Full text data of IDH2
IDH2
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Isocitrate dehydrogenase [NADP], mitochondrial; IDH; 1.1.1.42 (ICD-M; IDP; NADP(+)-specific ICDH; Oxalosuccinate decarboxylase; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Isocitrate dehydrogenase [NADP], mitochondrial; IDH; 1.1.1.42 (ICD-M; IDP; NADP(+)-specific ICDH; Oxalosuccinate decarboxylase; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P48735
ID IDHP_HUMAN Reviewed; 452 AA.
AC P48735; B2R6L6; Q96GT3;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 03-APR-2002, sequence version 2.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=Isocitrate dehydrogenase [NADP], mitochondrial;
DE Short=IDH;
DE EC=1.1.1.42;
DE AltName: Full=ICD-M;
DE AltName: Full=IDP;
DE AltName: Full=NADP(+)-specific ICDH;
DE AltName: Full=Oxalosuccinate decarboxylase;
DE Flags: Precursor;
GN Name=IDH2;
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].
RC TISSUE=Heart;
RA Huh T.-L., Oh I.-U., Kim Y.O., Huh J.-W., Song B.J.;
RL Submitted (NOV-1992) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Skin;
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 [5]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-67; LYS-106; LYS-155;
RP LYS-166; LYS-180; LYS-256; LYS-263; LYS-272; LYS-275; LYS-282 AND
RP LYS-442, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [7]
RP ACETYLATION AT LYS-413, AND MUTAGENESIS OF LYS-413.
RX PubMed=22416140; DOI=10.1074/jbc.M112.355206;
RA Yu W., Dittenhafer-Reed K.E., Denu J.M.;
RT "SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and
RT regulates mitochondrial redox status.";
RL J. Biol. Chem. 287:14078-14086(2012).
RN [8]
RP VARIANTS D2HGA2 GLN-140 AND GLY-140.
RX PubMed=20847235; DOI=10.1126/science.1192632;
RA Kranendijk M., Struys E.A., van Schaftingen E., Gibson K.M.,
RA Kanhai W.A., van der Knaap M.S., Amiel J., Buist N.R., Das A.M.,
RA de Klerk J.B., Feigenbaum A.S., Grange D.K., Hofstede F.C., Holme E.,
RA Kirk E.P., Korman S.H., Morava E., Morris A., Smeitink J.,
RA Sukhai R.N., Vallance H., Jakobs C., Salomons G.S.;
RT "IDH2 mutations in patients with D-2-hydroxyglutaric aciduria.";
RL Science 330:336-336(2010).
CC -!- FUNCTION: Plays a role in intermediary metabolism and energy
CC production. It may tightly associate or interact with the pyruvate
CC dehydrogenase complex.
CC -!- CATALYTIC ACTIVITY: Isocitrate + NADP(+) = 2-oxoglutarate + CO(2)
CC + NADPH.
CC -!- COFACTOR: Binds 1 magnesium or manganese ion per subunit (By
CC similarity).
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Mitochondrion.
CC -!- PTM: Acetylation at Lys-413 dramatically reduces catalytic
CC activity. Deacetylated by SIRT3.
CC -!- DISEASE: D-2-hydroxyglutaric aciduria 2 (D2HGA2) [MIM:613657]: A
CC neurometabolic disorder causing developmental delay, epilepsy,
CC hypotonia, and dysmorphic features. Both a mild and a severe
CC phenotype exist. The severe phenotype is homogeneous and is
CC characterized by early infantile-onset epileptic encephalopathy
CC and cardiomyopathy. The mild phenotype has a more variable
CC clinical presentation. Diagnosis is based on the presence of an
CC excess of D-2-hydroxyglutaric acid in the urine. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the isocitrate and isopropylmalate
CC dehydrogenases family.
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DR EMBL; X69433; CAA49208.1; -; mRNA.
DR EMBL; AK312627; BAG35513.1; -; mRNA.
DR EMBL; CH471101; EAX02082.1; -; Genomic_DNA.
DR EMBL; BC009244; AAH09244.1; -; mRNA.
DR EMBL; BC071828; AAH71828.1; -; mRNA.
DR PIR; S57499; S57499.
DR RefSeq; NP_002159.2; NM_002168.2.
DR UniGene; Hs.596461; -.
DR PDB; 4JA8; X-ray; 1.55 A; A/B=41-452.
DR PDBsum; 4JA8; -.
DR ProteinModelPortal; P48735; -.
DR SMR; P48735; 41-452.
DR IntAct; P48735; 2.
DR MINT; MINT-3016964; -.
DR STRING; 9606.ENSP00000331897; -.
DR PhosphoSite; P48735; -.
DR DMDM; 20141568; -.
DR OGP; P48735; -.
DR UCD-2DPAGE; P48735; -.
DR PaxDb; P48735; -.
DR PeptideAtlas; P48735; -.
DR PRIDE; P48735; -.
DR DNASU; 3418; -.
DR Ensembl; ENST00000330062; ENSP00000331897; ENSG00000182054.
DR GeneID; 3418; -.
DR KEGG; hsa:3418; -.
DR UCSC; uc002box.3; human.
DR CTD; 3418; -.
DR GeneCards; GC15M090626; -.
DR HGNC; HGNC:5383; IDH2.
DR HPA; HPA007831; -.
DR MIM; 147650; gene.
DR MIM; 613657; phenotype.
DR neXtProt; NX_P48735; -.
DR Orphanet; 79315; D-2-hydroxyglutaric aciduria.
DR Orphanet; 296; Enchondromatosis.
DR Orphanet; 163634; Maffucci syndrome.
DR PharmGKB; PA29631; -.
DR eggNOG; COG0538; -.
DR HOGENOM; HOG000019858; -.
DR HOVERGEN; HBG006119; -.
DR InParanoid; P48735; -.
DR KO; K00031; -.
DR OMA; GSGPTWA; -.
DR OrthoDB; EOG7QNVKS; -.
DR PhylomeDB; P48735; -.
DR BioCyc; MetaCyc:HS00021-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; IDH2; human.
DR GeneWiki; IDH2; -.
DR GenomeRNAi; 3418; -.
DR NextBio; 13474; -.
DR PRO; PR:P48735; -.
DR ArrayExpress; P48735; -.
DR Bgee; P48735; -.
DR CleanEx; HS_IDH2; -.
DR Genevestigator; P48735; -.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0004450; F:isocitrate dehydrogenase (NADP+) activity; ISS:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR GO; GO:0006103; P:2-oxoglutarate metabolic process; ISS:UniProtKB.
DR GO; GO:0005975; P:carbohydrate metabolic process; NAS:ProtInc.
DR GO; GO:0006097; P:glyoxylate cycle; IEA:UniProtKB-KW.
DR GO; GO:0006102; P:isocitrate metabolic process; ISS:UniProtKB.
DR GO; GO:0006099; P:tricarboxylic acid cycle; TAS:Reactome.
DR Gene3D; 3.40.718.10; -; 1.
DR InterPro; IPR019818; IsoCit/isopropylmalate_DH_CS.
DR InterPro; IPR004790; Isocitrate_DH_NADP.
DR InterPro; IPR024084; IsoPropMal-DH-like_dom.
DR PANTHER; PTHR11822; PTHR11822; 1.
DR Pfam; PF00180; Iso_dh; 1.
DR PIRSF; PIRSF000108; IDH_NADP; 1.
DR TIGRFAMs; TIGR00127; nadp_idh_euk; 1.
DR PROSITE; PS00470; IDH_IMDH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Disease mutation;
KW Glyoxylate bypass; Magnesium; Manganese; Metal-binding; Mitochondrion;
KW NADP; Oxidoreductase; Reference proteome; Transit peptide;
KW Tricarboxylic acid cycle.
FT TRANSIT 1 39 Mitochondrion (By similarity).
FT CHAIN 40 452 Isocitrate dehydrogenase [NADP],
FT mitochondrial.
FT /FTId=PRO_0000014420.
FT NP_BIND 115 117 NADP (By similarity).
FT NP_BIND 349 354 NADP (By similarity).
FT REGION 134 140 Substrate binding (By similarity).
FT METAL 291 291 Magnesium or manganese (By similarity).
FT METAL 314 314 Magnesium or manganese (By similarity).
FT BINDING 117 117 Substrate (By similarity).
FT BINDING 122 122 NADP (By similarity).
FT BINDING 149 149 Substrate (By similarity).
FT BINDING 172 172 Substrate (By similarity).
FT BINDING 299 299 NADP (By similarity).
FT BINDING 367 367 NADP; via amide nitrogen and carbonyl
FT oxygen (By similarity).
FT SITE 179 179 Critical for catalysis (By similarity).
FT SITE 251 251 Critical for catalysis (By similarity).
FT MOD_RES 45 45 N6-acetyllysine (By similarity).
FT MOD_RES 48 48 N6-acetyllysine (By similarity).
FT MOD_RES 67 67 N6-acetyllysine.
FT MOD_RES 69 69 N6-acetyllysine (By similarity).
FT MOD_RES 80 80 N6-acetyllysine (By similarity).
FT MOD_RES 106 106 N6-acetyllysine.
FT MOD_RES 155 155 N6-acetyllysine.
FT MOD_RES 166 166 N6-acetyllysine.
FT MOD_RES 180 180 N6-acetyllysine.
FT MOD_RES 193 193 N6-acetyllysine (By similarity).
FT MOD_RES 199 199 N6-acetyllysine (By similarity).
FT MOD_RES 256 256 N6-acetyllysine.
FT MOD_RES 263 263 N6-acetyllysine.
FT MOD_RES 272 272 N6-acetyllysine.
FT MOD_RES 275 275 N6-acetyllysine.
FT MOD_RES 280 280 N6-acetyllysine (By similarity).
FT MOD_RES 282 282 N6-acetyllysine.
FT MOD_RES 384 384 N6-acetyllysine (By similarity).
FT MOD_RES 400 400 N6-acetyllysine (By similarity).
FT MOD_RES 413 413 N6-acetyllysine.
FT MOD_RES 442 442 N6-acetyllysine.
FT VARIANT 140 140 R -> G (in D2HGA2).
FT /FTId=VAR_065174.
FT VARIANT 140 140 R -> Q (in D2HGA2).
FT /FTId=VAR_065175.
FT MUTAGEN 413 413 K->A: 44-fold loss in activity.
FT MUTAGEN 413 413 K->Q: 20-fold decrease in Vmax.
FT MUTAGEN 413 413 K->R: No appreciable difference in Km for
FT isocitrate and NADP.
FT CONFLICT 34 34 Q -> H (in Ref. 1; CAA49208).
FT CONFLICT 435 435 T -> M (in Ref. 1; CAA49208).
FT STRAND 50 54
FT HELIX 57 69
FT TURN 70 74
FT STRAND 79 83
FT HELIX 86 91
FT TURN 92 94
FT HELIX 95 107
FT STRAND 108 112
FT HELIX 120 126
FT HELIX 135 143
FT STRAND 146 151
FT STRAND 168 172
FT HELIX 177 180
FT STRAND 182 186
FT STRAND 190 198
FT STRAND 205 214
FT STRAND 216 224
FT HELIX 225 242
FT STRAND 246 250
FT TURN 252 254
FT HELIX 258 273
FT HELIX 275 280
FT STRAND 285 289
FT HELIX 290 299
FT STRAND 304 308
FT HELIX 310 323
FT HELIX 327 329
FT STRAND 330 335
FT STRAND 342 348
FT HELIX 352 359
FT HELIX 369 386
FT HELIX 389 407
FT HELIX 413 420
FT HELIX 422 424
FT TURN 427 429
FT HELIX 434 452
SQ SEQUENCE 452 AA; 50909 MW; 4DDC830AFC06AB52 CRC64;
MAGYLRVVRS LCRASGSRPA WAPAALTAPT SQEQPRRHYA DKRIKVAKPV VEMDGDEMTR
IIWQFIKEKL ILPHVDIQLK YFDLGLPNRD QTDDQVTIDS ALATQKYSVA VKCATITPDE
ARVEEFKLKK MWKSPNGTIR NILGGTVFRE PIICKNIPRL VPGWTKPITI GRHAHGDQYK
ATDFVADRAG TFKMVFTPKD GSGVKEWEVY NFPAGGVGMG MYNTDESISG FAHSCFQYAI
QKKWPLYMST KNTILKAYDG RFKDIFQEIF DKHYKTDFDK NKIWYEHRLI DDMVAQVLKS
SGGFVWACKN YDGDVQSDIL AQGFGSLGLM TSVLVCPDGK TIEAEAAHGT VTRHYREHQK
GRPTSTNPIA SIFAWTRGLE HRGKLDGNQD LIRFAQMLEK VCVETVESGA MTKDLAGCIH
GLSNVKLNEH FLNTTDFLDT IKSNLDRALG RQ
//
ID IDHP_HUMAN Reviewed; 452 AA.
AC P48735; B2R6L6; Q96GT3;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 03-APR-2002, sequence version 2.
DT 22-JAN-2014, entry version 137.
DE RecName: Full=Isocitrate dehydrogenase [NADP], mitochondrial;
DE Short=IDH;
DE EC=1.1.1.42;
DE AltName: Full=ICD-M;
DE AltName: Full=IDP;
DE AltName: Full=NADP(+)-specific ICDH;
DE AltName: Full=Oxalosuccinate decarboxylase;
DE Flags: Precursor;
GN Name=IDH2;
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].
RC TISSUE=Heart;
RA Huh T.-L., Oh I.-U., Kim Y.O., Huh J.-W., Song B.J.;
RL Submitted (NOV-1992) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Heart;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon, and Skin;
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 [5]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-67; LYS-106; LYS-155;
RP LYS-166; LYS-180; LYS-256; LYS-263; LYS-272; LYS-275; LYS-282 AND
RP LYS-442, AND MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [7]
RP ACETYLATION AT LYS-413, AND MUTAGENESIS OF LYS-413.
RX PubMed=22416140; DOI=10.1074/jbc.M112.355206;
RA Yu W., Dittenhafer-Reed K.E., Denu J.M.;
RT "SIRT3 protein deacetylates isocitrate dehydrogenase 2 (IDH2) and
RT regulates mitochondrial redox status.";
RL J. Biol. Chem. 287:14078-14086(2012).
RN [8]
RP VARIANTS D2HGA2 GLN-140 AND GLY-140.
RX PubMed=20847235; DOI=10.1126/science.1192632;
RA Kranendijk M., Struys E.A., van Schaftingen E., Gibson K.M.,
RA Kanhai W.A., van der Knaap M.S., Amiel J., Buist N.R., Das A.M.,
RA de Klerk J.B., Feigenbaum A.S., Grange D.K., Hofstede F.C., Holme E.,
RA Kirk E.P., Korman S.H., Morava E., Morris A., Smeitink J.,
RA Sukhai R.N., Vallance H., Jakobs C., Salomons G.S.;
RT "IDH2 mutations in patients with D-2-hydroxyglutaric aciduria.";
RL Science 330:336-336(2010).
CC -!- FUNCTION: Plays a role in intermediary metabolism and energy
CC production. It may tightly associate or interact with the pyruvate
CC dehydrogenase complex.
CC -!- CATALYTIC ACTIVITY: Isocitrate + NADP(+) = 2-oxoglutarate + CO(2)
CC + NADPH.
CC -!- COFACTOR: Binds 1 magnesium or manganese ion per subunit (By
CC similarity).
CC -!- SUBUNIT: Homodimer.
CC -!- SUBCELLULAR LOCATION: Mitochondrion.
CC -!- PTM: Acetylation at Lys-413 dramatically reduces catalytic
CC activity. Deacetylated by SIRT3.
CC -!- DISEASE: D-2-hydroxyglutaric aciduria 2 (D2HGA2) [MIM:613657]: A
CC neurometabolic disorder causing developmental delay, epilepsy,
CC hypotonia, and dysmorphic features. Both a mild and a severe
CC phenotype exist. The severe phenotype is homogeneous and is
CC characterized by early infantile-onset epileptic encephalopathy
CC and cardiomyopathy. The mild phenotype has a more variable
CC clinical presentation. Diagnosis is based on the presence of an
CC excess of D-2-hydroxyglutaric acid in the urine. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the isocitrate and isopropylmalate
CC dehydrogenases family.
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DR EMBL; X69433; CAA49208.1; -; mRNA.
DR EMBL; AK312627; BAG35513.1; -; mRNA.
DR EMBL; CH471101; EAX02082.1; -; Genomic_DNA.
DR EMBL; BC009244; AAH09244.1; -; mRNA.
DR EMBL; BC071828; AAH71828.1; -; mRNA.
DR PIR; S57499; S57499.
DR RefSeq; NP_002159.2; NM_002168.2.
DR UniGene; Hs.596461; -.
DR PDB; 4JA8; X-ray; 1.55 A; A/B=41-452.
DR PDBsum; 4JA8; -.
DR ProteinModelPortal; P48735; -.
DR SMR; P48735; 41-452.
DR IntAct; P48735; 2.
DR MINT; MINT-3016964; -.
DR STRING; 9606.ENSP00000331897; -.
DR PhosphoSite; P48735; -.
DR DMDM; 20141568; -.
DR OGP; P48735; -.
DR UCD-2DPAGE; P48735; -.
DR PaxDb; P48735; -.
DR PeptideAtlas; P48735; -.
DR PRIDE; P48735; -.
DR DNASU; 3418; -.
DR Ensembl; ENST00000330062; ENSP00000331897; ENSG00000182054.
DR GeneID; 3418; -.
DR KEGG; hsa:3418; -.
DR UCSC; uc002box.3; human.
DR CTD; 3418; -.
DR GeneCards; GC15M090626; -.
DR HGNC; HGNC:5383; IDH2.
DR HPA; HPA007831; -.
DR MIM; 147650; gene.
DR MIM; 613657; phenotype.
DR neXtProt; NX_P48735; -.
DR Orphanet; 79315; D-2-hydroxyglutaric aciduria.
DR Orphanet; 296; Enchondromatosis.
DR Orphanet; 163634; Maffucci syndrome.
DR PharmGKB; PA29631; -.
DR eggNOG; COG0538; -.
DR HOGENOM; HOG000019858; -.
DR HOVERGEN; HBG006119; -.
DR InParanoid; P48735; -.
DR KO; K00031; -.
DR OMA; GSGPTWA; -.
DR OrthoDB; EOG7QNVKS; -.
DR PhylomeDB; P48735; -.
DR BioCyc; MetaCyc:HS00021-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR ChiTaRS; IDH2; human.
DR GeneWiki; IDH2; -.
DR GenomeRNAi; 3418; -.
DR NextBio; 13474; -.
DR PRO; PR:P48735; -.
DR ArrayExpress; P48735; -.
DR Bgee; P48735; -.
DR CleanEx; HS_IDH2; -.
DR Genevestigator; P48735; -.
DR GO; GO:0005743; C:mitochondrial inner membrane; IEA:Ensembl.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0004450; F:isocitrate dehydrogenase (NADP+) activity; ISS:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0051287; F:NAD binding; IEA:InterPro.
DR GO; GO:0006103; P:2-oxoglutarate metabolic process; ISS:UniProtKB.
DR GO; GO:0005975; P:carbohydrate metabolic process; NAS:ProtInc.
DR GO; GO:0006097; P:glyoxylate cycle; IEA:UniProtKB-KW.
DR GO; GO:0006102; P:isocitrate metabolic process; ISS:UniProtKB.
DR GO; GO:0006099; P:tricarboxylic acid cycle; TAS:Reactome.
DR Gene3D; 3.40.718.10; -; 1.
DR InterPro; IPR019818; IsoCit/isopropylmalate_DH_CS.
DR InterPro; IPR004790; Isocitrate_DH_NADP.
DR InterPro; IPR024084; IsoPropMal-DH-like_dom.
DR PANTHER; PTHR11822; PTHR11822; 1.
DR Pfam; PF00180; Iso_dh; 1.
DR PIRSF; PIRSF000108; IDH_NADP; 1.
DR TIGRFAMs; TIGR00127; nadp_idh_euk; 1.
DR PROSITE; PS00470; IDH_IMDH; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Complete proteome; Disease mutation;
KW Glyoxylate bypass; Magnesium; Manganese; Metal-binding; Mitochondrion;
KW NADP; Oxidoreductase; Reference proteome; Transit peptide;
KW Tricarboxylic acid cycle.
FT TRANSIT 1 39 Mitochondrion (By similarity).
FT CHAIN 40 452 Isocitrate dehydrogenase [NADP],
FT mitochondrial.
FT /FTId=PRO_0000014420.
FT NP_BIND 115 117 NADP (By similarity).
FT NP_BIND 349 354 NADP (By similarity).
FT REGION 134 140 Substrate binding (By similarity).
FT METAL 291 291 Magnesium or manganese (By similarity).
FT METAL 314 314 Magnesium or manganese (By similarity).
FT BINDING 117 117 Substrate (By similarity).
FT BINDING 122 122 NADP (By similarity).
FT BINDING 149 149 Substrate (By similarity).
FT BINDING 172 172 Substrate (By similarity).
FT BINDING 299 299 NADP (By similarity).
FT BINDING 367 367 NADP; via amide nitrogen and carbonyl
FT oxygen (By similarity).
FT SITE 179 179 Critical for catalysis (By similarity).
FT SITE 251 251 Critical for catalysis (By similarity).
FT MOD_RES 45 45 N6-acetyllysine (By similarity).
FT MOD_RES 48 48 N6-acetyllysine (By similarity).
FT MOD_RES 67 67 N6-acetyllysine.
FT MOD_RES 69 69 N6-acetyllysine (By similarity).
FT MOD_RES 80 80 N6-acetyllysine (By similarity).
FT MOD_RES 106 106 N6-acetyllysine.
FT MOD_RES 155 155 N6-acetyllysine.
FT MOD_RES 166 166 N6-acetyllysine.
FT MOD_RES 180 180 N6-acetyllysine.
FT MOD_RES 193 193 N6-acetyllysine (By similarity).
FT MOD_RES 199 199 N6-acetyllysine (By similarity).
FT MOD_RES 256 256 N6-acetyllysine.
FT MOD_RES 263 263 N6-acetyllysine.
FT MOD_RES 272 272 N6-acetyllysine.
FT MOD_RES 275 275 N6-acetyllysine.
FT MOD_RES 280 280 N6-acetyllysine (By similarity).
FT MOD_RES 282 282 N6-acetyllysine.
FT MOD_RES 384 384 N6-acetyllysine (By similarity).
FT MOD_RES 400 400 N6-acetyllysine (By similarity).
FT MOD_RES 413 413 N6-acetyllysine.
FT MOD_RES 442 442 N6-acetyllysine.
FT VARIANT 140 140 R -> G (in D2HGA2).
FT /FTId=VAR_065174.
FT VARIANT 140 140 R -> Q (in D2HGA2).
FT /FTId=VAR_065175.
FT MUTAGEN 413 413 K->A: 44-fold loss in activity.
FT MUTAGEN 413 413 K->Q: 20-fold decrease in Vmax.
FT MUTAGEN 413 413 K->R: No appreciable difference in Km for
FT isocitrate and NADP.
FT CONFLICT 34 34 Q -> H (in Ref. 1; CAA49208).
FT CONFLICT 435 435 T -> M (in Ref. 1; CAA49208).
FT STRAND 50 54
FT HELIX 57 69
FT TURN 70 74
FT STRAND 79 83
FT HELIX 86 91
FT TURN 92 94
FT HELIX 95 107
FT STRAND 108 112
FT HELIX 120 126
FT HELIX 135 143
FT STRAND 146 151
FT STRAND 168 172
FT HELIX 177 180
FT STRAND 182 186
FT STRAND 190 198
FT STRAND 205 214
FT STRAND 216 224
FT HELIX 225 242
FT STRAND 246 250
FT TURN 252 254
FT HELIX 258 273
FT HELIX 275 280
FT STRAND 285 289
FT HELIX 290 299
FT STRAND 304 308
FT HELIX 310 323
FT HELIX 327 329
FT STRAND 330 335
FT STRAND 342 348
FT HELIX 352 359
FT HELIX 369 386
FT HELIX 389 407
FT HELIX 413 420
FT HELIX 422 424
FT TURN 427 429
FT HELIX 434 452
SQ SEQUENCE 452 AA; 50909 MW; 4DDC830AFC06AB52 CRC64;
MAGYLRVVRS LCRASGSRPA WAPAALTAPT SQEQPRRHYA DKRIKVAKPV VEMDGDEMTR
IIWQFIKEKL ILPHVDIQLK YFDLGLPNRD QTDDQVTIDS ALATQKYSVA VKCATITPDE
ARVEEFKLKK MWKSPNGTIR NILGGTVFRE PIICKNIPRL VPGWTKPITI GRHAHGDQYK
ATDFVADRAG TFKMVFTPKD GSGVKEWEVY NFPAGGVGMG MYNTDESISG FAHSCFQYAI
QKKWPLYMST KNTILKAYDG RFKDIFQEIF DKHYKTDFDK NKIWYEHRLI DDMVAQVLKS
SGGFVWACKN YDGDVQSDIL AQGFGSLGLM TSVLVCPDGK TIEAEAAHGT VTRHYREHQK
GRPTSTNPIA SIFAWTRGLE HRGKLDGNQD LIRFAQMLEK VCVETVESGA MTKDLAGCIH
GLSNVKLNEH FLNTTDFLDT IKSNLDRALG RQ
//
MIM
147650
*RECORD*
*FIELD* NO
147650
*FIELD* TI
*147650 ISOCITRATE DEHYDROGENASE 2; IDH2
;;ISOCITRATE DEHYDROGENASE, NADP(+)-SPECIFIC, MITOCHONDRIAL; IDPM
read more*FIELD* TX
DESCRIPTION
IDH2 is a mitochondrial NADP-dependent isocitrate dehydrogenase (EC
1.1.1.42) that catalyzes oxidative decarboxylation of isocitrate to
alpha-ketoglutarate, producing NADPH. By providing NADPH for
NADPH-dependent antioxidant enzymes, IDH2 plays a major role in
controlling the mitochondrial redox balance and mitigating cellular
oxidative damage (Park et al., 2008).
CLONING
Using a subtraction approach to identify genes upregulated in activated
B cells, followed by screening a heart cDNA library, Luo et al. (1996)
cloned IDH2, which they called mNADP-IDH. The deduced 419-amino acid
protein contains 7 conserved cysteines, including 1 located in the
putative NADP-binding pocket, 7 residues implicated in binding of
isocitrate and Mg(2+), and 2 conserved N-glycosylation sites. Northern
blot analysis detected very high expression in heart and skeletal
muscle, with little to no expression in other tissues examined.
GENE FUNCTION
Luo et al. (1996) showed that basal IDH2 activity in mitochondria
prepared from several human tissues correlated with IDH2 mRNA levels in
these tissues. IDH2 mRNA expression and enzymatic activity were low in
resting human tonsillar T and B lymphocytes, but they were induced
following mitogen stimulation. Induction of IDH2 was detected in late G1
phase after activation, but it was independent of the cell cycle.
Cytosolic IDH1 (147700) activity was unaffected by lymphocyte
activation. The immunosuppressants rapamycin and cyclosporin A inhibited
mitogen-induced expression of IDH2 in T and B cells.
Myeloperoxidase (MPO; 606989) catalyzes formation of hypochlorous acid
(HOCl), which plays a major role in the immune system by killing
bacteria and other invading pathogens. However, excessive generation of
HOCl can cause tissue damage. Park et al. (2008) showed that HOCl caused
a concentration-dependent loss of mouse Idpm activity in vitro. Idpm
activity was protected from HOCl-induced damage by cotreatment with
thiols or by addition of the substrates NADP+ and isocitrate. Treatment
of HeLa cells with small interfering RNA directed against IDPM
exacerbated HOCl-induced generation of reactive oxygen species, cellular
oxidative damage, and mitochondrial dysfunction. Park et al. (2008)
concluded that HOCl causes cellular oxidative damage by oxidizing
critical cysteine residues in the IDPM active site, leading to IDPM
inactivation and perturbation of the cellular antioxidant defense
system.
Lu et al. (2012) reported that 2-hydroxyglutarate (2HG)-producing IDH
mutants can prevent the histone demethylation that is required for
lineage-specific progenitor cells to differentiate into terminally
differentiated cells. In tumor samples from glioma patients, IDH
mutations were associated with a distinct gene expression profile
enriched for genes expressed in neural progenitor cells, and this was
associated with increased histone methylation. To test whether the
ability of IDH mutants to promote histone methylation contributes to a
block in cell differentiation in nontransformed cells, Lu et al. (2012)
tested the effect of neomorphic IDH mutants on adipocyte differentiation
in vitro. Introduction of either mutant IDH or cell-permeable 2HG was
associated with repression of the inducible expression of
lineage-specific differentiation genes and a block to differentiation.
This correlated with a significant increase in repressive histone
methylation marks without observable changes in promoter DNA
methylation. Gliomas were found to have elevated levels of similar
histone repressive marks. Stable transfection of a 2HG-producing mutant
IDH into immortalized astrocytes resulted in progressive accumulation of
histone methylation. Of the marks examined, increased H3K9 methylation
reproducibly preceded a rise in DNA methylation as cells were passaged
in culture. Furthermore, Lu et al. (2012) found that the 2HG-inhibitable
H3K9 demethylase KDM4C (605469) was induced during adipocyte
differentiation, and that RNA-interference suppression of KDM4C was
sufficient to block differentiation. Lu et al. (2012) concluded that,
taken together, their data demonstrated that 2HG can inhibit histone
demethylation and that inhibition of histone demethylation can be
sufficient to block the differentiation of nontransformed cells.
Koivunen et al. (2012) showed that the R-enantiomer of 2HG (R-2HG),
produced by cancer-associated mutant IDH1 or IDH2, but not S-2HG,
stimulates EGLN (e.g., EGLN1; 606425) activity, leading to diminished
HIF (see 603348) levels, which enhances the proliferation and soft agar
growth of human astrocytes. Koivunen et al. (2012) concluded that their
findings defined an enantiomer-specific mechanism by which the R-2HG
that accumulates in IDH mutant brain tumors promotes transformation.
MOLECULAR GENETICS
- Somatic Mutations
Yan et al. (2009) determined the sequence of the IDH1 (147700) gene and
related IDH2 gene in 445 central nervous system (CNS) tumors and 494
non-CNS tumors. The enzymatic activity of the proteins that were
produced from normal and mutant IDH1 and IDH2 genes was determined in
cultured glioma cells that were transfected with these genes. Yan et al.
(2009) identified mutations that affected amino acid 132 of IDH1 in more
than 70% of World Health Organization (WHO) grade II and III
astrocytomas and oligodendrogliomas and in glioblastomas that developed
from these lower-grade lesions. Tumors without mutations in IDH1 often
had mutations affecting the analogous amino acid (R172) of the IDH2
gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and
clinical characteristics, and patients with such tumors had a better
outcome than those with wildtype IDH genes. Each of the 4 tested IDH1
and IDH2 mutations reduced the enzymatic activity of the encoded
protein. Yan et al. (2009) concluded that mutations of NADP(+)-dependent
isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority
of several types of malignant gliomas.
For a discussion of somatic IDH1 and IDH2 mutations in multiple
endochondromatosis, see Ollier disease (166000) and Maffucci syndrome
(614569).
The Cancer Genome Atlas Research Network (2013) analyzed the genomes of
200 clinically annotated adult cases of de novo AML, using either
whole-genome sequencing (50 cases) or whole-exome sequencing (150
cases), along with RNA and microRNA sequencing and DNA methylation
analysis. The Cancer Genome Atlas Research Network (2013) identified
recurrent mutations in the IDH1 or IDH2 genes in 39/200 (20%) samples.
Brewin et al. (2013) noted that the study of the Cancer Genome Atlas
Research Network (2013) did not reveal which mutations occurred in the
founding clone, as would be expected for an initiator of disease, and
which occurred in minor clones, which subsequently drive disease. Miller
et al. (2013) responded that genes mutated almost exclusively in
founding clones in their study included IDH2 (13 of 14 mutations in
founding clones). They identified several other genes that contained
mutations they considered probable initiators, and other genes mutations
in which were considered probably cooperating mutations.
- D-2-Hydroxyglutaric Aciduria 2
In 15 of 17 cases of D-2-hydroxyglutaric aciduria not caused by mutation
in the D2HGDH gene (D2HGA2; 609186), Kranendijk et al. (2010) identified
a heterozygous mutation in the IDH2 gene. Fourteen of the 15 patients
had an arg140-to-gln mutation (R140Q; 147650.0001) and 1 had an
arg140-to-gly mutation (R140G; 147650.0002). In 8 of 9 sets of parents
this mutation could not be detected, indicating a de novo mutation and
that D2HGA2 is an autosomal dominant trait. The mother of 1 patient
demonstrated germline mosaicism.
MAPPING
Huh et al. (1996) quoted preliminary observations by fluorescence in
situ hybridization indicating that the IDH2 gene maps to chromosome
15q26.1; see the report by Oh et al. (1996).
*FIELD* AV
.0001
D-2-HYDROXYGLUTARIC ACIDURIA 2
IDH2, ARG140GLN
In 14 of 15 patients with D-2-hydroxyglutaric aciduria type 2 (D2HGA2;
613657), Kranendijk et al. (2010) identified a G-to-A transition at
nucleotide 419 of the IDH2 gene, resulting in an arg-to-gln substitution
at codon 140 (R140Q). This mutation occurred de novo in 13 of the 14
patients but was identified in 1 patient's mother with somatic and
germline mosaicism. Somatic R140Q mutation had been identified in acute
myeloid leukemia and shown to lead to abnormal production of
D-2-hydroxyglutaric acid (Ward et al., 2010).
Nota et al. (2013) reported 2 D-2-hydroxyglutaric aciduria-2 patients.
In 1 patient mosaicism for the 419G-A (R140Q) mutation in IDH2 had
occurred de novo; in the other the heterozygous R140Q mutation had been
inherited from the unaffected mother, who was a mosaic carrier.
.0002
D-2-HYDROXYGLUTARIC ACIDURIA 2
IDH2, ARG140GLY
In 1 patient with D-2-hydroxyglutaric aciduria (D2HGA2; 613657),
Kranendijk et al. (2010) identified a C-to-G transversion at nucleotide
418 of the IDH2 gene, resulting in an arg-to-gly substitution at codon
140 (R140G). This mutation arose de novo in the affected individual.
*FIELD* SA
Bruns et al. (1976); Champion et al. (1978); Shimizu et al. (1977);
Turcan et al. (2012)
*FIELD* RF
1. Brewin, J.; Horne, G.; Chevassut, T.: Genomic landscapes and clonality
of de novo AML. (Letter) New Eng. J. Med. 369: 1472-1473, 2013.
2. Bruns, G. A. P.; Eisenman, R. E.; Gerald, P. S.: Human mitochondrial
NADP-dependent isocitrate dehydrogenase in man-mouse somatic cell
hybrids. Cytogenet. Cell Genet. 17: 200-211, 1976.
3. Cancer Genome Atlas Research Network: Genomic and epigenomic
landscapes of adult de novo acute myeloid leukemia. New Eng. J. Med. 368:
2059-2074, 2013. Note: Erratum: New Eng. J. Med. 369: 98 only, 2013.
4. Champion, M. J.; Brown, J. A.; Shows, T. B.: Assignment of cytoplasmic
alpha-mannosidase (MAN-A) and confirmation of the mitochondrial isocitrate
dehydrogenase (IDH-M) genes to the q11-qter region of chromosome 15
in man. Cytogenet. Cell Genet. 22: 498-502, 1978.
5. Huh, T.-L.; Kim, Y.-O.; Oh, I.-U.; Song, B. J.; Inazawa, J.: Assignment
of the human mitochondrial NAD(+)-specific isocitrate dehydrogenase
alpha subunit (IDH3A) gene to 15q25.1-q25.2 by in situ hybridization. Genomics 32:
295-296, 1996. Note: Erratum: Genomics 35: 274 only, 1996.
6. Koivunen, P.; Lee, S.; Duncan, C. G.; Lopez, G.; Lu, G.; Ramkissoon,
S.; Losman, J. A.; Joensuu, P.; Bergmann, U.; Gross, S.; Travins,
J.; Weiss, S.; Looper, R.; Ligon, K. L.; Verhaak, R. G. W.; Yan, H.;
Kaelin, W. G., Jr.: Transformation by the (R)-enantiomer of 2-hydroxyglutarate
linked to EGLN activation. Nature 483: 484-488, 2012.
7. Kranendijk, M.; Struys, E. A.; van Schaftingen, E.; Gibson, K.
M.; Kanhai, W. A.; van der Knapp, M. S.; Amiel, J.; Buist, N. R.;
Das, A. M.; de Klerk, J. B.; Feigenbaum, A. S.; Grange, D. K.; and
11 others: IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330:
336 only, 2010.
8. Lu, C.; Ward, P. S.; Kapoor, G. S.; Rohle, D.; Turcan, S.; Abdel-Wahab,
O.; Edwards, C. R.; Khanin, R.; Figueroa, M. E.; Melnick, A.; Wellen,
K. E.; O'Rourke, D. M.; Berger, S. L.; Chan, T. A.; Levine, R. L.;
Mellinghoff, I. K.; Thompson, C. B.: IDH mutation impairs histone
demethylation and results in a block to cell differentiation. Nature 483:
474-478, 2012.
9. Luo, H.; Shan, X.; Wu, J.: Expression of human mitochondrial NADP-dependent
isocitrate dehydrogenase during lymphocyte activation. J. Cell. Biochem. 60:
495-507, 1996.
10. Miller, C. A.; Wilson, R. K.; Ley, T. J.: Reply to Brewin et
al. (Letter) New Eng. J. Med. 369: 1473 only, 2013.
11. Nota, B.; Hamilton, E. M.; Sie, D.; Ozturk, S.; van Dooren, S.
J. M.; Ojeda, M. R. F.; Jakobs, C.; Christensen, E.; Kirk, E. P.;
Sykut-Cegielska, J.; Lund, A. M.; van der Knaap, M. S.; Salomons,
G. S.: Novel cases of D-2-hydroxyglutaric aciduria with IDH1 or IDH2
mosaic mutations identified by amplicon deep sequencing. J. Med.
Genet. 50: 754-759, 2013.
12. Oh, I.-U.; Inazawa, J.; Kim, Y.-O.; Song, B. J.; Huh, T.-L.:
Assignment of the human mitochondrial NADP(+)-specific isocitrate
dehydrogenase (IDH2) gene to 15q26.1 by in situ hybridization. Genomics 38:
104-106, 1996.
13. Park, S. Y.; Lee, S.-M.; Shin, S. W.; Park, J.-W.: Inactivation
of mitochondrial NADP(+)-dependent isocitrate dehydrogenase by hypochlorous
acid. Free Radical Res. 42: 467-473, 2008.
14. Shimizu, N.; Giles, R. E.; Kucherlapati, R. S.; Shimizu, Y.; Ruddle,
F. H.: Somatic cell genetic assignment of the human gene for mitochondrial
NADP-linked isocitrate dehydrogenase to the long arm of chromosome
15. Somat. Cell Genet. 3: 47-60, 1977.
15. Turcan, S.; Rohle, D.; Goenka, A.; Walsh, L. A.; Fang, F.; Yilmaz,
E.; Campos, C.; Fabius, A. W. M.; Lu, C.; Ward, P. S.; Thompson, C.
B.; Kaufman, A.; Guryanova, O.; Levine, R.; Heguy, A.; Viale, A.;
Morris, L. G. T.; Huse, J. T.; Mellinghoff, I. K.; Chan, T. A.: IDH1
mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:
479-483, 2012.
16. Ward, P. S.; Patel, J.; Wise, D. R.; Abdel-Wahab, O.; Bennett,
B. D.; Coller, H. A.; Cross, J. R.; Fantin, V. R.; Hedvat, C. V.;
Perl, A. E.; Rabinowitz, J. D.; Carroll, M.; Su, S. M.; Sharp, K.
A.; Levine, R. L.; Thompson, C. B.: The common feature of leukemia-associated
IDH1 and IDH2 mutations is a neomorphic enzyme activity converting
alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225-234,
2010.
17. Yan, H.; Parsons, D. W.; Jin, G.; McLendon, R.; Rasheed, B. A.;
Yuan, W.; Kos, I.; Batinic-Haberle, I.; Jones, S.; Riggins, G. J.;
Friedman, H.; Friedman, A.; Reardon, D.; Herndon, J.; Kinzler, K.
W.; Velculescu, V. E.; Vogelstein, B.; Bigner, D. D.: IDH1 and IDH2
mutations in gliomas. New Eng. J. Med. 360: 765-773, 2009.
*FIELD* CN
Ada Hamosh - updated: 01/14/2014
Ada Hamosh - updated: 11/25/2013
Ada Hamosh - updated: 7/9/2013
Ada Hamosh - updated: 7/17/2012
Nara Sobreira - updated: 5/25/2012
Ada Hamosh - updated: 11/29/2010
Ada Hamosh - updated: 3/12/2009
Patricia A. Hartz - updated: 9/12/2008
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
alopez: 01/14/2014
alopez: 11/25/2013
alopez: 7/9/2013
alopez: 7/19/2012
terry: 7/17/2012
terry: 7/6/2012
terry: 6/11/2012
carol: 5/25/2012
alopez: 11/30/2010
terry: 11/29/2010
alopez: 3/18/2009
terry: 3/12/2009
mgross: 9/18/2008
terry: 9/12/2008
psherman: 2/9/2000
alopez: 9/5/1997
terry: 12/10/1996
mark: 3/25/1996
terry: 3/14/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 6/2/1986
*RECORD*
*FIELD* NO
147650
*FIELD* TI
*147650 ISOCITRATE DEHYDROGENASE 2; IDH2
;;ISOCITRATE DEHYDROGENASE, NADP(+)-SPECIFIC, MITOCHONDRIAL; IDPM
read more*FIELD* TX
DESCRIPTION
IDH2 is a mitochondrial NADP-dependent isocitrate dehydrogenase (EC
1.1.1.42) that catalyzes oxidative decarboxylation of isocitrate to
alpha-ketoglutarate, producing NADPH. By providing NADPH for
NADPH-dependent antioxidant enzymes, IDH2 plays a major role in
controlling the mitochondrial redox balance and mitigating cellular
oxidative damage (Park et al., 2008).
CLONING
Using a subtraction approach to identify genes upregulated in activated
B cells, followed by screening a heart cDNA library, Luo et al. (1996)
cloned IDH2, which they called mNADP-IDH. The deduced 419-amino acid
protein contains 7 conserved cysteines, including 1 located in the
putative NADP-binding pocket, 7 residues implicated in binding of
isocitrate and Mg(2+), and 2 conserved N-glycosylation sites. Northern
blot analysis detected very high expression in heart and skeletal
muscle, with little to no expression in other tissues examined.
GENE FUNCTION
Luo et al. (1996) showed that basal IDH2 activity in mitochondria
prepared from several human tissues correlated with IDH2 mRNA levels in
these tissues. IDH2 mRNA expression and enzymatic activity were low in
resting human tonsillar T and B lymphocytes, but they were induced
following mitogen stimulation. Induction of IDH2 was detected in late G1
phase after activation, but it was independent of the cell cycle.
Cytosolic IDH1 (147700) activity was unaffected by lymphocyte
activation. The immunosuppressants rapamycin and cyclosporin A inhibited
mitogen-induced expression of IDH2 in T and B cells.
Myeloperoxidase (MPO; 606989) catalyzes formation of hypochlorous acid
(HOCl), which plays a major role in the immune system by killing
bacteria and other invading pathogens. However, excessive generation of
HOCl can cause tissue damage. Park et al. (2008) showed that HOCl caused
a concentration-dependent loss of mouse Idpm activity in vitro. Idpm
activity was protected from HOCl-induced damage by cotreatment with
thiols or by addition of the substrates NADP+ and isocitrate. Treatment
of HeLa cells with small interfering RNA directed against IDPM
exacerbated HOCl-induced generation of reactive oxygen species, cellular
oxidative damage, and mitochondrial dysfunction. Park et al. (2008)
concluded that HOCl causes cellular oxidative damage by oxidizing
critical cysteine residues in the IDPM active site, leading to IDPM
inactivation and perturbation of the cellular antioxidant defense
system.
Lu et al. (2012) reported that 2-hydroxyglutarate (2HG)-producing IDH
mutants can prevent the histone demethylation that is required for
lineage-specific progenitor cells to differentiate into terminally
differentiated cells. In tumor samples from glioma patients, IDH
mutations were associated with a distinct gene expression profile
enriched for genes expressed in neural progenitor cells, and this was
associated with increased histone methylation. To test whether the
ability of IDH mutants to promote histone methylation contributes to a
block in cell differentiation in nontransformed cells, Lu et al. (2012)
tested the effect of neomorphic IDH mutants on adipocyte differentiation
in vitro. Introduction of either mutant IDH or cell-permeable 2HG was
associated with repression of the inducible expression of
lineage-specific differentiation genes and a block to differentiation.
This correlated with a significant increase in repressive histone
methylation marks without observable changes in promoter DNA
methylation. Gliomas were found to have elevated levels of similar
histone repressive marks. Stable transfection of a 2HG-producing mutant
IDH into immortalized astrocytes resulted in progressive accumulation of
histone methylation. Of the marks examined, increased H3K9 methylation
reproducibly preceded a rise in DNA methylation as cells were passaged
in culture. Furthermore, Lu et al. (2012) found that the 2HG-inhibitable
H3K9 demethylase KDM4C (605469) was induced during adipocyte
differentiation, and that RNA-interference suppression of KDM4C was
sufficient to block differentiation. Lu et al. (2012) concluded that,
taken together, their data demonstrated that 2HG can inhibit histone
demethylation and that inhibition of histone demethylation can be
sufficient to block the differentiation of nontransformed cells.
Koivunen et al. (2012) showed that the R-enantiomer of 2HG (R-2HG),
produced by cancer-associated mutant IDH1 or IDH2, but not S-2HG,
stimulates EGLN (e.g., EGLN1; 606425) activity, leading to diminished
HIF (see 603348) levels, which enhances the proliferation and soft agar
growth of human astrocytes. Koivunen et al. (2012) concluded that their
findings defined an enantiomer-specific mechanism by which the R-2HG
that accumulates in IDH mutant brain tumors promotes transformation.
MOLECULAR GENETICS
- Somatic Mutations
Yan et al. (2009) determined the sequence of the IDH1 (147700) gene and
related IDH2 gene in 445 central nervous system (CNS) tumors and 494
non-CNS tumors. The enzymatic activity of the proteins that were
produced from normal and mutant IDH1 and IDH2 genes was determined in
cultured glioma cells that were transfected with these genes. Yan et al.
(2009) identified mutations that affected amino acid 132 of IDH1 in more
than 70% of World Health Organization (WHO) grade II and III
astrocytomas and oligodendrogliomas and in glioblastomas that developed
from these lower-grade lesions. Tumors without mutations in IDH1 often
had mutations affecting the analogous amino acid (R172) of the IDH2
gene. Tumors with IDH1 or IDH2 mutations had distinctive genetic and
clinical characteristics, and patients with such tumors had a better
outcome than those with wildtype IDH genes. Each of the 4 tested IDH1
and IDH2 mutations reduced the enzymatic activity of the encoded
protein. Yan et al. (2009) concluded that mutations of NADP(+)-dependent
isocitrate dehydrogenases encoded by IDH1 and IDH2 occur in a majority
of several types of malignant gliomas.
For a discussion of somatic IDH1 and IDH2 mutations in multiple
endochondromatosis, see Ollier disease (166000) and Maffucci syndrome
(614569).
The Cancer Genome Atlas Research Network (2013) analyzed the genomes of
200 clinically annotated adult cases of de novo AML, using either
whole-genome sequencing (50 cases) or whole-exome sequencing (150
cases), along with RNA and microRNA sequencing and DNA methylation
analysis. The Cancer Genome Atlas Research Network (2013) identified
recurrent mutations in the IDH1 or IDH2 genes in 39/200 (20%) samples.
Brewin et al. (2013) noted that the study of the Cancer Genome Atlas
Research Network (2013) did not reveal which mutations occurred in the
founding clone, as would be expected for an initiator of disease, and
which occurred in minor clones, which subsequently drive disease. Miller
et al. (2013) responded that genes mutated almost exclusively in
founding clones in their study included IDH2 (13 of 14 mutations in
founding clones). They identified several other genes that contained
mutations they considered probable initiators, and other genes mutations
in which were considered probably cooperating mutations.
- D-2-Hydroxyglutaric Aciduria 2
In 15 of 17 cases of D-2-hydroxyglutaric aciduria not caused by mutation
in the D2HGDH gene (D2HGA2; 609186), Kranendijk et al. (2010) identified
a heterozygous mutation in the IDH2 gene. Fourteen of the 15 patients
had an arg140-to-gln mutation (R140Q; 147650.0001) and 1 had an
arg140-to-gly mutation (R140G; 147650.0002). In 8 of 9 sets of parents
this mutation could not be detected, indicating a de novo mutation and
that D2HGA2 is an autosomal dominant trait. The mother of 1 patient
demonstrated germline mosaicism.
MAPPING
Huh et al. (1996) quoted preliminary observations by fluorescence in
situ hybridization indicating that the IDH2 gene maps to chromosome
15q26.1; see the report by Oh et al. (1996).
*FIELD* AV
.0001
D-2-HYDROXYGLUTARIC ACIDURIA 2
IDH2, ARG140GLN
In 14 of 15 patients with D-2-hydroxyglutaric aciduria type 2 (D2HGA2;
613657), Kranendijk et al. (2010) identified a G-to-A transition at
nucleotide 419 of the IDH2 gene, resulting in an arg-to-gln substitution
at codon 140 (R140Q). This mutation occurred de novo in 13 of the 14
patients but was identified in 1 patient's mother with somatic and
germline mosaicism. Somatic R140Q mutation had been identified in acute
myeloid leukemia and shown to lead to abnormal production of
D-2-hydroxyglutaric acid (Ward et al., 2010).
Nota et al. (2013) reported 2 D-2-hydroxyglutaric aciduria-2 patients.
In 1 patient mosaicism for the 419G-A (R140Q) mutation in IDH2 had
occurred de novo; in the other the heterozygous R140Q mutation had been
inherited from the unaffected mother, who was a mosaic carrier.
.0002
D-2-HYDROXYGLUTARIC ACIDURIA 2
IDH2, ARG140GLY
In 1 patient with D-2-hydroxyglutaric aciduria (D2HGA2; 613657),
Kranendijk et al. (2010) identified a C-to-G transversion at nucleotide
418 of the IDH2 gene, resulting in an arg-to-gly substitution at codon
140 (R140G). This mutation arose de novo in the affected individual.
*FIELD* SA
Bruns et al. (1976); Champion et al. (1978); Shimizu et al. (1977);
Turcan et al. (2012)
*FIELD* RF
1. Brewin, J.; Horne, G.; Chevassut, T.: Genomic landscapes and clonality
of de novo AML. (Letter) New Eng. J. Med. 369: 1472-1473, 2013.
2. Bruns, G. A. P.; Eisenman, R. E.; Gerald, P. S.: Human mitochondrial
NADP-dependent isocitrate dehydrogenase in man-mouse somatic cell
hybrids. Cytogenet. Cell Genet. 17: 200-211, 1976.
3. Cancer Genome Atlas Research Network: Genomic and epigenomic
landscapes of adult de novo acute myeloid leukemia. New Eng. J. Med. 368:
2059-2074, 2013. Note: Erratum: New Eng. J. Med. 369: 98 only, 2013.
4. Champion, M. J.; Brown, J. A.; Shows, T. B.: Assignment of cytoplasmic
alpha-mannosidase (MAN-A) and confirmation of the mitochondrial isocitrate
dehydrogenase (IDH-M) genes to the q11-qter region of chromosome 15
in man. Cytogenet. Cell Genet. 22: 498-502, 1978.
5. Huh, T.-L.; Kim, Y.-O.; Oh, I.-U.; Song, B. J.; Inazawa, J.: Assignment
of the human mitochondrial NAD(+)-specific isocitrate dehydrogenase
alpha subunit (IDH3A) gene to 15q25.1-q25.2 by in situ hybridization. Genomics 32:
295-296, 1996. Note: Erratum: Genomics 35: 274 only, 1996.
6. Koivunen, P.; Lee, S.; Duncan, C. G.; Lopez, G.; Lu, G.; Ramkissoon,
S.; Losman, J. A.; Joensuu, P.; Bergmann, U.; Gross, S.; Travins,
J.; Weiss, S.; Looper, R.; Ligon, K. L.; Verhaak, R. G. W.; Yan, H.;
Kaelin, W. G., Jr.: Transformation by the (R)-enantiomer of 2-hydroxyglutarate
linked to EGLN activation. Nature 483: 484-488, 2012.
7. Kranendijk, M.; Struys, E. A.; van Schaftingen, E.; Gibson, K.
M.; Kanhai, W. A.; van der Knapp, M. S.; Amiel, J.; Buist, N. R.;
Das, A. M.; de Klerk, J. B.; Feigenbaum, A. S.; Grange, D. K.; and
11 others: IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330:
336 only, 2010.
8. Lu, C.; Ward, P. S.; Kapoor, G. S.; Rohle, D.; Turcan, S.; Abdel-Wahab,
O.; Edwards, C. R.; Khanin, R.; Figueroa, M. E.; Melnick, A.; Wellen,
K. E.; O'Rourke, D. M.; Berger, S. L.; Chan, T. A.; Levine, R. L.;
Mellinghoff, I. K.; Thompson, C. B.: IDH mutation impairs histone
demethylation and results in a block to cell differentiation. Nature 483:
474-478, 2012.
9. Luo, H.; Shan, X.; Wu, J.: Expression of human mitochondrial NADP-dependent
isocitrate dehydrogenase during lymphocyte activation. J. Cell. Biochem. 60:
495-507, 1996.
10. Miller, C. A.; Wilson, R. K.; Ley, T. J.: Reply to Brewin et
al. (Letter) New Eng. J. Med. 369: 1473 only, 2013.
11. Nota, B.; Hamilton, E. M.; Sie, D.; Ozturk, S.; van Dooren, S.
J. M.; Ojeda, M. R. F.; Jakobs, C.; Christensen, E.; Kirk, E. P.;
Sykut-Cegielska, J.; Lund, A. M.; van der Knaap, M. S.; Salomons,
G. S.: Novel cases of D-2-hydroxyglutaric aciduria with IDH1 or IDH2
mosaic mutations identified by amplicon deep sequencing. J. Med.
Genet. 50: 754-759, 2013.
12. Oh, I.-U.; Inazawa, J.; Kim, Y.-O.; Song, B. J.; Huh, T.-L.:
Assignment of the human mitochondrial NADP(+)-specific isocitrate
dehydrogenase (IDH2) gene to 15q26.1 by in situ hybridization. Genomics 38:
104-106, 1996.
13. Park, S. Y.; Lee, S.-M.; Shin, S. W.; Park, J.-W.: Inactivation
of mitochondrial NADP(+)-dependent isocitrate dehydrogenase by hypochlorous
acid. Free Radical Res. 42: 467-473, 2008.
14. Shimizu, N.; Giles, R. E.; Kucherlapati, R. S.; Shimizu, Y.; Ruddle,
F. H.: Somatic cell genetic assignment of the human gene for mitochondrial
NADP-linked isocitrate dehydrogenase to the long arm of chromosome
15. Somat. Cell Genet. 3: 47-60, 1977.
15. Turcan, S.; Rohle, D.; Goenka, A.; Walsh, L. A.; Fang, F.; Yilmaz,
E.; Campos, C.; Fabius, A. W. M.; Lu, C.; Ward, P. S.; Thompson, C.
B.; Kaufman, A.; Guryanova, O.; Levine, R.; Heguy, A.; Viale, A.;
Morris, L. G. T.; Huse, J. T.; Mellinghoff, I. K.; Chan, T. A.: IDH1
mutation is sufficient to establish the glioma hypermethylator phenotype. Nature 483:
479-483, 2012.
16. Ward, P. S.; Patel, J.; Wise, D. R.; Abdel-Wahab, O.; Bennett,
B. D.; Coller, H. A.; Cross, J. R.; Fantin, V. R.; Hedvat, C. V.;
Perl, A. E.; Rabinowitz, J. D.; Carroll, M.; Su, S. M.; Sharp, K.
A.; Levine, R. L.; Thompson, C. B.: The common feature of leukemia-associated
IDH1 and IDH2 mutations is a neomorphic enzyme activity converting
alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225-234,
2010.
17. Yan, H.; Parsons, D. W.; Jin, G.; McLendon, R.; Rasheed, B. A.;
Yuan, W.; Kos, I.; Batinic-Haberle, I.; Jones, S.; Riggins, G. J.;
Friedman, H.; Friedman, A.; Reardon, D.; Herndon, J.; Kinzler, K.
W.; Velculescu, V. E.; Vogelstein, B.; Bigner, D. D.: IDH1 and IDH2
mutations in gliomas. New Eng. J. Med. 360: 765-773, 2009.
*FIELD* CN
Ada Hamosh - updated: 01/14/2014
Ada Hamosh - updated: 11/25/2013
Ada Hamosh - updated: 7/9/2013
Ada Hamosh - updated: 7/17/2012
Nara Sobreira - updated: 5/25/2012
Ada Hamosh - updated: 11/29/2010
Ada Hamosh - updated: 3/12/2009
Patricia A. Hartz - updated: 9/12/2008
*FIELD* CD
Victor A. McKusick: 6/2/1986
*FIELD* ED
alopez: 01/14/2014
alopez: 11/25/2013
alopez: 7/9/2013
alopez: 7/19/2012
terry: 7/17/2012
terry: 7/6/2012
terry: 6/11/2012
carol: 5/25/2012
alopez: 11/30/2010
terry: 11/29/2010
alopez: 3/18/2009
terry: 3/12/2009
mgross: 9/18/2008
terry: 9/12/2008
psherman: 2/9/2000
alopez: 9/5/1997
terry: 12/10/1996
mark: 3/25/1996
terry: 3/14/1996
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 6/2/1986
MIM
613657
*RECORD*
*FIELD* NO
613657
*FIELD* TI
#613657 D-2-@HYDROXYGLUTARIC ACIDURIA 2
;;D2HGA2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreD-2-hydroxyglutaric aciduria-2 (D2HGA2) is caused by heterozygous
mutations in the mitochondrial isocitrate dehydrogenase-2 (IDH2; 147650)
gene on chromosome 15q26.1.
For a general phenotypic description and a discussion of genetic
heterogeneity of D-2-hydroxyglutaric aciduria, see D2HGA1 (600721).
CLINICAL FEATURES
Kranendijk et al. (2010) phenotypically characterized 17 unrelated
patients with D-2-hydroxyglutaric aciduria without mutations in the
D2HGDH gene (609186). These individuals had the same phenotypic spectrum
associated with D2HGA caused by mutations in the D2HGDH gene (i.e.,
ranging from asymptomatic to developmental delay, epilepsy, hypotonia,
cardiomyopathy, and dysmorphic features). Among the 15 patients there
were 9 females and 6 males. Those still living ranged in age from 3 to
22 years. The age of death of the 9 remaining patients ranged from a few
months to 14 years. The mean urinary D-2-hydroxyglutaric acid in
mmol/mol creatinine was 2,153 among 14 individuals, higher than
excretion of D-2-hydroxyglutaric acid in D2HGA1, where the mean was 969
among 20 individuals.
MOLECULAR GENETICS
Somatic mutation in the IDH1 (147700) or IDH2 genes had been shown to
result in the enzyme's abnormal ability to convert 2-ketoglutarate
(2-KG) to D-2-hydroxyglutarate (D2HG) (Yan et al., 2009; Ward et al.,
2010). For this reason Kranendijk et al. (2010) sought mutations in the
IDH1 or IDH2 genes in 17 unrelated patients with D2HGA without mutations
in the D2HGDH gene. Kranendijk et al. (2010) found no mutations in the
IDH1 gene but identified mutations in the IDH2 gene in 15 of the 17
individuals. Fourteen had a R140Q mutation (147650.0001) and 1 had R140G
(147650.0002). Somatic R140Q mutation had been identified in acute
myeloid leukemia and shown to lead to abnormal production of
D-2-hydroxyglutaric acid (Ward et al., 2010). The higher excretion of
D-2-hydroxyglutaric acid in type 2 patients compared to type 1 patients
could best be explained by hyperproduction of this metabolite. The
involvement of mitochondrial IDH2 is also consistent with the finding
that D-2-hydroxyglutaric acid is derived from mitochondrial 2-KG. In 8
of 9 sets of parents the mutation could not be detected, indicating that
the heterozygous mutation arose de novo and that D2HGA type 2 is an
autosomal dominant trait. In 1 family, however, 3 affected pregnancies
were diagnosed with increased D-2-hydroxyglutaric acid levels in
amniotic fluid, suggesting germline mosaicism in the mother who herself
had normal urinary D-2-hydroxyglutaric acid levels and showed somatic
mosaicism in her blood.
PATHOGENESIS
Kranendijk et al. (2010) suggested that although the D2HGDH enzyme
functions normally in patients with IDH2 mutations, the active D2HGDH
protein appears to lack the catalytic capacity to oxidize all
D-2-hydroxyglutaric acid formed by IDH2 containing an R140 mutation.
Thus, Kranendijk et al. (2010) denoted the disorder in these patients
D2HGA type 2.
*FIELD* RF
1. Kranendijk, M.; Struys, E. A.; van Schaftingen, E.; Gibson, K.
M.; Kanhai, W. A.; van der Knapp, M. S.; Amiel, J.; Buist, N. R.;
Das, A. M.; de Klerk, J. B.; Feigenbaum, A. S.; Grange, D. K.; and
11 others: IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330:
336 only, 2010.
2. Ward, P. S.; Patel, J.; Wise, D. R.; Abdel-Wahab, O.; Bennett,
B. D.; Coller, H. A.; Cross, J. R.; Fantin, V. R.; Hedvat, C. V.;
Perl, A. E.; Rabinowitz, J. D.; Carroll, M.; Su, S. M.; Sharp, K.
A.; Levine, R. L.; Thompson, C. B.: The common feature of leukemia-associated
IDH1 and IDH2 mutations is a neomorphic enzyme activity converting
alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225-234,
2010.
3. Yan, H.; Parsons, D. W.; Jin, G.; McLendon, R.; Rasheed, B. A.;
Yuan, W.; Kos, I.; Batinic-Haberle, I.; Jones, S.; Riggins, G. J.;
Friedman, H.; Friedman, A.; Reardon, D.; Herndon, J.; Kinzler, K.
W.; Velculescu, V. E.; Vogelstein, B.; Bigner, D. D.: IDH1 and IDH2
mutations in gliomas. New Eng. J. Med. 360: 765-773, 2009.
*FIELD* CD
Ada Hamosh: 11/30/2010
*FIELD* ED
alopez: 12/01/2010
*RECORD*
*FIELD* NO
613657
*FIELD* TI
#613657 D-2-@HYDROXYGLUTARIC ACIDURIA 2
;;D2HGA2
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
read moreD-2-hydroxyglutaric aciduria-2 (D2HGA2) is caused by heterozygous
mutations in the mitochondrial isocitrate dehydrogenase-2 (IDH2; 147650)
gene on chromosome 15q26.1.
For a general phenotypic description and a discussion of genetic
heterogeneity of D-2-hydroxyglutaric aciduria, see D2HGA1 (600721).
CLINICAL FEATURES
Kranendijk et al. (2010) phenotypically characterized 17 unrelated
patients with D-2-hydroxyglutaric aciduria without mutations in the
D2HGDH gene (609186). These individuals had the same phenotypic spectrum
associated with D2HGA caused by mutations in the D2HGDH gene (i.e.,
ranging from asymptomatic to developmental delay, epilepsy, hypotonia,
cardiomyopathy, and dysmorphic features). Among the 15 patients there
were 9 females and 6 males. Those still living ranged in age from 3 to
22 years. The age of death of the 9 remaining patients ranged from a few
months to 14 years. The mean urinary D-2-hydroxyglutaric acid in
mmol/mol creatinine was 2,153 among 14 individuals, higher than
excretion of D-2-hydroxyglutaric acid in D2HGA1, where the mean was 969
among 20 individuals.
MOLECULAR GENETICS
Somatic mutation in the IDH1 (147700) or IDH2 genes had been shown to
result in the enzyme's abnormal ability to convert 2-ketoglutarate
(2-KG) to D-2-hydroxyglutarate (D2HG) (Yan et al., 2009; Ward et al.,
2010). For this reason Kranendijk et al. (2010) sought mutations in the
IDH1 or IDH2 genes in 17 unrelated patients with D2HGA without mutations
in the D2HGDH gene. Kranendijk et al. (2010) found no mutations in the
IDH1 gene but identified mutations in the IDH2 gene in 15 of the 17
individuals. Fourteen had a R140Q mutation (147650.0001) and 1 had R140G
(147650.0002). Somatic R140Q mutation had been identified in acute
myeloid leukemia and shown to lead to abnormal production of
D-2-hydroxyglutaric acid (Ward et al., 2010). The higher excretion of
D-2-hydroxyglutaric acid in type 2 patients compared to type 1 patients
could best be explained by hyperproduction of this metabolite. The
involvement of mitochondrial IDH2 is also consistent with the finding
that D-2-hydroxyglutaric acid is derived from mitochondrial 2-KG. In 8
of 9 sets of parents the mutation could not be detected, indicating that
the heterozygous mutation arose de novo and that D2HGA type 2 is an
autosomal dominant trait. In 1 family, however, 3 affected pregnancies
were diagnosed with increased D-2-hydroxyglutaric acid levels in
amniotic fluid, suggesting germline mosaicism in the mother who herself
had normal urinary D-2-hydroxyglutaric acid levels and showed somatic
mosaicism in her blood.
PATHOGENESIS
Kranendijk et al. (2010) suggested that although the D2HGDH enzyme
functions normally in patients with IDH2 mutations, the active D2HGDH
protein appears to lack the catalytic capacity to oxidize all
D-2-hydroxyglutaric acid formed by IDH2 containing an R140 mutation.
Thus, Kranendijk et al. (2010) denoted the disorder in these patients
D2HGA type 2.
*FIELD* RF
1. Kranendijk, M.; Struys, E. A.; van Schaftingen, E.; Gibson, K.
M.; Kanhai, W. A.; van der Knapp, M. S.; Amiel, J.; Buist, N. R.;
Das, A. M.; de Klerk, J. B.; Feigenbaum, A. S.; Grange, D. K.; and
11 others: IDH2 mutations in patients with D-2-hydroxyglutaric aciduria. Science 330:
336 only, 2010.
2. Ward, P. S.; Patel, J.; Wise, D. R.; Abdel-Wahab, O.; Bennett,
B. D.; Coller, H. A.; Cross, J. R.; Fantin, V. R.; Hedvat, C. V.;
Perl, A. E.; Rabinowitz, J. D.; Carroll, M.; Su, S. M.; Sharp, K.
A.; Levine, R. L.; Thompson, C. B.: The common feature of leukemia-associated
IDH1 and IDH2 mutations is a neomorphic enzyme activity converting
alpha-ketoglutarate to 2-hydroxyglutarate. Cancer Cell 17: 225-234,
2010.
3. Yan, H.; Parsons, D. W.; Jin, G.; McLendon, R.; Rasheed, B. A.;
Yuan, W.; Kos, I.; Batinic-Haberle, I.; Jones, S.; Riggins, G. J.;
Friedman, H.; Friedman, A.; Reardon, D.; Herndon, J.; Kinzler, K.
W.; Velculescu, V. E.; Vogelstein, B.; Bigner, D. D.: IDH1 and IDH2
mutations in gliomas. New Eng. J. Med. 360: 765-773, 2009.
*FIELD* CD
Ada Hamosh: 11/30/2010
*FIELD* ED
alopez: 12/01/2010