Alternative titles; symbols
HGNC Approved Gene Symbol: AKR1C4
Cytogenetic location: 10p15.1 Genomic coordinates (GRCh38): 10:5,196,837-5,218,949 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10p15.1 | {46XY sex reversal 8, modifier of} | 614279 | Autosomal recessive | 3 |
The best known 3-alpha-HSD activity is the transformation of the most potent natural androgen, dihydrotestosterone, into 5-alpha-androstan-3-alpha,17-beta-diol (3-alpha-diol), a compound having much lower activity (Dufort et al., 2001). Type I 3-alpha-hydroxysteroid dehydrogenase was first identified as chlordecone reductase (EC 1.1.1.225), an aldo-keto reductase that catalyzes the bioreduction of chlordecone to chlordecone alcohol in human liver (Molowa et al., 1986).
By screening a human liver expression library with antibodies against CDR, Winters et al. (1990) isolated CCDR12, a cDNA encoding CDR, and MCDR2 (AKR1C2; 600450), a cDNA encoding a related protein. The predicted human CDR protein shared 43% and 50% identity with human and rat aldehyde reductases (103880), respectively.
Qin et al. (1993) isolated cDNAs encoding 4 distinct human aldo-keto reductases, HAKRa (CDR), HAKRb (AKR1C3; 603966), HAKRc (AKR1C1; 600449), and HAKRd (AKR1C2). They noted that HAKRa and CDR are identical except that the HAKRa cDNA contains a much longer 5-prime-coding sequence. The predicted 323-amino acid HAKR proteins share more than 85% identity. Northern blot analysis revealed that HAKRa is expressed as a major 1.4-kb mRNA and a minor 3.5-kb mRNA in liver. The smaller transcript is also expressed in several other human tissues.
3-Alpha-hydroxysteroid dehydrogenase (3-alpha-HSD) catalyzes an NAD(P)-dependent reversible oxidation of the 3-alpha-hydroxy group of various steroids and functions in the metabolism of steroid hormones and bile acids. Dihydrodiol dehydrogenases (DD; EC 1.3.1.20) catalyze the NADP-linked oxidation of trans-dihydrodiols of aromatic hydrocarbons to the corresponding catechols, and are involved in the metabolism of xenobiotics. Deyashiki et al. (1994) isolated C11 and C9, cDNAs encoding 2 human liver dihydrodiol dehydrogenases (DDs) associated with 3-alpha-HSD activity. The C11 cDNA encodes chlordecone reductase, which they designated DD4. Hara et al. (1996) stated that the C9 cDNA encodes DD1 (AKR1C1).
Khanna et al. (1995) isolated 2 genes encoding dihydrodiol dehydrogenase, referred to as type I or DDH1, and type II or DDH2, as well as a gene for chlordecone reductase (CHDR). However, sequence analysis revealed that the type I gene of Khanna et al. (1995) corresponds to either AKR1C1 or AKR1C2, the type II gene matches AKR1C3 (HAKRb), and the CHDR gene matches AKR1C4 (White, 1999).
Fluck et al. (2011) performed quantitative RT-PCR expression profiling of AKR1C genes in normal fetal and adult testes and normal fetal and adult adrenal tissues. AKR1C4 was expressed in fetal and adult testes, and was abundant in fetal adrenals as well as present in adult adrenals.
By sequence analysis, Khanna et al. (1995) determined that the AKR1C4 and AKR1C3 genes contain 9 exons and span 15 to 20 kb. The sizes and boundaries of the 9 exons are identical in both genes.
By a combination of somatic cell hybrid analysis and fluorescence in situ hybridization, Khanna et al. (1995) mapped the AKR1C1, AKR1C4, and AKR1C3 genes to 10p15-p14.
Chlordecone (Kepone), a toxic organochlorine pesticide, undergoes bioreduction to chlordecone alcohol in human liver (Winters et al., 1990). This reaction is controlled by a cytosolic enzyme, chlordecone reductase (CDR), an aldo-keto reductase. Like other members of the aldo-keto reductase family, CDR is a monomeric enzyme that requires NADPH as a cofactor.
Khanna et al. (1995) reported that recombinant type I (HAKRa) and type II (HAKRb) human 3-alpha-HSD proteins exhibited both reductase and dehydrogenase activities. Using RT-PCR with gene-specific primers, Khanna et al. (1995) determined that the type I mRNA is expressed only in liver.
3-Alpha-HSDs are involved in the metabolism of glucocorticoids, progestins, prostaglandins, bile acid precursors, and xenobiotics. Human type III 3-alpha-HSD (AKR1C2) shares 81.7% amino acid sequence identity with type I 3-alpha-HSD (AKR1C4) (Dufort et al., 2001). By transfection of vectors expressing types I and III 3-alpha-HSD in transformed human embryonic kidney (HEK293) cells, Dufort et al. (2001) demonstrated that both enzymes efficiently catalyze the transformation of dihydrotestosterone into 3-alpha-diol in intact cells. RNA expression analysis indicated that human type I 3-alpha-HSD is expressed exclusively in the liver, whereas type 3 is more widely expressed and is found in the liver, adrenal, testis, brain, prostate, and keratinocytes. Based on enzymatic characteristics and sequence homology, the authors suggested that type I 3-alpha-HSD is an ortholog of rat 3-alpha-HSD, while type III 3-alpha-HSD, which must have diverged recently, seems unique to human and is probably more involved in intracrine activity.
In a Swiss family with 46,XY sex reversal (SRXY8; 614279) originally studied by Zachmann et al. (1972), Fluck et al. (2011) identified a splice site mutation in the AKR1C4 gene (600451.0001) that segregated with the AKR1C2 I79V mutation (600450.0001) in all cases. Two other mutations in the AKR1C2 gene (600450.0002-600450.0003) segregated in the family. Noting that the consequences of AKR1C2 mutations in this family were a sex-limited autosomal recessive trait, with all affected individuals having a 46,XY karyotype, Fluck et al. (2011) suggested a mode of inheritance in which the severity of the developmental defect depended on the number of mutations in the 2 genes. Because all of the mutations identified in this family retained partial activity, Fluck et al. (2011) stated that the relative importance of AKR1C2 and AKR1C4 was uncertain; however, the presence of mutations in AKR1C2 but not AKR1C4 in a second Swiss patient from an unrelated family (600450.0004) suggested that AKR1C2 mutation is sufficient for disease manifestation and that AKR1C2 might serve a more important role than AKR1C4 in this disorder of sexual development.
In a Swiss family with 46,XY sex reversal (SRXY8; 614279) originally studied by Zachmann et al. (1972), Fluck et al. (2011) identified a splice site mutation in the AKR1C4 gene that segregated with the AKR1C2 I79V mutation (600450.0001) in all cases. On the hypothesis that members of the AKR1C family besides AKR1C2 might also catalyze 3-alpha-HSD reactions and that microsatellite analysis could not distinguish these closely linked genes, Fluck et al. (2011) sequenced the 5 closely linked AKR1C genes on chromosome 10p15 and detected a splice site mutation in intron 1 106 bp upstream of exon 2 (c.85-106G-T) of the AKR1C4 gene that segregated with the AKR1C2 I79V mutation in all 5 individuals who carried it. An exon-trapping assay showed that the splice site mutation, which was not found in 50 controls, resulted in loss of exon 2 (c.85_252del), which was predicted to cause a configuration that would hinder binding of steroid substrates. Functional analysis in COS-1 cells demonstrated that the AKR1C4 mutant had only about 10% of wildtype activity.
Deyashiki, Y., Ogasawara, A., Nakayama, T., Nakanishi, M., Miyabe, Y., Sato, K., Hara, A. Molecular cloning of two human liver 3-alpha-hydroxysteroid/dihydrodiol dehydrogenase isoenzymes that are identical with chlordecone reductase and bile-acid binder. Biochem. J. 299: 545-552, 1994. [PubMed: 8172617] [Full Text: https://doi.org/10.1042/bj2990545]
Dufort, I., Labrie, F., Luu-The, V. Human types 1 and 3 3-alpha-hydroxysteroid dehydrogenases: differential lability and tissue distribution. J. Clin. Endocr. Metab. 86: 841-846, 2001. [PubMed: 11158055] [Full Text: https://doi.org/10.1210/jcem.86.2.7216]
Fluck, C. E., Meyer-Boni, M., Pandey, A. V., Kempna, P., Miller, W. L., Schoenle, E. J., Biason-Lauber, A. Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation. Am. J. Hum. Genet. 89: 201-218, 2011. Note: Erratum: Am. J. Hum. Genet. 89: 347 only, 2011. [PubMed: 21802064] [Full Text: https://doi.org/10.1016/j.ajhg.2011.06.009]
Hara, A., Matsuura, K., Tamada, Y., Sato, K., Miyabe, Y., Deyashiki, Y., Ishida, N. Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and oxidoreductase of human colon cells. Biochem. J. 313: 373-376, 1996. [PubMed: 8573067] [Full Text: https://doi.org/10.1042/bj3130373]
Khanna, M., Qin, K.-N., Klisak, I., Belkin, S., Sparkes, R. S., Cheng, K.-C. Localization of multiple human dihydrodiol dehydrogenase (DDH1 and DDH2) and chlordecone reductase (CHDR) genes in chromosome 10 by the polymerase chain reaction and fluorescence in situ hybridization. Genomics 25: 588-590, 1995. [PubMed: 7789999] [Full Text: https://doi.org/10.1016/0888-7543(95)80066-u]
Khanna, M., Qin, K.-N., Wang, R. W., Cheng, K.-C. Substrate specificity, gene structure, and tissue-specific distribution of multiple human 3-alpha-hydroxysteroid dehydrogenases. J. Biol. Chem. 270: 20162-20168, 1995. [PubMed: 7650035] [Full Text: https://doi.org/10.1074/jbc.270.34.20162]
Molowa, D. T., Shayne, A. G., Guzelian, P. S. Purification and characterization of chlordecone reductase from human liver. J. Biol. Chem. 261: 12624-12627, 1986. [PubMed: 2427522]
Qin, K.-N., New, M. I., Cheng, K.-C. Molecular cloning of multiple cDNAs encoding human enzymes structurally related to 3-alpha-hydroxysteroid dehydrogenase. J. Steroid Biochem. Molec. Biol. 46: 673-679, 1993. [PubMed: 8274401] [Full Text: https://doi.org/10.1016/0960-0760(93)90308-j]
White, J. Personal Communication. London, England 6/14/1999.
Winters, C. J., Molowa, D. T., Guzelian, P. S. Isolation and characterization of cloned cDNAs encoding human liver chlordecone reductase. Biochemistry 29: 1080-1087, 1990. [PubMed: 2187532] [Full Text: https://doi.org/10.1021/bi00456a034]
Zachmann, M., Vollmin, J. A., Hamilton, W., Prader, A. Steroid 17, 20-desmolase deficiency: a new cause of male pseudohermaphroditism. Clin. Endocr. 1: 369-385, 1972. [PubMed: 4352099] [Full Text: https://doi.org/10.1111/j.1365-2265.1972.tb00407.x]