Family, Female, Fetus, Gene Expression Regulation, Humans, Hydroxysteroid Dehydrogenases, Male, Models, Molecular, Molecular Sequence Data, Mutation, Oxidoreductases, Pedigree, Sex Differentiation, Dihydrotestosterone, Testis, Alternative Splicing, Gene Expression Profiling, 3-alpha-Hydroxysteroid Dehydrogenase (B-Specific), Mutant Proteins, Biosynthetic Pathways
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