Why Boys Will Be Boys: Two Pathways of Fetal Testicular Androgen Biosynthesis Are Needed for Male Sexual Differentiation

• Published in: American journal of human genetics Vol. 89; no. 2; pp. 201 - 218
• Main Authors: Flück, Christa E., Meyer-Böni, Monika, Pandey, Amit V., Kempná, Petra, Miller, Walter L., Schoenle, Eugen J., Biason-Lauber, Anna
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Inc 12-08-2011; Cell Press; Elsevier
• Subjects: Alternative Splicing - genetics; Amino Acid Sequence; Androgens; Androgens - biosynthesis; Base Sequence; Biological and medical sciences; Biosynthesis; Biosynthetic Pathways; Cholesterol; Dihydrotestosterone - metabolism; Family; Female; Fetus - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene Expression Regulation; General aspects. Genetic counseling; Genes; Genetics of eukaryotes. Biological and molecular evolution; Humans; Hydroxysteroid Dehydrogenases - chemistry; Hydroxysteroid Dehydrogenases - genetics; Hydroxysteroid Dehydrogenases - metabolism; Male; Medical genetics; Medical sciences; Men; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Mutant Proteins - metabolism; Mutation; Mutation - genetics; Oxidoreductases - chemistry; Oxidoreductases - genetics; Oxidoreductases - metabolism; Pedigree; Sex Differentiation; Testis - embryology; Testis - metabolism; Human; Need; Androgen; Fetus; Genetics; Male; Biosynthesis; Testicle; Sexual differentiation; Child
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2011.06.009

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.