Full text data of AKR1C2
AKR1C2
(DDH2)
[Confidence: low (only semi-automatic identification from reviews)]
Aldo-keto reductase family 1 member C2; 1.-.-.- (3-alpha-HSD3; Chlordecone reductase homolog HAKRD; Dihydrodiol dehydrogenase 2; DD-2; DD2; Dihydrodiol dehydrogenase/bile acid-binding protein; DD/BABP; Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase; 1.3.1.20; Type III 3-alpha-hydroxysteroid dehydrogenase; 1.1.1.357)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Aldo-keto reductase family 1 member C2; 1.-.-.- (3-alpha-HSD3; Chlordecone reductase homolog HAKRD; Dihydrodiol dehydrogenase 2; DD-2; DD2; Dihydrodiol dehydrogenase/bile acid-binding protein; DD/BABP; Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase; 1.3.1.20; Type III 3-alpha-hydroxysteroid dehydrogenase; 1.1.1.357)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P52895
ID AK1C2_HUMAN Reviewed; 323 AA.
AC P52895; A8K2N9; B4DKR9; Q14133; Q5SR16; Q7M4N1; Q96A71;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 10-MAY-2002, sequence version 3.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Aldo-keto reductase family 1 member C2;
DE EC=1.-.-.-;
DE AltName: Full=3-alpha-HSD3;
DE AltName: Full=Chlordecone reductase homolog HAKRD;
DE AltName: Full=Dihydrodiol dehydrogenase 2;
DE Short=DD-2;
DE Short=DD2;
DE AltName: Full=Dihydrodiol dehydrogenase/bile acid-binding protein;
DE Short=DD/BABP;
DE AltName: Full=Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase;
DE EC=1.3.1.20;
DE AltName: Full=Type III 3-alpha-hydroxysteroid dehydrogenase;
DE EC=1.1.1.357;
GN Name=AKR1C2; Synonyms=DDH2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=8274401; DOI=10.1016/0960-0760(93)90308-J;
RA Qin K.-N., New M.I., Cheng K.-C.;
RT "Molecular cloning of multiple cDNAs encoding human enzymes
RT structurally related to 3 alpha-hydroxysteroid dehydrogenase.";
RL J. Steroid Biochem. Mol. Biol. 46:673-679(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Colon;
RX PubMed=8011662; DOI=10.1016/0005-2728(94)90144-9;
RA Ciaccio P.J., Tew K.D.;
RT "cDNA and deduced amino acid sequences of a human colon dihydrodiol
RT dehydrogenase.";
RL Biochim. Biophys. Acta 1186:129-132(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), AND VARIANT TYR-46.
RX PubMed=7959017; DOI=10.1016/0378-1119(94)90176-7;
RA Qin K.-N., Khanna M., Cheng K.-C.;
RT "Structure of a gene coding for human dihydrodiol dehydrogenase/bile
RT acid-binding protein.";
RL Gene 149:357-361(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RC TISSUE=Prostate;
RX PubMed=8920937; DOI=10.1006/bbrc.1996.1684;
RA Dufort I., Soucy P., Labrie F., Luu-The V.;
RT "Molecular cloning of human type 3 3 alpha-hydroxysteroid
RT dehydrogenase that differs from 20 alpha-hydroxysteroid dehydrogenase
RT by seven amino acids.";
RL Biochem. Biophys. Res. Commun. 228:474-479(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=9716498;
RA Shiraishi H., Ishikura S., Matsuura K., Deyashiki Y., Ninomiya M.,
RA Sakai S., Hara A.;
RT "Sequence of the cDNA of a human dihydrodiol dehydrogenase isoform
RT (AKR1C2) and tissue distribution of its mRNA.";
RL Biochem. J. 334:399-405(1998).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=10672042; DOI=10.1046/j.1365-2443.2000.00310.x;
RA Nishizawa M., Nakajima T., Yasuda K., Kanzaki H., Sasaguri Y.,
RA Watanabe K., Ito S.;
RT "Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with
RT three aldo-keto reductase genes.";
RL Genes Cells 5:111-125(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung, and Urinary bladder;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 2-31; 40-62; 69-100; 105-131; 137-153; 162-206;
RP 209-231; 250-269 AND 271-323, FUNCTION, CATALYTIC ACTIVITY, ENZYME
RP REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=8573067;
RA Hara A., Matsuura K., Tamada Y., Sato K., Miyabe Y., Deyashiki Y.,
RA Ishida N.;
RT "Relationship of human liver dihydrodiol dehydrogenases to hepatic
RT bile-acid-binding protein and an oxidoreductase of human colon
RT cells.";
RL Biochem. J. 313:373-376(1996).
RN [12]
RP PROTEIN SEQUENCE OF 10-29; 40-55; 76-101; 105-128; 137-146; 162-197;
RP 208-223; 259-270 AND 305-322.
RC TISSUE=Liver;
RX PubMed=8486699;
RA Stolz A., Hammond L., Lou H., Takikawa H., Ronk M., Shively J.E.;
RT "cDNA cloning and expression of the human hepatic bile acid-binding
RT protein. A member of the monomeric reductase gene family.";
RL J. Biol. Chem. 268:10448-10457(1993).
RN [13]
RP TISSUE SPECIFICITY, VARIANTS SRXY8 VAL-79; GLN-90; GLN-222 AND
RP THR-300, AND CHARACTERIZATION OF VARIANTS SRXY8 VAL-79; GLN-90;
RP GLN-222 AND THR-300.
RX PubMed=21802064; DOI=10.1016/j.ajhg.2011.06.009;
RA Fluck C.E., Meyer-Boni M., Pandey A.V., Kempna P., Miller W.L.,
RA Schoenle E.J., Biason-Lauber A.;
RT "Why boys will be boys: two pathways of fetal testicular androgen
RT biosynthesis are needed for male sexual differentiation.";
RL Am. J. Hum. Genet. 89:201-218(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) IN COMPLEX WITH NADP AND
RP URSODEOXYCHOLATE.
RX PubMed=11513593; DOI=10.1021/bi010919a;
RA Jin Y., Stayrook S.E., Albert R.H., Palackal N.T., Penning T.M.,
RA Lewis M.;
RT "Crystal structure of human type III 3alpha-hydroxysteroid
RT dehydrogenase/bile acid binding protein complexed with NADP(+) and
RT ursodeoxycholate.";
RL Biochemistry 40:10161-10168(2001).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS) IN COMPLEX WITH NADP AND
RP TESTOSTERONE.
RX PubMed=11514561; DOI=10.1074/jbc.M105610200;
RA Nahoum V., Gangloff A., Legrand P., Zhu D.-W., Cantin L., Zhorov B.S.,
RA Luu-The V., Labrie F., Breton R., Lin S.X.;
RT "Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in
RT complex with testosterone and NADP at 1.25-A resolution.";
RL J. Biol. Chem. 276:42091-42098(2001).
CC -!- FUNCTION: Works in concert with the 5-alpha/5-beta-steroid
CC reductases to convert steroid hormones into the 3-alpha/5-alpha
CC and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation
CC of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha-
CC DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol).
CC Has a high bile-binding ability.
CC -!- CATALYTIC ACTIVITY: Trans-1,2-dihydrobenzene-1,2-diol + NADP(+) =
CC catechol + NADPH.
CC -!- CATALYTIC ACTIVITY: A 3-alpha-hydroxysteroid + NAD(P)(+) = a 3-
CC oxosteroid + NAD(P)H.
CC -!- ENZYME REGULATION: Inhibited by hexestrol with an IC(50) of 2.8
CC uM, 1,10-phenanthroline with an IC(50) of 2100 uM, 1,7-
CC phenanthroline with an IC(50) of 1500 uM, flufenamic acid with an
CC IC(50) of 0.9 uM, indomethacin with an IC(50) of 75 uM, ibuprofen
CC with an IC(50) of 6.9 uM, lithocholic acid with an IC(50) of 0.07
CC uM, ursodeoxycholic acid with an IC(50) of 0.08 uM and
CC chenodeoxycholic acid with an IC(50) of 0.13 uM.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=260 uM for (s)-tetralol;
CC KM=520 uM for (s)-indan-1-ol;
CC KM=5000 uM for benzene dihydrodiol;
CC KM=1 uM for 5-beta-pregnane-3-alpha,20-alpha-diol;
CC KM=208 uM for 9-alpha,11-beta-PGF2;
CC KM=0.3 uM for 5-beta-androstane-3,17-dione;
CC KM=79 uM for PGD2;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (Potential).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P52895-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P52895-2; Sequence=VSP_043779, VSP_043780;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in fetal testes. Expressed in fetal
CC and adult adrenal glands.
CC -!- DISEASE: 46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of
CC sex development. Affected individuals have a 46,XY karyotype but
CC present as phenotypically normal females. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family.
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DR EMBL; S68330; AAD14013.1; -; mRNA.
DR EMBL; U05598; AAA20937.1; -; mRNA.
DR EMBL; L32592; AAB38486.1; -; Genomic_DNA.
DR EMBL; AB021654; BAA36169.1; -; mRNA.
DR EMBL; AB031084; BAA92884.1; -; mRNA.
DR EMBL; AB032153; BAA92891.1; -; Genomic_DNA.
DR EMBL; AK290304; BAF82993.1; -; mRNA.
DR EMBL; AK296686; BAG59281.1; -; mRNA.
DR EMBL; BT006653; AAP35299.1; -; mRNA.
DR EMBL; AL713867; CAI16408.1; -; Genomic_DNA.
DR EMBL; AL391427; CAI16408.1; JOINED; Genomic_DNA.
DR EMBL; BC007024; AAH07024.1; -; mRNA.
DR EMBL; BC063574; AAH63574.1; -; mRNA.
DR PIR; I73676; I73676.
DR PIR; JC5240; JC5240.
DR PIR; S61516; S61516.
DR RefSeq; NP_001128713.1; NM_001135241.2.
DR RefSeq; NP_001345.1; NM_001354.5.
DR RefSeq; NP_995317.1; NM_205845.2.
DR RefSeq; XP_005276152.1; XM_005276095.1.
DR UniGene; Hs.460260; -.
DR UniGene; Hs.567256; -.
DR UniGene; Hs.734597; -.
DR PDB; 1IHI; X-ray; 3.00 A; A/B=1-323.
DR PDB; 1J96; X-ray; 1.25 A; A/B=2-323.
DR PDB; 1XJB; X-ray; 1.90 A; A/B=2-323.
DR PDB; 2HDJ; X-ray; 2.00 A; A/B=1-323.
DR PDB; 2IPJ; X-ray; 1.80 A; A/B=3-323.
DR PDBsum; 1IHI; -.
DR PDBsum; 1J96; -.
DR PDBsum; 1XJB; -.
DR PDBsum; 2HDJ; -.
DR PDBsum; 2IPJ; -.
DR ProteinModelPortal; P52895; -.
DR SMR; P52895; 2-323.
DR IntAct; P52895; 1.
DR STRING; 9606.ENSP00000370129; -.
DR BindingDB; P52895; -.
DR ChEMBL; CHEMBL5847; -.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB01586; Ursodeoxycholic acid.
DR PhosphoSite; P52895; -.
DR DMDM; 20532374; -.
DR PaxDb; P52895; -.
DR PRIDE; P52895; -.
DR DNASU; 1646; -.
DR Ensembl; ENST00000380753; ENSP00000370129; ENSG00000151632.
DR Ensembl; ENST00000407674; ENSP00000385221; ENSG00000151632.
DR Ensembl; ENST00000455190; ENSP00000408440; ENSG00000151632.
DR Ensembl; ENST00000580545; ENSP00000464045; ENSG00000265231.
DR GeneID; 101930400; -.
DR GeneID; 1646; -.
DR KEGG; hsa:1646; -.
DR UCSC; uc001ihs.3; human.
DR CTD; 1646; -.
DR GeneCards; GC10M005021; -.
DR HGNC; HGNC:385; AKR1C2.
DR HPA; CAB047304; -.
DR MIM; 600450; gene.
DR MIM; 614279; phenotype.
DR neXtProt; NX_P52895; -.
DR Orphanet; 90796; 46,XY disorder of sex development due to isolated 17, 20 lyase deficiency.
DR PharmGKB; PA24678; -.
DR eggNOG; COG0656; -.
DR HOGENOM; HOG000250272; -.
DR HOVERGEN; HBG000020; -.
DR InParanoid; P52895; -.
DR KO; K00089; -.
DR KO; K00212; -.
DR OMA; LWVQDMN; -.
DR PhylomeDB; P52895; -.
DR BioCyc; MetaCyc:HS07754-MONOMER; -.
DR BRENDA; 1.1.1.213; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P52895; -.
DR SignaLink; P52895; -.
DR EvolutionaryTrace; P52895; -.
DR GenomeRNAi; 1646; -.
DR NextBio; 6772; -.
DR PRO; PR:P52895; -.
DR ArrayExpress; P52895; -.
DR Bgee; P52895; -.
DR CleanEx; HS_AKR1C2; -.
DR Genevestigator; P52895; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0032052; F:bile acid binding; IDA:UniProtKB.
DR GO; GO:0047086; F:ketosteroid monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0016655; F:oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor; IDA:UniProtKB.
DR GO; GO:0018636; F:phenanthrene 9,10-monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0004958; F:prostaglandin F receptor activity; IDA:UniProtKB.
DR GO; GO:0047115; F:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0071395; P:cellular response to jasmonic acid stimulus; IDA:UniProtKB.
DR GO; GO:0044597; P:daunorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0007586; P:digestion; IDA:UniProtKB.
DR GO; GO:0044598; P:doxorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling cascade; IDA:UniProtKB.
DR GO; GO:0042448; P:progesterone metabolic process; IDA:UniProtKB.
DR GO; GO:0006693; P:prostaglandin metabolic process; IDA:UniProtKB.
DR GO; GO:0034694; P:response to prostaglandin stimulus; IDA:UniProtKB.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR001395; Aldo/ket_red.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR020471; Aldo/keto_reductase_subgr.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR PANTHER; PTHR11732; PTHR11732; 1.
DR Pfam; PF00248; Aldo_ket_red; 1.
DR PIRSF; PIRSF000097; AKR; 1.
DR PRINTS; PR00069; ALDKETRDTASE.
DR SUPFAM; SSF51430; SSF51430; 1.
DR PROSITE; PS00798; ALDOKETO_REDUCTASE_1; FALSE_NEG.
DR PROSITE; PS00062; ALDOKETO_REDUCTASE_2; 1.
DR PROSITE; PS00063; ALDOKETO_REDUCTASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Lipid metabolism; NADP;
KW Oxidoreductase; Polymorphism; Reference proteome; Steroid metabolism.
FT CHAIN 1 323 Aldo-keto reductase family 1 member C2.
FT /FTId=PRO_0000124637.
FT NP_BIND 216 280 NADP.
FT ACT_SITE 55 55 Proton donor.
FT BINDING 117 117 Substrate.
FT SITE 84 84 Lowers pKa of active site Tyr (By
FT similarity).
FT VAR_SEQ 124 139 PGEEVIPKDENGKILF -> EDIGILTWKKSPKHNS (in
FT isoform 2).
FT /FTId=VSP_043779.
FT VAR_SEQ 140 323 Missing (in isoform 2).
FT /FTId=VSP_043780.
FT VARIANT 46 46 F -> Y (in dbSNP:rs2854482).
FT /FTId=VAR_048216.
FT VARIANT 79 79 I -> V (in SRXY8; partially impaired
FT activity).
FT /FTId=VAR_066632.
FT VARIANT 90 90 H -> Q (in SRXY8; partially impaired
FT activity).
FT /FTId=VAR_066633.
FT VARIANT 172 172 L -> Q (in dbSNP:rs11474).
FT /FTId=VAR_014748.
FT VARIANT 222 222 H -> Q (in SRXY8; partially impaired
FT activity).
FT /FTId=VAR_066634.
FT VARIANT 300 300 N -> T (in SRXY8; partially impaired
FT activity).
FT /FTId=VAR_066635.
FT CONFLICT 76 76 R -> S (in Ref. 12; AA sequence).
FT CONFLICT 87 87 S -> C (in Ref. 12; AA sequence).
FT CONFLICT 93 93 E -> EE (in Ref. 12; AA sequence).
FT CONFLICT 111 111 V -> A (in Ref. 3; AAB38486).
FT CONFLICT 164 164 G -> R (in Ref. 7; BAF82993).
FT CONFLICT 179 179 K -> E (in Ref. 1; AAD14013 and 3;
FT AAB38486).
FT CONFLICT 185 185 K -> E (in Ref. 1; AAD14013 and 3;
FT AAB38486).
FT CONFLICT 188 188 C -> H (in Ref. 12; AA sequence).
FT CONFLICT 193 193 C -> H (in Ref. 12; AA sequence).
FT CONFLICT 319 319 F -> I (in Ref. 1; AAD14013 and 3;
FT AAB38486).
FT STRAND 7 9
FT STRAND 15 22
FT HELIX 32 44
FT STRAND 48 50
FT HELIX 53 55
FT HELIX 58 70
FT HELIX 76 78
FT STRAND 80 85
FT HELIX 87 89
FT HELIX 92 94
FT HELIX 95 106
FT STRAND 111 116
FT STRAND 119 122
FT STRAND 124 126
FT HELIX 144 156
FT STRAND 159 167
FT HELIX 170 177
FT STRAND 187 192
FT HELIX 200 208
FT STRAND 212 217
FT TURN 225 227
FT HELIX 235 237
FT HELIX 239 248
FT HELIX 252 262
FT STRAND 266 270
FT HELIX 274 280
FT HELIX 281 285
FT HELIX 290 297
FT HELIX 309 311
FT STRAND 318 321
SQ SEQUENCE 323 AA; 36735 MW; 0D7B6F983FCE85E1 CRC64;
MDSKYQCVKL NDGHFMPVLG FGTYAPAEVP KSKALEAVKL AIEAGFHHID SAHVYNNEEQ
VGLAIRSKIA DGSVKREDIF YTSKLWSNSH RPELVRPALE RSLKNLQLDY VDLYLIHFPV
SVKPGEEVIP KDENGKILFD TVDLCATWEA MEKCKDAGLA KSIGVSNFNH RLLEMILNKP
GLKYKPVCNQ VECHPYFNQR KLLDFCKSKD IVLVAYSALG SHREEPWVDP NSPVLLEDPV
LCALAKKHKR TPALIALRYQ LQRGVVVLAK SYNEQRIRQN VQVFEFQLTS EEMKAIDGLN
RNVRYLTLDI FAGPPNYPFS DEY
//
ID AK1C2_HUMAN Reviewed; 323 AA.
AC P52895; A8K2N9; B4DKR9; Q14133; Q5SR16; Q7M4N1; Q96A71;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 10-MAY-2002, sequence version 3.
DT 22-JAN-2014, entry version 141.
DE RecName: Full=Aldo-keto reductase family 1 member C2;
DE EC=1.-.-.-;
DE AltName: Full=3-alpha-HSD3;
DE AltName: Full=Chlordecone reductase homolog HAKRD;
DE AltName: Full=Dihydrodiol dehydrogenase 2;
DE Short=DD-2;
DE Short=DD2;
DE AltName: Full=Dihydrodiol dehydrogenase/bile acid-binding protein;
DE Short=DD/BABP;
DE AltName: Full=Trans-1,2-dihydrobenzene-1,2-diol dehydrogenase;
DE EC=1.3.1.20;
DE AltName: Full=Type III 3-alpha-hydroxysteroid dehydrogenase;
DE EC=1.1.1.357;
GN Name=AKR1C2; Synonyms=DDH2;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=8274401; DOI=10.1016/0960-0760(93)90308-J;
RA Qin K.-N., New M.I., Cheng K.-C.;
RT "Molecular cloning of multiple cDNAs encoding human enzymes
RT structurally related to 3 alpha-hydroxysteroid dehydrogenase.";
RL J. Steroid Biochem. Mol. Biol. 46:673-679(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Colon;
RX PubMed=8011662; DOI=10.1016/0005-2728(94)90144-9;
RA Ciaccio P.J., Tew K.D.;
RT "cDNA and deduced amino acid sequences of a human colon dihydrodiol
RT dehydrogenase.";
RL Biochim. Biophys. Acta 1186:129-132(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1), AND VARIANT TYR-46.
RX PubMed=7959017; DOI=10.1016/0378-1119(94)90176-7;
RA Qin K.-N., Khanna M., Cheng K.-C.;
RT "Structure of a gene coding for human dihydrodiol dehydrogenase/bile
RT acid-binding protein.";
RL Gene 149:357-361(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RC TISSUE=Prostate;
RX PubMed=8920937; DOI=10.1006/bbrc.1996.1684;
RA Dufort I., Soucy P., Labrie F., Luu-The V.;
RT "Molecular cloning of human type 3 3 alpha-hydroxysteroid
RT dehydrogenase that differs from 20 alpha-hydroxysteroid dehydrogenase
RT by seven amino acids.";
RL Biochem. Biophys. Res. Commun. 228:474-479(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=9716498;
RA Shiraishi H., Ishikura S., Matsuura K., Deyashiki Y., Ninomiya M.,
RA Sakai S., Hara A.;
RT "Sequence of the cDNA of a human dihydrodiol dehydrogenase isoform
RT (AKR1C2) and tissue distribution of its mRNA.";
RL Biochem. J. 334:399-405(1998).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
RC TISSUE=Liver;
RX PubMed=10672042; DOI=10.1046/j.1365-2443.2000.00310.x;
RA Nishizawa M., Nakajima T., Yasuda K., Kanzaki H., Sasaguri Y.,
RA Watanabe K., Ito S.;
RT "Close kinship of human 20alpha-hydroxysteroid dehydrogenase gene with
RT three aldo-keto reductase genes.";
RL Genes Cells 5:111-125(2000).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RA Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S.,
RA Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y.,
RA Phelan M., Farmer A.;
RT "Cloning of human full-length CDSs in BD Creator(TM) system donor
RT vector.";
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung, and Urinary bladder;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [11]
RP PROTEIN SEQUENCE OF 2-31; 40-62; 69-100; 105-131; 137-153; 162-206;
RP 209-231; 250-269 AND 271-323, FUNCTION, CATALYTIC ACTIVITY, ENZYME
RP REGULATION, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=8573067;
RA Hara A., Matsuura K., Tamada Y., Sato K., Miyabe Y., Deyashiki Y.,
RA Ishida N.;
RT "Relationship of human liver dihydrodiol dehydrogenases to hepatic
RT bile-acid-binding protein and an oxidoreductase of human colon
RT cells.";
RL Biochem. J. 313:373-376(1996).
RN [12]
RP PROTEIN SEQUENCE OF 10-29; 40-55; 76-101; 105-128; 137-146; 162-197;
RP 208-223; 259-270 AND 305-322.
RC TISSUE=Liver;
RX PubMed=8486699;
RA Stolz A., Hammond L., Lou H., Takikawa H., Ronk M., Shively J.E.;
RT "cDNA cloning and expression of the human hepatic bile acid-binding
RT protein. A member of the monomeric reductase gene family.";
RL J. Biol. Chem. 268:10448-10457(1993).
RN [13]
RP TISSUE SPECIFICITY, VARIANTS SRXY8 VAL-79; GLN-90; GLN-222 AND
RP THR-300, AND CHARACTERIZATION OF VARIANTS SRXY8 VAL-79; GLN-90;
RP GLN-222 AND THR-300.
RX PubMed=21802064; DOI=10.1016/j.ajhg.2011.06.009;
RA Fluck C.E., Meyer-Boni M., Pandey A.V., Kempna P., Miller W.L.,
RA Schoenle E.J., Biason-Lauber A.;
RT "Why boys will be boys: two pathways of fetal testicular androgen
RT biosynthesis are needed for male sexual differentiation.";
RL Am. J. Hum. Genet. 89:201-218(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (3.0 ANGSTROMS) IN COMPLEX WITH NADP AND
RP URSODEOXYCHOLATE.
RX PubMed=11513593; DOI=10.1021/bi010919a;
RA Jin Y., Stayrook S.E., Albert R.H., Palackal N.T., Penning T.M.,
RA Lewis M.;
RT "Crystal structure of human type III 3alpha-hydroxysteroid
RT dehydrogenase/bile acid binding protein complexed with NADP(+) and
RT ursodeoxycholate.";
RL Biochemistry 40:10161-10168(2001).
RN [15]
RP X-RAY CRYSTALLOGRAPHY (1.25 ANGSTROMS) IN COMPLEX WITH NADP AND
RP TESTOSTERONE.
RX PubMed=11514561; DOI=10.1074/jbc.M105610200;
RA Nahoum V., Gangloff A., Legrand P., Zhu D.-W., Cantin L., Zhorov B.S.,
RA Luu-The V., Labrie F., Breton R., Lin S.X.;
RT "Structure of the human 3alpha-hydroxysteroid dehydrogenase type 3 in
RT complex with testosterone and NADP at 1.25-A resolution.";
RL J. Biol. Chem. 276:42091-42098(2001).
CC -!- FUNCTION: Works in concert with the 5-alpha/5-beta-steroid
CC reductases to convert steroid hormones into the 3-alpha/5-alpha
CC and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation
CC of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha-
CC DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol).
CC Has a high bile-binding ability.
CC -!- CATALYTIC ACTIVITY: Trans-1,2-dihydrobenzene-1,2-diol + NADP(+) =
CC catechol + NADPH.
CC -!- CATALYTIC ACTIVITY: A 3-alpha-hydroxysteroid + NAD(P)(+) = a 3-
CC oxosteroid + NAD(P)H.
CC -!- ENZYME REGULATION: Inhibited by hexestrol with an IC(50) of 2.8
CC uM, 1,10-phenanthroline with an IC(50) of 2100 uM, 1,7-
CC phenanthroline with an IC(50) of 1500 uM, flufenamic acid with an
CC IC(50) of 0.9 uM, indomethacin with an IC(50) of 75 uM, ibuprofen
CC with an IC(50) of 6.9 uM, lithocholic acid with an IC(50) of 0.07
CC uM, ursodeoxycholic acid with an IC(50) of 0.08 uM and
CC chenodeoxycholic acid with an IC(50) of 0.13 uM.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=260 uM for (s)-tetralol;
CC KM=520 uM for (s)-indan-1-ol;
CC KM=5000 uM for benzene dihydrodiol;
CC KM=1 uM for 5-beta-pregnane-3-alpha,20-alpha-diol;
CC KM=208 uM for 9-alpha,11-beta-PGF2;
CC KM=0.3 uM for 5-beta-androstane-3,17-dione;
CC KM=79 uM for PGD2;
CC -!- SUBCELLULAR LOCATION: Cytoplasm (Potential).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P52895-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P52895-2; Sequence=VSP_043779, VSP_043780;
CC Note=No experimental confirmation available;
CC -!- TISSUE SPECIFICITY: Expressed in fetal testes. Expressed in fetal
CC and adult adrenal glands.
CC -!- DISEASE: 46,XY sex reversal 8 (SRXY8) [MIM:614279]: A disorder of
CC sex development. Affected individuals have a 46,XY karyotype but
CC present as phenotypically normal females. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the aldo/keto reductase family.
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DR EMBL; S68330; AAD14013.1; -; mRNA.
DR EMBL; U05598; AAA20937.1; -; mRNA.
DR EMBL; L32592; AAB38486.1; -; Genomic_DNA.
DR EMBL; AB021654; BAA36169.1; -; mRNA.
DR EMBL; AB031084; BAA92884.1; -; mRNA.
DR EMBL; AB032153; BAA92891.1; -; Genomic_DNA.
DR EMBL; AK290304; BAF82993.1; -; mRNA.
DR EMBL; AK296686; BAG59281.1; -; mRNA.
DR EMBL; BT006653; AAP35299.1; -; mRNA.
DR EMBL; AL713867; CAI16408.1; -; Genomic_DNA.
DR EMBL; AL391427; CAI16408.1; JOINED; Genomic_DNA.
DR EMBL; BC007024; AAH07024.1; -; mRNA.
DR EMBL; BC063574; AAH63574.1; -; mRNA.
DR PIR; I73676; I73676.
DR PIR; JC5240; JC5240.
DR PIR; S61516; S61516.
DR RefSeq; NP_001128713.1; NM_001135241.2.
DR RefSeq; NP_001345.1; NM_001354.5.
DR RefSeq; NP_995317.1; NM_205845.2.
DR RefSeq; XP_005276152.1; XM_005276095.1.
DR UniGene; Hs.460260; -.
DR UniGene; Hs.567256; -.
DR UniGene; Hs.734597; -.
DR PDB; 1IHI; X-ray; 3.00 A; A/B=1-323.
DR PDB; 1J96; X-ray; 1.25 A; A/B=2-323.
DR PDB; 1XJB; X-ray; 1.90 A; A/B=2-323.
DR PDB; 2HDJ; X-ray; 2.00 A; A/B=1-323.
DR PDB; 2IPJ; X-ray; 1.80 A; A/B=3-323.
DR PDBsum; 1IHI; -.
DR PDBsum; 1J96; -.
DR PDBsum; 1XJB; -.
DR PDBsum; 2HDJ; -.
DR PDBsum; 2IPJ; -.
DR ProteinModelPortal; P52895; -.
DR SMR; P52895; 2-323.
DR IntAct; P52895; 1.
DR STRING; 9606.ENSP00000370129; -.
DR BindingDB; P52895; -.
DR ChEMBL; CHEMBL5847; -.
DR DrugBank; DB00157; NADH.
DR DrugBank; DB01586; Ursodeoxycholic acid.
DR PhosphoSite; P52895; -.
DR DMDM; 20532374; -.
DR PaxDb; P52895; -.
DR PRIDE; P52895; -.
DR DNASU; 1646; -.
DR Ensembl; ENST00000380753; ENSP00000370129; ENSG00000151632.
DR Ensembl; ENST00000407674; ENSP00000385221; ENSG00000151632.
DR Ensembl; ENST00000455190; ENSP00000408440; ENSG00000151632.
DR Ensembl; ENST00000580545; ENSP00000464045; ENSG00000265231.
DR GeneID; 101930400; -.
DR GeneID; 1646; -.
DR KEGG; hsa:1646; -.
DR UCSC; uc001ihs.3; human.
DR CTD; 1646; -.
DR GeneCards; GC10M005021; -.
DR HGNC; HGNC:385; AKR1C2.
DR HPA; CAB047304; -.
DR MIM; 600450; gene.
DR MIM; 614279; phenotype.
DR neXtProt; NX_P52895; -.
DR Orphanet; 90796; 46,XY disorder of sex development due to isolated 17, 20 lyase deficiency.
DR PharmGKB; PA24678; -.
DR eggNOG; COG0656; -.
DR HOGENOM; HOG000250272; -.
DR HOVERGEN; HBG000020; -.
DR InParanoid; P52895; -.
DR KO; K00089; -.
DR KO; K00212; -.
DR OMA; LWVQDMN; -.
DR PhylomeDB; P52895; -.
DR BioCyc; MetaCyc:HS07754-MONOMER; -.
DR BRENDA; 1.1.1.213; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P52895; -.
DR SignaLink; P52895; -.
DR EvolutionaryTrace; P52895; -.
DR GenomeRNAi; 1646; -.
DR NextBio; 6772; -.
DR PRO; PR:P52895; -.
DR ArrayExpress; P52895; -.
DR Bgee; P52895; -.
DR CleanEx; HS_AKR1C2; -.
DR Genevestigator; P52895; -.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0004032; F:alditol:NADP+ 1-oxidoreductase activity; IDA:UniProtKB.
DR GO; GO:0032052; F:bile acid binding; IDA:UniProtKB.
DR GO; GO:0047086; F:ketosteroid monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0016655; F:oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor; IDA:UniProtKB.
DR GO; GO:0018636; F:phenanthrene 9,10-monooxygenase activity; IDA:UniProtKB.
DR GO; GO:0004958; F:prostaglandin F receptor activity; IDA:UniProtKB.
DR GO; GO:0047115; F:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0071395; P:cellular response to jasmonic acid stimulus; IDA:UniProtKB.
DR GO; GO:0044597; P:daunorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0007586; P:digestion; IDA:UniProtKB.
DR GO; GO:0044598; P:doxorubicin metabolic process; IMP:UniProtKB.
DR GO; GO:0008284; P:positive regulation of cell proliferation; IDA:UniProtKB.
DR GO; GO:0051897; P:positive regulation of protein kinase B signaling cascade; IDA:UniProtKB.
DR GO; GO:0042448; P:progesterone metabolic process; IDA:UniProtKB.
DR GO; GO:0006693; P:prostaglandin metabolic process; IDA:UniProtKB.
DR GO; GO:0034694; P:response to prostaglandin stimulus; IDA:UniProtKB.
DR Gene3D; 3.20.20.100; -; 1.
DR InterPro; IPR001395; Aldo/ket_red.
DR InterPro; IPR018170; Aldo/ket_reductase_CS.
DR InterPro; IPR020471; Aldo/keto_reductase_subgr.
DR InterPro; IPR023210; NADP_OxRdtase_dom.
DR PANTHER; PTHR11732; PTHR11732; 1.
DR Pfam; PF00248; Aldo_ket_red; 1.
DR PIRSF; PIRSF000097; AKR; 1.
DR PRINTS; PR00069; ALDKETRDTASE.
DR SUPFAM; SSF51430; SSF51430; 1.
DR PROSITE; PS00798; ALDOKETO_REDUCTASE_1; FALSE_NEG.
DR PROSITE; PS00062; ALDOKETO_REDUCTASE_2; 1.
DR PROSITE; PS00063; ALDOKETO_REDUCTASE_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Lipid metabolism; NADP;
KW Oxidoreductase; Polymorphism; Reference proteome; Steroid metabolism.
FT CHAIN 1 323 Aldo-keto reductase family 1 member C2.
FT /FTId=PRO_0000124637.
FT NP_BIND 216 280 NADP.
FT ACT_SITE 55 55 Proton donor.
FT BINDING 117 117 Substrate.
FT SITE 84 84 Lowers pKa of active site Tyr (By
FT similarity).
FT VAR_SEQ 124 139 PGEEVIPKDENGKILF -> EDIGILTWKKSPKHNS (in
FT isoform 2).
FT /FTId=VSP_043779.
FT VAR_SEQ 140 323 Missing (in isoform 2).
FT /FTId=VSP_043780.
FT VARIANT 46 46 F -> Y (in dbSNP:rs2854482).
FT /FTId=VAR_048216.
FT VARIANT 79 79 I -> V (in SRXY8; partially impaired
FT activity).
FT /FTId=VAR_066632.
FT VARIANT 90 90 H -> Q (in SRXY8; partially impaired
FT activity).
FT /FTId=VAR_066633.
FT VARIANT 172 172 L -> Q (in dbSNP:rs11474).
FT /FTId=VAR_014748.
FT VARIANT 222 222 H -> Q (in SRXY8; partially impaired
FT activity).
FT /FTId=VAR_066634.
FT VARIANT 300 300 N -> T (in SRXY8; partially impaired
FT activity).
FT /FTId=VAR_066635.
FT CONFLICT 76 76 R -> S (in Ref. 12; AA sequence).
FT CONFLICT 87 87 S -> C (in Ref. 12; AA sequence).
FT CONFLICT 93 93 E -> EE (in Ref. 12; AA sequence).
FT CONFLICT 111 111 V -> A (in Ref. 3; AAB38486).
FT CONFLICT 164 164 G -> R (in Ref. 7; BAF82993).
FT CONFLICT 179 179 K -> E (in Ref. 1; AAD14013 and 3;
FT AAB38486).
FT CONFLICT 185 185 K -> E (in Ref. 1; AAD14013 and 3;
FT AAB38486).
FT CONFLICT 188 188 C -> H (in Ref. 12; AA sequence).
FT CONFLICT 193 193 C -> H (in Ref. 12; AA sequence).
FT CONFLICT 319 319 F -> I (in Ref. 1; AAD14013 and 3;
FT AAB38486).
FT STRAND 7 9
FT STRAND 15 22
FT HELIX 32 44
FT STRAND 48 50
FT HELIX 53 55
FT HELIX 58 70
FT HELIX 76 78
FT STRAND 80 85
FT HELIX 87 89
FT HELIX 92 94
FT HELIX 95 106
FT STRAND 111 116
FT STRAND 119 122
FT STRAND 124 126
FT HELIX 144 156
FT STRAND 159 167
FT HELIX 170 177
FT STRAND 187 192
FT HELIX 200 208
FT STRAND 212 217
FT TURN 225 227
FT HELIX 235 237
FT HELIX 239 248
FT HELIX 252 262
FT STRAND 266 270
FT HELIX 274 280
FT HELIX 281 285
FT HELIX 290 297
FT HELIX 309 311
FT STRAND 318 321
SQ SEQUENCE 323 AA; 36735 MW; 0D7B6F983FCE85E1 CRC64;
MDSKYQCVKL NDGHFMPVLG FGTYAPAEVP KSKALEAVKL AIEAGFHHID SAHVYNNEEQ
VGLAIRSKIA DGSVKREDIF YTSKLWSNSH RPELVRPALE RSLKNLQLDY VDLYLIHFPV
SVKPGEEVIP KDENGKILFD TVDLCATWEA MEKCKDAGLA KSIGVSNFNH RLLEMILNKP
GLKYKPVCNQ VECHPYFNQR KLLDFCKSKD IVLVAYSALG SHREEPWVDP NSPVLLEDPV
LCALAKKHKR TPALIALRYQ LQRGVVVLAK SYNEQRIRQN VQVFEFQLTS EEMKAIDGLN
RNVRYLTLDI FAGPPNYPFS DEY
//
MIM
600450
*RECORD*
*FIELD* NO
600450
*FIELD* TI
*600450 ALDO-KETO REDUCTASE FAMILY 1, MEMBER C2; AKR1C2
;;DIHYDRODIOL DEHYDROGENASE, TYPE II; DDH2; DD2;;
read moreALDO-KETO REDUCTASE D; HAKRD;;
3-@ALPHA-HYDROXYSTEROID DEHYDROGENASE, TYPE III
*FIELD* TX
DESCRIPTION
Dihydrodiol dehydrogenase (DD; EC 1.3.1.20), a member of the aldo-oxo
reductase (AKR) superfamily, catalyzes the NADP-linked oxidation of
trans-dihydrodiols of aromatic hydrocarbons to corresponding catechols.
DD in mammalian liver has been implicated in the metabolism of
xenobiotic carbonyl compounds, steroids, and prostaglandins because of
its broad substrate specificity. Human liver contains 3 isoforms (DD1,
600449; DD2; and DD4, 600451) of DD with 20-alpha- or
3-alpha-hydroxysteroid dehydrogenase activity (Shiraishi et al. (1998)).
Dihydrotestosterone (DHT), the primary active androgen in peripheral
target tissues, is metabolized by 3-alpha-hydroxysteroid dehydrogenase
type III (3-alpha-HSD), encoded by the AKR1C2 gene, forming
5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol) (Steiner et al.,
2008).
CLONING
By screening a human liver expression library with an antibody against
rat 3-alpha-hydroxysteroid dehydrogenase (3-alpha-HSD), Qin et al.
(1993) isolated cDNAs encoding 4 distinct human aldo-keto reductases,
HAKRa (DD4), HAKRb (603966), HAKRc (DD1), and HAKRd (DD2). The predicted
323-amino acid HAKRc and HAKRd proteins are 95% identical. Northern blot
analysis revealed that both are expressed as 1.4-kb mRNAs in several
human tissues.
Bile acids perform a crucial role in the intestinal absorption of fats,
promotion of bile flow, and regulation of hepatic cholesterol
homeostasis. In rat liver, 3-alpha-HSD interacts extensively with bile
acids during their intercellular translocation and appears to be an
important determinant in net hepatic bile acid transport. Stolz et al.
(1993) identified HBAB (high affinity bile acid-binding protein), a
human liver dihydrodiol dehydrogenase that binds bile acid with high
affinity and has minimal 3-alpha-HSD activity. They suggested that HBAB
might function in mediating the transcellular cytosolic transport of
bile acids. By screening a human liver library with a rat 3-alpha-HSD
cDNA, they isolated a putative HBAB cDNA. The predicted protein shared
significant sequence homology with other members of the oxidoreductase
family, including human CHDR (DD4), bovine prostaglandin f synthetase,
and rat 3-alpha-HSD. However, the recombinant protein encoded by the
cDNA did not exhibit the high affinity bile acid binding of native HBAB.
Hara et al. (1996) determined that the HBAB cDNA isolated by Stolz et
al. (1993) encodes DD1, while native HBAB protein appears to correspond
to DD2. Hara et al. (1996) noted that while the DD1 and DD2 isozymes
share high sequence identity, they exhibit differences in their
substrate specificities for steroidal substrates, inhibitor
sensitivities, and ability to bind bile acids.
Ciaccio et al. (1994) identified H37, a human oxidoreductase that is
overexpressed in ethacrynic acid-resistant HT29 colon cells, as a DD.
They isolated a putative H37 cDNA, which they designated c32 or DDH, and
reported that c32 expression is inducible by Michael acceptor
xenobiotics. By screening an HT29 cell library with a segment of the
bovine lung prostaglandin f synthase gene, Ciaccio and Tew (1994)
isolated the c81 cDNA, which encoded an additional human DD. Hara et al.
(1996) stated that the c32 cDNA is identical to the DD1 (600449) cDNA,
even though the native H37 protein probably corresponds to DD2. Thus,
DD2, HBAB, and H37 may be the same protein, but the cDNAs previously
isolated as those for these proteins may encode DD1. The c81 cDNA
appears to encode the DD2/HBAB/H37 protein.
Shiraishi et al. (1998) isolated a DD2 cDNA and confirmed its identity
by comparing the properties of the recombinant and native hepatic
enzymes. They reported that the type three 3-alpha-HSD cDNA isolated by
Dufort et al. (1996), c81, and DD2 all encode an identical protein. The
predicted HAKRd and DD2 proteins differ at 3 positions, all of which are
outside the binding sites for substrates and coenzymes. In addition, the
sequence of the predicted DD2 protein is identical except at 1 position
to that deduced from the partial MCDR2 cDNA cloned by Winters et al.
(1990). RT-PCR of tissue samples from multiple individuals revealed only
1 mRNA species corresponding to the DD2 cDNA. Shiraishi et al. (1998)
suggested that the DD2 cDNA represents the principal AKR1C2 allele, and
that the other cDNA species might be derived from rare variants or from
sequencing errors. RT-PCR analysis indicated that DD2 is expressed in
various extrahepatic tissues. The authors proposed that DD2 is able to
act as the major 3-alpha-HSD in peripheral steroid-producing and
steroid-target tissues, where inhibitory bile acids are not present.
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 1 gene for chlordecone reductase (CHDR). However, sequence
analysis revealed that the type I gene of Khanna et al. (1995)
corresponded to either DD1 or DD2, the type II gene corresponded to
AKR1C4 (600451), and the CHDR gene corresponded to AKR1C3 (603966)
(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. AKR1C2 cDNA could be readily amplified from fetal
but not adult testes, whereas adult adrenals expressed markedly more
AKR1C2 than fetal adrenals.
MAPPING
By a combination of somatic cell hybrid analysis and fluorescence in
situ hybridization, Khanna et al. (1995) mapped the AKR1C2, AKR1C3, and
AKR1C4 genes to 10p15-p14.
GENE FUNCTION
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.
To study the role of 3-alpha-HSD in hirsutism, Steiner et al. (2008)
compared tissue levels of active androgens, relative gene expression of
AKR1C2, and activity of 3-alpha-HSD in genital skin from normal and
hirsute women. Tissue dihydrotestosterone (DHT) and testosterone (T)
concentrations in hirsute women were 1.90-fold and 1.84-fold higher than
in normal women, and relative expression of AKR1C2 mRNA was reduced
approximately 7-fold. Genital skin from hirsute women showed less
metabolism of DHT to 3-alpha-diol. Expression of AKR1C2, as measured by
mRNA production, was dramatically reduced in hirsute women. Steiner et
al. (2008) concluded that in hirsute women, reduced AKR1C2 gene
expression in skin results in reduced 3-alpha-HSD activity, decreased
DHT metabolism, and elevated tissue levels of DHT, and that diminished
DHT metabolism may play an important role in the pathogenesis of
hirsutism.
Using proteomics and mass spectrometric analysis, Leivonen et al. (2011)
identified 14-3-3-zeta (YWHAZ; 601288), SHMT2 (138450), and AKR1C2 as
major targets of microRNA-193B (MIR193B; 614734) in MCF-7 human breast
cancer cells. Cotransfection experiments confirmed that MIR193B
downregulated expression of reporter genes containing the 3-prime UTRs
of SHMT2 or YWHAZ or the 5-prime UTR of AKR1C2. Neutralization of
MIR193B with anti-MIR193B led to elevated SHMT2 and AKR1C2 protein
levels, with lesser upregulation of YWHAZ protein. Specific combinations
of knockdowns of these target genes via small interfering RNAs inhibited
growth in MCF-7 cells.
MOLECULAR GENETICS
In a Swiss family with 46,XY sex reversal (SRXY8; 614279) originally
studied by Zachmann et al. (1972), Fluck et al. (2011) excluded
mutations in candidate genes from the classic pathway of steroid
biosynthesis, e.g., CYP17A1 (609300), POR (124015), NR5A1 (184757), CYB5
(see 613218), and NR3C4 (AR; 313700). Subsequent analysis of AKR1C2, a
candidate gene from the alternative pathway for production of
dihydrotestosterone, revealed 3 different missense mutations mutations
segregating in the family (600450.0001-600450.0003). Fluck et al. (2011)
noted 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. Analysis of 4 closely linked AKR1C genes on
chromosome 10p15 revealed the presence of a splice site mutation in the
AKR1C4 gene (600451.0001) that segregated with the AKR1C2 I79V mutation
in all cases, suggesting a mode of inheritance in which the severity of
the developmental defect depended on the number of mutations in the 2
genes. In a 46,XY sex-reversed individual from an unrelated Swiss
family, Fluck et al. (2011) analyzed the AKR1C locus and identified a
complex rearrangement that resulted in the patient having a single
AKR1C1 (600449)/AKR1C2 hybrid on allele 1, and paternal AKR1C1, an
AKR1C1/AKR1C2 hybrid, and maternal AKR1C2 genes on allele 2. The intact
maternal AKR1C2 gene on allele 2 also carried a missense mutation
(H222Q; 600450.0004); no mutations were found in the paternal copy of
AKR1C1, the AKR1C1/AKR1C2 hybrids, or the AKR1C4 gene. Functional
studies demonstrated that the identified AKR1C2 mutations partially
impair the 3-alpha-HSD activity of AKR1C2, but not to the degree
typically associated with recessive disorders of steroidogenesis. Noting
that the AKR1C4 mutation identified in the first Swiss family also
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 the patient from the second Swiss
family 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.
*FIELD* AV
.0001
46,XY SEX REVERSAL 8
AKR1C2, ILE79VAL
In a Swiss family with 46,XY sex reversal (SRXY8; 614279) originally
studied by Zachmann et al. (1972), Fluck et al. (2011) identified 3
different missense mutations in the AKR1C2 gene: a 235A-G transition in
exon 5, resulting in an ile79-to-val (I79V) substitution; a 270T-G
transversion in exon 6, resulting in a his90-to-gln (H90Q; 600450.0002)
substitution; and an 899A-C transversion in exon 10, resulting in
asn300-to-thr (N300T; 600450.0003). None of the 3 mutations was found in
200 controls, and all 3 demonstrated reduced activity compared to
wildtype in functional assays. The maternal 46,XY aunt of the 2
originally studied affected male cousins was compound heterozygous for
the I79V and H90Q mutations, whereas 1 of the 2 male cousins was
heterozygous for I79V; the second male cousin declined genetic testing,
but his 46,XY sister was compound heterozygous for I79V and N300T, and a
phenotypically normal 46,XX sister carried the H90Q mutation. Fluck et
al. (2011) observed that all affected individuals had a 46,XY karyotype:
a 46,XX sister of the 46,XY aunt was compound heterozygous for the same
2 AKR1C2 mutations, I79V and H90Q, but was phenotypically normal and had
borne 3 children, and another phenotypically normal 46,XX sister was
heterozygous for the same I79V mutation in AKR1C2 carried by her
moderately affected son. The 46,XY phenotypically normal father of the 3
children also carried a heterozygous mutation in AKR1C2, N300T. Fluck et
al. (2011) also identified a splice site mutation in the AKR1C4 gene
(600451.0001) that segregated with the I79V mutation all cases. The
authors stated that their findings suggested a mode of inheritance in
which the severity of the developmental defect depended on the number of
mutations in the 2 genes in a given individual.
.0002
46,XY SEX REVERSAL 8
AKR1C2, HIS90GLN
See 600450.0001 and Fluck et al. (2011).
.0003
46,XY SEX REVERSAL 8
AKR1C2, ASN300THR
See 600450.0001 and Fluck et al. (2011).
.0004
46,XY SEX REVERSAL 8
AKR1C2, HIS222GLN
In a Swiss phenotypic female with 46,XY sex reversal (SRXY8; 614279),
Fluck et al. (2011) identified a complex rearrangement that resulted in
the patient having a single AKR1C1 (600449)/AKR1C2 hybrid on allele 1,
and paternal AKR1C1, an AKR1C1/AKR1C2 hybrid, and maternal AKR1C2 genes
on allele 2. The intact maternal AKR1C2 gene on allele 2 carried a
666T-G transversion in exon 9, resulting in a his222-to-gln (H222Q)
substitution. The mutation was not found in 200 controls, and functional
analysis demonstrated markedly reduced activity compared to wildtype.
*FIELD* RF
1. Ciaccio, P. J.; Jaiswal, A. K.; Tew, K. D.: Regulation of human
dihydrodiol dehydrogenase by Michael acceptor xenobiotics. J. Biol.
Chem. 269: 15558-15562, 1994.
2. Ciaccio, P. J.; Tew, K. D.: cDNA and deduced amino acid sequences
of a human colon dihydrodiol dehydrogenase. Biochim. Biophys. Acta 1186:
129-132, 1994.
3. 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.
4. Dufort, I.; Soucy, P.; Labrie, F.; Luu-The, V.: Molecular cloning
of human type 3 3-alpha-hydroxysteroid dehydrogenase that differs
from 20-alpha-hydroxysteroid dehydrogenase by seven amino acids. Biochem.
Biophys. Res. Commun. 228: 474-479, 1996.
5. 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.
6. 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.
7. 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. Gen
omics 25: 588-590, 1995.
8. Leivonen, S.-K.; Rokka, A.; Ostling, P.; Kohonen, P.; Corthals,
G. L.; Kallioniemi, O.; Perala, M.: Identification of miR-193b targets
in breast cancer cells and systems biological analysis of their functional
impact. Molec. Cell. Proteomics 10: 1Nov, 2011. Note: Electronic
Article.
9. 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.
10. Shiraishi, H.; Ishikura, S.; Matsuura, K.; Deyashiki, Y.; Ninomiya,
M.; Sakai, S.; Hara, A.: Sequence of the cDNA of a human dihydrodiol
dehydrogenase isoform (AKR1C2) and tissue distribution of its mRNA. Biochem.
J. 334: 399-405, 1998.
11. Steiner, A. Z.; Chang, L.; Ji, Q.; Ookhtens, M.; Stolz, A.; Paulson,
R. J.; Stanczyk, F. Z.: 3-alpha-hydroxysteroid dehydrogenase type
III deficiency: a novel mechanism for hirsutism. J. Clin. Endocr.
Metab. 93: 1298-1303, 2008.
12. Stolz, A.; Hammond, L.; Lou, H.; Takikawa, H.; Ronk, M.; Shively,
J. E.: cDNA cloning and expression of the human hepatic bile acid-binding
protein: a member of the monomeric reductase gene family. J. Biol.
Chem. 268: 10448-10457, 1993.
13. White, J.: Personal Communication. London, England 6/14/1999.
14. 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.
15. 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.
*FIELD* CN
Patricia A. Hartz - updated: 07/20/2012
Marla J. F. O'Neill - updated: 9/27/2011
John A. Phillips, III - updated: 1/15/2009
John A. Phillips, III - updated: 7/25/2001
Rebekah S. Rasooly - updated: 7/8/1999
*FIELD* CD
Victor A. McKusick: 3/9/1995
*FIELD* ED
mgross: 07/20/2012
alopez: 10/6/2011
terry: 9/27/2011
alopez: 1/15/2009
tkritzer: 3/3/2003
alopez: 7/25/2001
alopez: 7/8/1999
mark: 3/24/1995
carol: 3/10/1995
carol: 3/9/1995
*RECORD*
*FIELD* NO
600450
*FIELD* TI
*600450 ALDO-KETO REDUCTASE FAMILY 1, MEMBER C2; AKR1C2
;;DIHYDRODIOL DEHYDROGENASE, TYPE II; DDH2; DD2;;
read moreALDO-KETO REDUCTASE D; HAKRD;;
3-@ALPHA-HYDROXYSTEROID DEHYDROGENASE, TYPE III
*FIELD* TX
DESCRIPTION
Dihydrodiol dehydrogenase (DD; EC 1.3.1.20), a member of the aldo-oxo
reductase (AKR) superfamily, catalyzes the NADP-linked oxidation of
trans-dihydrodiols of aromatic hydrocarbons to corresponding catechols.
DD in mammalian liver has been implicated in the metabolism of
xenobiotic carbonyl compounds, steroids, and prostaglandins because of
its broad substrate specificity. Human liver contains 3 isoforms (DD1,
600449; DD2; and DD4, 600451) of DD with 20-alpha- or
3-alpha-hydroxysteroid dehydrogenase activity (Shiraishi et al. (1998)).
Dihydrotestosterone (DHT), the primary active androgen in peripheral
target tissues, is metabolized by 3-alpha-hydroxysteroid dehydrogenase
type III (3-alpha-HSD), encoded by the AKR1C2 gene, forming
5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol) (Steiner et al.,
2008).
CLONING
By screening a human liver expression library with an antibody against
rat 3-alpha-hydroxysteroid dehydrogenase (3-alpha-HSD), Qin et al.
(1993) isolated cDNAs encoding 4 distinct human aldo-keto reductases,
HAKRa (DD4), HAKRb (603966), HAKRc (DD1), and HAKRd (DD2). The predicted
323-amino acid HAKRc and HAKRd proteins are 95% identical. Northern blot
analysis revealed that both are expressed as 1.4-kb mRNAs in several
human tissues.
Bile acids perform a crucial role in the intestinal absorption of fats,
promotion of bile flow, and regulation of hepatic cholesterol
homeostasis. In rat liver, 3-alpha-HSD interacts extensively with bile
acids during their intercellular translocation and appears to be an
important determinant in net hepatic bile acid transport. Stolz et al.
(1993) identified HBAB (high affinity bile acid-binding protein), a
human liver dihydrodiol dehydrogenase that binds bile acid with high
affinity and has minimal 3-alpha-HSD activity. They suggested that HBAB
might function in mediating the transcellular cytosolic transport of
bile acids. By screening a human liver library with a rat 3-alpha-HSD
cDNA, they isolated a putative HBAB cDNA. The predicted protein shared
significant sequence homology with other members of the oxidoreductase
family, including human CHDR (DD4), bovine prostaglandin f synthetase,
and rat 3-alpha-HSD. However, the recombinant protein encoded by the
cDNA did not exhibit the high affinity bile acid binding of native HBAB.
Hara et al. (1996) determined that the HBAB cDNA isolated by Stolz et
al. (1993) encodes DD1, while native HBAB protein appears to correspond
to DD2. Hara et al. (1996) noted that while the DD1 and DD2 isozymes
share high sequence identity, they exhibit differences in their
substrate specificities for steroidal substrates, inhibitor
sensitivities, and ability to bind bile acids.
Ciaccio et al. (1994) identified H37, a human oxidoreductase that is
overexpressed in ethacrynic acid-resistant HT29 colon cells, as a DD.
They isolated a putative H37 cDNA, which they designated c32 or DDH, and
reported that c32 expression is inducible by Michael acceptor
xenobiotics. By screening an HT29 cell library with a segment of the
bovine lung prostaglandin f synthase gene, Ciaccio and Tew (1994)
isolated the c81 cDNA, which encoded an additional human DD. Hara et al.
(1996) stated that the c32 cDNA is identical to the DD1 (600449) cDNA,
even though the native H37 protein probably corresponds to DD2. Thus,
DD2, HBAB, and H37 may be the same protein, but the cDNAs previously
isolated as those for these proteins may encode DD1. The c81 cDNA
appears to encode the DD2/HBAB/H37 protein.
Shiraishi et al. (1998) isolated a DD2 cDNA and confirmed its identity
by comparing the properties of the recombinant and native hepatic
enzymes. They reported that the type three 3-alpha-HSD cDNA isolated by
Dufort et al. (1996), c81, and DD2 all encode an identical protein. The
predicted HAKRd and DD2 proteins differ at 3 positions, all of which are
outside the binding sites for substrates and coenzymes. In addition, the
sequence of the predicted DD2 protein is identical except at 1 position
to that deduced from the partial MCDR2 cDNA cloned by Winters et al.
(1990). RT-PCR of tissue samples from multiple individuals revealed only
1 mRNA species corresponding to the DD2 cDNA. Shiraishi et al. (1998)
suggested that the DD2 cDNA represents the principal AKR1C2 allele, and
that the other cDNA species might be derived from rare variants or from
sequencing errors. RT-PCR analysis indicated that DD2 is expressed in
various extrahepatic tissues. The authors proposed that DD2 is able to
act as the major 3-alpha-HSD in peripheral steroid-producing and
steroid-target tissues, where inhibitory bile acids are not present.
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 1 gene for chlordecone reductase (CHDR). However, sequence
analysis revealed that the type I gene of Khanna et al. (1995)
corresponded to either DD1 or DD2, the type II gene corresponded to
AKR1C4 (600451), and the CHDR gene corresponded to AKR1C3 (603966)
(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. AKR1C2 cDNA could be readily amplified from fetal
but not adult testes, whereas adult adrenals expressed markedly more
AKR1C2 than fetal adrenals.
MAPPING
By a combination of somatic cell hybrid analysis and fluorescence in
situ hybridization, Khanna et al. (1995) mapped the AKR1C2, AKR1C3, and
AKR1C4 genes to 10p15-p14.
GENE FUNCTION
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.
To study the role of 3-alpha-HSD in hirsutism, Steiner et al. (2008)
compared tissue levels of active androgens, relative gene expression of
AKR1C2, and activity of 3-alpha-HSD in genital skin from normal and
hirsute women. Tissue dihydrotestosterone (DHT) and testosterone (T)
concentrations in hirsute women were 1.90-fold and 1.84-fold higher than
in normal women, and relative expression of AKR1C2 mRNA was reduced
approximately 7-fold. Genital skin from hirsute women showed less
metabolism of DHT to 3-alpha-diol. Expression of AKR1C2, as measured by
mRNA production, was dramatically reduced in hirsute women. Steiner et
al. (2008) concluded that in hirsute women, reduced AKR1C2 gene
expression in skin results in reduced 3-alpha-HSD activity, decreased
DHT metabolism, and elevated tissue levels of DHT, and that diminished
DHT metabolism may play an important role in the pathogenesis of
hirsutism.
Using proteomics and mass spectrometric analysis, Leivonen et al. (2011)
identified 14-3-3-zeta (YWHAZ; 601288), SHMT2 (138450), and AKR1C2 as
major targets of microRNA-193B (MIR193B; 614734) in MCF-7 human breast
cancer cells. Cotransfection experiments confirmed that MIR193B
downregulated expression of reporter genes containing the 3-prime UTRs
of SHMT2 or YWHAZ or the 5-prime UTR of AKR1C2. Neutralization of
MIR193B with anti-MIR193B led to elevated SHMT2 and AKR1C2 protein
levels, with lesser upregulation of YWHAZ protein. Specific combinations
of knockdowns of these target genes via small interfering RNAs inhibited
growth in MCF-7 cells.
MOLECULAR GENETICS
In a Swiss family with 46,XY sex reversal (SRXY8; 614279) originally
studied by Zachmann et al. (1972), Fluck et al. (2011) excluded
mutations in candidate genes from the classic pathway of steroid
biosynthesis, e.g., CYP17A1 (609300), POR (124015), NR5A1 (184757), CYB5
(see 613218), and NR3C4 (AR; 313700). Subsequent analysis of AKR1C2, a
candidate gene from the alternative pathway for production of
dihydrotestosterone, revealed 3 different missense mutations mutations
segregating in the family (600450.0001-600450.0003). Fluck et al. (2011)
noted 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. Analysis of 4 closely linked AKR1C genes on
chromosome 10p15 revealed the presence of a splice site mutation in the
AKR1C4 gene (600451.0001) that segregated with the AKR1C2 I79V mutation
in all cases, suggesting a mode of inheritance in which the severity of
the developmental defect depended on the number of mutations in the 2
genes. In a 46,XY sex-reversed individual from an unrelated Swiss
family, Fluck et al. (2011) analyzed the AKR1C locus and identified a
complex rearrangement that resulted in the patient having a single
AKR1C1 (600449)/AKR1C2 hybrid on allele 1, and paternal AKR1C1, an
AKR1C1/AKR1C2 hybrid, and maternal AKR1C2 genes on allele 2. The intact
maternal AKR1C2 gene on allele 2 also carried a missense mutation
(H222Q; 600450.0004); no mutations were found in the paternal copy of
AKR1C1, the AKR1C1/AKR1C2 hybrids, or the AKR1C4 gene. Functional
studies demonstrated that the identified AKR1C2 mutations partially
impair the 3-alpha-HSD activity of AKR1C2, but not to the degree
typically associated with recessive disorders of steroidogenesis. Noting
that the AKR1C4 mutation identified in the first Swiss family also
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 the patient from the second Swiss
family 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.
*FIELD* AV
.0001
46,XY SEX REVERSAL 8
AKR1C2, ILE79VAL
In a Swiss family with 46,XY sex reversal (SRXY8; 614279) originally
studied by Zachmann et al. (1972), Fluck et al. (2011) identified 3
different missense mutations in the AKR1C2 gene: a 235A-G transition in
exon 5, resulting in an ile79-to-val (I79V) substitution; a 270T-G
transversion in exon 6, resulting in a his90-to-gln (H90Q; 600450.0002)
substitution; and an 899A-C transversion in exon 10, resulting in
asn300-to-thr (N300T; 600450.0003). None of the 3 mutations was found in
200 controls, and all 3 demonstrated reduced activity compared to
wildtype in functional assays. The maternal 46,XY aunt of the 2
originally studied affected male cousins was compound heterozygous for
the I79V and H90Q mutations, whereas 1 of the 2 male cousins was
heterozygous for I79V; the second male cousin declined genetic testing,
but his 46,XY sister was compound heterozygous for I79V and N300T, and a
phenotypically normal 46,XX sister carried the H90Q mutation. Fluck et
al. (2011) observed that all affected individuals had a 46,XY karyotype:
a 46,XX sister of the 46,XY aunt was compound heterozygous for the same
2 AKR1C2 mutations, I79V and H90Q, but was phenotypically normal and had
borne 3 children, and another phenotypically normal 46,XX sister was
heterozygous for the same I79V mutation in AKR1C2 carried by her
moderately affected son. The 46,XY phenotypically normal father of the 3
children also carried a heterozygous mutation in AKR1C2, N300T. Fluck et
al. (2011) also identified a splice site mutation in the AKR1C4 gene
(600451.0001) that segregated with the I79V mutation all cases. The
authors stated that their findings suggested a mode of inheritance in
which the severity of the developmental defect depended on the number of
mutations in the 2 genes in a given individual.
.0002
46,XY SEX REVERSAL 8
AKR1C2, HIS90GLN
See 600450.0001 and Fluck et al. (2011).
.0003
46,XY SEX REVERSAL 8
AKR1C2, ASN300THR
See 600450.0001 and Fluck et al. (2011).
.0004
46,XY SEX REVERSAL 8
AKR1C2, HIS222GLN
In a Swiss phenotypic female with 46,XY sex reversal (SRXY8; 614279),
Fluck et al. (2011) identified a complex rearrangement that resulted in
the patient having a single AKR1C1 (600449)/AKR1C2 hybrid on allele 1,
and paternal AKR1C1, an AKR1C1/AKR1C2 hybrid, and maternal AKR1C2 genes
on allele 2. The intact maternal AKR1C2 gene on allele 2 carried a
666T-G transversion in exon 9, resulting in a his222-to-gln (H222Q)
substitution. The mutation was not found in 200 controls, and functional
analysis demonstrated markedly reduced activity compared to wildtype.
*FIELD* RF
1. Ciaccio, P. J.; Jaiswal, A. K.; Tew, K. D.: Regulation of human
dihydrodiol dehydrogenase by Michael acceptor xenobiotics. J. Biol.
Chem. 269: 15558-15562, 1994.
2. Ciaccio, P. J.; Tew, K. D.: cDNA and deduced amino acid sequences
of a human colon dihydrodiol dehydrogenase. Biochim. Biophys. Acta 1186:
129-132, 1994.
3. 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.
4. Dufort, I.; Soucy, P.; Labrie, F.; Luu-The, V.: Molecular cloning
of human type 3 3-alpha-hydroxysteroid dehydrogenase that differs
from 20-alpha-hydroxysteroid dehydrogenase by seven amino acids. Biochem.
Biophys. Res. Commun. 228: 474-479, 1996.
5. 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.
6. 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.
7. 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. Gen
omics 25: 588-590, 1995.
8. Leivonen, S.-K.; Rokka, A.; Ostling, P.; Kohonen, P.; Corthals,
G. L.; Kallioniemi, O.; Perala, M.: Identification of miR-193b targets
in breast cancer cells and systems biological analysis of their functional
impact. Molec. Cell. Proteomics 10: 1Nov, 2011. Note: Electronic
Article.
9. 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.
10. Shiraishi, H.; Ishikura, S.; Matsuura, K.; Deyashiki, Y.; Ninomiya,
M.; Sakai, S.; Hara, A.: Sequence of the cDNA of a human dihydrodiol
dehydrogenase isoform (AKR1C2) and tissue distribution of its mRNA. Biochem.
J. 334: 399-405, 1998.
11. Steiner, A. Z.; Chang, L.; Ji, Q.; Ookhtens, M.; Stolz, A.; Paulson,
R. J.; Stanczyk, F. Z.: 3-alpha-hydroxysteroid dehydrogenase type
III deficiency: a novel mechanism for hirsutism. J. Clin. Endocr.
Metab. 93: 1298-1303, 2008.
12. Stolz, A.; Hammond, L.; Lou, H.; Takikawa, H.; Ronk, M.; Shively,
J. E.: cDNA cloning and expression of the human hepatic bile acid-binding
protein: a member of the monomeric reductase gene family. J. Biol.
Chem. 268: 10448-10457, 1993.
13. White, J.: Personal Communication. London, England 6/14/1999.
14. 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.
15. 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.
*FIELD* CN
Patricia A. Hartz - updated: 07/20/2012
Marla J. F. O'Neill - updated: 9/27/2011
John A. Phillips, III - updated: 1/15/2009
John A. Phillips, III - updated: 7/25/2001
Rebekah S. Rasooly - updated: 7/8/1999
*FIELD* CD
Victor A. McKusick: 3/9/1995
*FIELD* ED
mgross: 07/20/2012
alopez: 10/6/2011
terry: 9/27/2011
alopez: 1/15/2009
tkritzer: 3/3/2003
alopez: 7/25/2001
alopez: 7/8/1999
mark: 3/24/1995
carol: 3/10/1995
carol: 3/9/1995
MIM
614279
*RECORD*
*FIELD* NO
614279
*FIELD* TI
#614279 46,XY SEX REVERSAL 8; SRXY8
;;MALE PSEUDOHERMAPHRODITISM DUE TO DEFICIENCY OF TESTICULAR 17,20-DESMOLASE;
read moreTDD
*FIELD* TX
A number sign (#) is used with this entry because of evidence that 46,XY
sex reversal can be caused by mutation in the AKR1C2 gene (600450) on
chromosome 10p15. A mutation in the closely linked AKR1C4 gene (600451)
that segregates with mutation in the AKR1C2 gene may contribute to the
phenotype.
For a discussion of genetic heterogeneity of 46,XY sex reversal, see
SRXY1 (400044).
CLINICAL FEATURES
Zachmann et al. (1972) studied 2 male cousins, karyotype 46,XY, who were
the sons of sisters and who had ambiguous genitalia and cryptorchidism.
One of the boys had 2 older sibs who were phenotypic females. A 46,XY
maternal 'aunt,' who was raised as a female, underwent evaluation at 18
years of age due to primary amenorrhea, at which time she had Prader
type II external genitalia and sparse pubic hair. At laparotomy, a
rudimentary uterus-like structure consisting only of a cervical canal
was found; a right inguinal gonad and left intraabdominal gonad were
removed, and histologic examination confirmed testicular and epididymal
tissue with interstitial cells but no spermatogonia. Based on evidence
from steroid studies using incubated testicular tissue from 1 of the
boys, as well as urinary steroid results from the 3 affected
individuals, Zachmann et al. (1972) concluded that all 3 patients
suffered from the same testicular and adrenal steroid 17,20-desmolase
deficiency, resulting in a defect of androgen biosynthesis.
Fluck et al. (2011) provided follow-up on the Swiss family with
ambiguous genitalia originally studied by Zachmann et al. (1972).
Examination of the 2 older sibs of 1 affected boy, who were phenotypic
females, revealed that whereas 1 sib was 46,XX with normal female
external genitalia and a sonographically detectable uterus, the other
was 46,XY, with normal female external genitalia but no uterus, and
steroidal responses to chorionic gonadotropin (see 118860) and
corticotropin that were similar to those of the previously studied male
cousins. No family members had signs or steroidal findings of adrenal
insufficiency (see 300200); the family declined any further hormonal
testing. Fluck et al. (2011) also studied a patient from an unrelated
Swiss family who was diagnosed with 46,XY disordered sexual development
(DSD) during surgery for bilateral inguinal hernias at 7 weeks of age,
at which time normal-appearing testes were found in the completely
feminized infant, with no evidence of mullerian structures. Laparascopic
gonadectomy was performed at 2 years of age. No hormonal assessment was
done.
INHERITANCE
In a Swiss family with 2 affected male cousins and an affected 46,XY
maternal aunt, Zachmann et al. (1972) stated that the inheritance
appeared to be autosomal dominant or X-linked recessive.
Fluck et al. (2011) restudied the Swiss family with 46,XY sex reversal
originally reported by Zachmann et al. (1972) and characterized the
inheritance pattern as sex-linked autosomal recessive trait.
MOLECULAR GENETICS
In the Swiss family with 46,XY sex reversal originally studied by
Zachmann et al. (1972), Fluck et al. (2011) excluded mutations in
candidate genes from the classic pathway of steroid biosynthesis, e.g.,
CYP17A1 (609300), POR (124015), NR5A1 (184757), CYB5 (see 613218), and
NR3C4 (AR; 313700). Subsequent analysis of a candidate gene from the
alternative pathway for production of dihydrotestosterone, AKR1C2
(600450), revealed 3 different missense mutations segregating in the
family (600450.0001-600450.0003). Fluck et al. (2011) noted 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, consistent with androgens playing no essential role in female
sexual development. Analysis of 5 closely linked AKR1C genes on
chromosome 10p15 revealed the presence of a splice site mutation in the
AKR1C4 gene (600451.0001) that segregated with the AKR1C2 I79V mutation
in all cases, suggesting a mode of inheritance in which the severity of
the developmental defect depended on the number of mutations in the 2
genes. In a 46,XY sex-reversed individual from an unrelated Swiss
family, Fluck et al. (2011) analyzed the AKR1C locus and identified a
complex rearrangement that resulted in the patient having a single
AKR1C1 (600449)/AKR1C2 hybrid on allele 1, and paternal AKR1C1, an
AKR1C1/AKR1C2 hybrid, and maternal AKR1C2 genes on allele 2. The intact
maternal AKR1C2 gene on allele 2 also carried a missense mutation
(H222Q; 600450.0004); no mutations were found in the paternal copy of
AKR1C1, the AKR1C1/AKR1C2 hybrids, or the AKR1C4 gene. Functional
studies demonstrated that the identified AKR1C2 mutations partially
impair the 3-alpha-HSD activity of AKR1C2, but not to the degree
typically associated with recessive disorders of steroidogenesis. Noting
that the AKR1C4 mutation identified in the first Swiss family also
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 the patient from the second Swiss
family 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.
*FIELD* SA
Goebelsmann et al. (1976); Zachmann et al. (1971)
*FIELD* RF
1. 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.
2. Goebelsmann, U.; Zachmann, M.; Davajan, V.; Israel, R.; Mestman,
J. H.; Mishell, D. R.: Male pseudohermaphroditism consistent with
17,20-desmolase deficiency. Gynec. Invest. 7: 138-156, 1976.
3. Zachmann, M.; Hamilton, W.; Vollmin, J. A.; Prader, A.: Testicular
17, 20-desmolase deficiency causing male pseudohermaphroditism. Acta
Endocr. 155 (suppl.): 65-80, 1971.
4. 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.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[External genitalia, male];
Ambiguous external genitalia;
[Internal genitalia, male];
Testicular tissue able to convert dihydroepiandrosterone and androstenedione
to testosterone;
Cryptorchidism;
[Internal genitalia, female];
Rudimentary mullerian structures (rare)
ENDOCRINE FEATURES:
Undervirilization;
Elevated urinary gonadotropins;
Low urinary estrogens;
Urinary 17-oxosteroids normal;
Urinary 17-hydroxycorticoids normal;
Baseline pregnanediol and pregnanetriol normal;
Pregnanetriolone (Ptl) present in urine;
Absent dehydroepiandrosterone-sulphate, even after ACTH stimulation;
No increase in testosterone after HCG or ACTH stimulation;
Absent or minimal increase in pregnanetriol after HCG stimulation;
Marked increase in pregnanetriolone after HCG or ACTH stimulation;
Increase in pregnanediol and pregnanetriol after ACTH stimulation;
Minimal testosterone yielded by progesterone and pregnenolone or their
respective 17-alpha-hydroxylates
MISCELLANEOUS:
Only 46,XY individuals are affected
MOLECULAR BASIS:
Caused by mutation in aldo-keto reductase family 1, member C2 gene
(AKR1C2, 600450.0001)
*FIELD* CD
Marla J. F. O'Neill: 10/17/2011
*FIELD* ED
joanna: 07/03/2013
joanna: 10/17/2011
*FIELD* CD
Marla J. F. O'Neill: 10/6/2011
*FIELD* ED
alopez: 10/06/2011
*RECORD*
*FIELD* NO
614279
*FIELD* TI
#614279 46,XY SEX REVERSAL 8; SRXY8
;;MALE PSEUDOHERMAPHRODITISM DUE TO DEFICIENCY OF TESTICULAR 17,20-DESMOLASE;
read moreTDD
*FIELD* TX
A number sign (#) is used with this entry because of evidence that 46,XY
sex reversal can be caused by mutation in the AKR1C2 gene (600450) on
chromosome 10p15. A mutation in the closely linked AKR1C4 gene (600451)
that segregates with mutation in the AKR1C2 gene may contribute to the
phenotype.
For a discussion of genetic heterogeneity of 46,XY sex reversal, see
SRXY1 (400044).
CLINICAL FEATURES
Zachmann et al. (1972) studied 2 male cousins, karyotype 46,XY, who were
the sons of sisters and who had ambiguous genitalia and cryptorchidism.
One of the boys had 2 older sibs who were phenotypic females. A 46,XY
maternal 'aunt,' who was raised as a female, underwent evaluation at 18
years of age due to primary amenorrhea, at which time she had Prader
type II external genitalia and sparse pubic hair. At laparotomy, a
rudimentary uterus-like structure consisting only of a cervical canal
was found; a right inguinal gonad and left intraabdominal gonad were
removed, and histologic examination confirmed testicular and epididymal
tissue with interstitial cells but no spermatogonia. Based on evidence
from steroid studies using incubated testicular tissue from 1 of the
boys, as well as urinary steroid results from the 3 affected
individuals, Zachmann et al. (1972) concluded that all 3 patients
suffered from the same testicular and adrenal steroid 17,20-desmolase
deficiency, resulting in a defect of androgen biosynthesis.
Fluck et al. (2011) provided follow-up on the Swiss family with
ambiguous genitalia originally studied by Zachmann et al. (1972).
Examination of the 2 older sibs of 1 affected boy, who were phenotypic
females, revealed that whereas 1 sib was 46,XX with normal female
external genitalia and a sonographically detectable uterus, the other
was 46,XY, with normal female external genitalia but no uterus, and
steroidal responses to chorionic gonadotropin (see 118860) and
corticotropin that were similar to those of the previously studied male
cousins. No family members had signs or steroidal findings of adrenal
insufficiency (see 300200); the family declined any further hormonal
testing. Fluck et al. (2011) also studied a patient from an unrelated
Swiss family who was diagnosed with 46,XY disordered sexual development
(DSD) during surgery for bilateral inguinal hernias at 7 weeks of age,
at which time normal-appearing testes were found in the completely
feminized infant, with no evidence of mullerian structures. Laparascopic
gonadectomy was performed at 2 years of age. No hormonal assessment was
done.
INHERITANCE
In a Swiss family with 2 affected male cousins and an affected 46,XY
maternal aunt, Zachmann et al. (1972) stated that the inheritance
appeared to be autosomal dominant or X-linked recessive.
Fluck et al. (2011) restudied the Swiss family with 46,XY sex reversal
originally reported by Zachmann et al. (1972) and characterized the
inheritance pattern as sex-linked autosomal recessive trait.
MOLECULAR GENETICS
In the Swiss family with 46,XY sex reversal originally studied by
Zachmann et al. (1972), Fluck et al. (2011) excluded mutations in
candidate genes from the classic pathway of steroid biosynthesis, e.g.,
CYP17A1 (609300), POR (124015), NR5A1 (184757), CYB5 (see 613218), and
NR3C4 (AR; 313700). Subsequent analysis of a candidate gene from the
alternative pathway for production of dihydrotestosterone, AKR1C2
(600450), revealed 3 different missense mutations segregating in the
family (600450.0001-600450.0003). Fluck et al. (2011) noted 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, consistent with androgens playing no essential role in female
sexual development. Analysis of 5 closely linked AKR1C genes on
chromosome 10p15 revealed the presence of a splice site mutation in the
AKR1C4 gene (600451.0001) that segregated with the AKR1C2 I79V mutation
in all cases, suggesting a mode of inheritance in which the severity of
the developmental defect depended on the number of mutations in the 2
genes. In a 46,XY sex-reversed individual from an unrelated Swiss
family, Fluck et al. (2011) analyzed the AKR1C locus and identified a
complex rearrangement that resulted in the patient having a single
AKR1C1 (600449)/AKR1C2 hybrid on allele 1, and paternal AKR1C1, an
AKR1C1/AKR1C2 hybrid, and maternal AKR1C2 genes on allele 2. The intact
maternal AKR1C2 gene on allele 2 also carried a missense mutation
(H222Q; 600450.0004); no mutations were found in the paternal copy of
AKR1C1, the AKR1C1/AKR1C2 hybrids, or the AKR1C4 gene. Functional
studies demonstrated that the identified AKR1C2 mutations partially
impair the 3-alpha-HSD activity of AKR1C2, but not to the degree
typically associated with recessive disorders of steroidogenesis. Noting
that the AKR1C4 mutation identified in the first Swiss family also
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 the patient from the second Swiss
family 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.
*FIELD* SA
Goebelsmann et al. (1976); Zachmann et al. (1971)
*FIELD* RF
1. 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.
2. Goebelsmann, U.; Zachmann, M.; Davajan, V.; Israel, R.; Mestman,
J. H.; Mishell, D. R.: Male pseudohermaphroditism consistent with
17,20-desmolase deficiency. Gynec. Invest. 7: 138-156, 1976.
3. Zachmann, M.; Hamilton, W.; Vollmin, J. A.; Prader, A.: Testicular
17, 20-desmolase deficiency causing male pseudohermaphroditism. Acta
Endocr. 155 (suppl.): 65-80, 1971.
4. 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.
*FIELD* CS
INHERITANCE:
Autosomal recessive
GENITOURINARY:
[External genitalia, male];
Ambiguous external genitalia;
[Internal genitalia, male];
Testicular tissue able to convert dihydroepiandrosterone and androstenedione
to testosterone;
Cryptorchidism;
[Internal genitalia, female];
Rudimentary mullerian structures (rare)
ENDOCRINE FEATURES:
Undervirilization;
Elevated urinary gonadotropins;
Low urinary estrogens;
Urinary 17-oxosteroids normal;
Urinary 17-hydroxycorticoids normal;
Baseline pregnanediol and pregnanetriol normal;
Pregnanetriolone (Ptl) present in urine;
Absent dehydroepiandrosterone-sulphate, even after ACTH stimulation;
No increase in testosterone after HCG or ACTH stimulation;
Absent or minimal increase in pregnanetriol after HCG stimulation;
Marked increase in pregnanetriolone after HCG or ACTH stimulation;
Increase in pregnanediol and pregnanetriol after ACTH stimulation;
Minimal testosterone yielded by progesterone and pregnenolone or their
respective 17-alpha-hydroxylates
MISCELLANEOUS:
Only 46,XY individuals are affected
MOLECULAR BASIS:
Caused by mutation in aldo-keto reductase family 1, member C2 gene
(AKR1C2, 600450.0001)
*FIELD* CD
Marla J. F. O'Neill: 10/17/2011
*FIELD* ED
joanna: 07/03/2013
joanna: 10/17/2011
*FIELD* CD
Marla J. F. O'Neill: 10/6/2011
*FIELD* ED
alopez: 10/06/2011