Full text data of GRHPR
GRHPR
(GLXR)
[Confidence: low (only semi-automatic identification from reviews)]
Glyoxylate reductase/hydroxypyruvate reductase; 1.1.1.79; 1.1.1.81
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Glyoxylate reductase/hydroxypyruvate reductase; 1.1.1.79; 1.1.1.81
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
Q9UBQ7
ID GRHPR_HUMAN Reviewed; 328 AA.
AC Q9UBQ7; Q5T945; Q9H3E9; Q9UKX1;
DT 10-MAY-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 126.
DE RecName: Full=Glyoxylate reductase/hydroxypyruvate reductase;
DE EC=1.1.1.79;
DE EC=1.1.1.81;
GN Name=GRHPR; Synonyms=GLXR; ORFNames=MSTP035;
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], AND SUBUNIT.
RC TISSUE=Liver;
RX PubMed=10524214; DOI=10.1016/S0167-4781(99)00105-0;
RA Rumsby G., Cregeen D.P.;
RT "Identification and expression of a cDNA for human
RT hydroxypyruvate/glyoxylate reductase.";
RL Biochim. Biophys. Acta 1446:383-388(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND INVOLVEMENT IN HP2.
RC TISSUE=Liver;
RX PubMed=10484776; DOI=10.1093/hmg/8.11.2063;
RA Cramer S.D., Ferree P.M., Lin K., Milliner D.S., Holmes R.P.;
RT "The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in
RT patients with primary hyperoxaluria type II.";
RL Hum. Mol. Genet. 8:2063-2069(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Aorta;
RA Liu B., Liu Y.Q., Wang X.Y., Zhao B., Sheng H., Zhao X.W., Liu S.,
RA Xu Y.Y., Ye J., Song L., Gao Y., Zhang C.L., Zhang J., Wei Y.J.,
RA Cao H.Q., Zhao Y., Liu L.S., Ding J.F., Gao R.L., Wu Q.Y., Qiang B.Q.,
RA Yuan J.G., Liew C.C., Zhao M.S., Hui R.T.;
RL Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 45-328, AND TISSUE SPECIFICITY.
RX PubMed=10679197; DOI=10.1006/bbrc.2000.2122;
RA Huang T., Yang W., Pereira A.C., Craigen W.J., Shih V.E.;
RT "Cloning and characterization of a putative human D-2-hydroxyacid
RT dehydrogenase in chromosome 9q.";
RL Biochem. Biophys. Res. Commun. 268:298-301(2000).
RN [9]
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 [10]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SUBSTRATE, AND SUBUNIT.
RX PubMed=16756993; DOI=10.1016/j.jmb.2006.05.018;
RA Booth M.P.S., Conners R., Rumsby G., Brady R.L.;
RT "Structural basis of substrate specificity in human glyoxylate
RT reductase/hydroxypyruvate reductase.";
RL J. Mol. Biol. 360:178-189(2006).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) OF 2-328.
RG Center for eukaryotic structural genomics (CESG);
RT "Crystal structure of a glyoxylate/hydroxypyruvate reductase from Homo
RT sapiens.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Enzyme with hydroxy-pyruvate reductase, glyoxylate
CC reductase and D-glycerate dehydrogenase enzymatic activities.
CC Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate
CC oxidizes D-glycerate to hydroxypyruvate.
CC -!- CATALYTIC ACTIVITY: Glycolate + NADP(+) = glyoxylate + NADPH.
CC -!- CATALYTIC ACTIVITY: D-glycerate + NAD(P)(+) = hydroxypyruvate +
CC NAD(P)H.
CC -!- SUBUNIT: Homodimer.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Most abundantly expressed in the
CC liver.
CC -!- DISEASE: Hyperoxaluria primary 2 (HP2) [MIM:260000]: A disorder
CC characterized by elevated urinary excretion of oxalate and L-
CC glycerate, progressive tissue accumulation of insoluble calcium
CC oxalate, nephrolithiasis, nephrocalcinosis, and end-stage renal
CC disease. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the D-isomer specific 2-hydroxyacid
CC dehydrogenase family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD54066.1; Type=Frameshift; Positions=109, 137;
CC Sequence=AAG39286.1; Type=Frameshift; Positions=237;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GRHPR";
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DR EMBL; AF134895; AAF00111.1; -; mRNA.
DR EMBL; AF146018; AAD45886.1; -; mRNA.
DR EMBL; AF146689; AAD46517.1; -; Genomic_DNA.
DR EMBL; AF113215; AAG39286.1; ALT_FRAME; mRNA.
DR EMBL; AK315690; BAG38053.1; -; mRNA.
DR EMBL; AL158155; CAI13848.1; -; Genomic_DNA.
DR EMBL; CH471071; EAW58284.1; -; Genomic_DNA.
DR EMBL; BC000605; AAH00605.1; -; mRNA.
DR EMBL; AF113251; AAD54066.1; ALT_FRAME; mRNA.
DR PIR; JC7190; JC7190.
DR RefSeq; NP_036335.1; NM_012203.1.
DR UniGene; Hs.155742; -.
DR PDB; 2GCG; X-ray; 2.20 A; A/B/C/D=1-328.
DR PDB; 2H1S; X-ray; 2.45 A; A/B/C/D=2-328.
DR PDB; 2Q50; X-ray; 2.45 A; A/B/C/D=2-328.
DR PDB; 2WWR; X-ray; 2.82 A; A/B/C/D=1-328.
DR PDBsum; 2GCG; -.
DR PDBsum; 2H1S; -.
DR PDBsum; 2Q50; -.
DR PDBsum; 2WWR; -.
DR ProteinModelPortal; Q9UBQ7; -.
DR SMR; Q9UBQ7; 5-328.
DR IntAct; Q9UBQ7; 5.
DR MINT; MINT-5005010; -.
DR STRING; 9606.ENSP00000313432; -.
DR PhosphoSite; Q9UBQ7; -.
DR DMDM; 47116943; -.
DR REPRODUCTION-2DPAGE; IPI00037448; -.
DR UCD-2DPAGE; Q9UBQ7; -.
DR PaxDb; Q9UBQ7; -.
DR PRIDE; Q9UBQ7; -.
DR DNASU; 9380; -.
DR Ensembl; ENST00000318158; ENSP00000313432; ENSG00000137106.
DR GeneID; 9380; -.
DR KEGG; hsa:9380; -.
DR UCSC; uc003zzt.1; human.
DR CTD; 9380; -.
DR GeneCards; GC09P037412; -.
DR HGNC; HGNC:4570; GRHPR.
DR HPA; HPA022971; -.
DR MIM; 260000; phenotype.
DR MIM; 604296; gene.
DR neXtProt; NX_Q9UBQ7; -.
DR Orphanet; 93599; Primary hyperoxaluria type 2.
DR PharmGKB; PA28965; -.
DR eggNOG; COG1052; -.
DR HOVERGEN; HBG051838; -.
DR KO; K00049; -.
DR OMA; ERSMKPS; -.
DR PhylomeDB; Q9UBQ7; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; Q9UBQ7; -.
DR ChiTaRS; GRHPR; human.
DR EvolutionaryTrace; Q9UBQ7; -.
DR GeneWiki; GRHPR; -.
DR GenomeRNAi; 9380; -.
DR NextBio; 35148; -.
DR PRO; PR:Q9UBQ7; -.
DR ArrayExpress; Q9UBQ7; -.
DR Bgee; Q9UBQ7; -.
DR CleanEx; HS_GRHPR; -.
DR Genevestigator; Q9UBQ7; -.
DR GO; GO:0005782; C:peroxisomal matrix; TAS:Reactome.
DR GO; GO:0008465; F:glycerate dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0030267; F:glyoxylate reductase (NADP) activity; IDA:UniProtKB.
DR GO; GO:0016618; F:hydroxypyruvate reductase activity; IDA:UniProtKB.
DR GO; GO:0051287; F:NAD binding; TAS:UniProtKB.
DR GO; GO:0070402; F:NADPH binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0034641; P:cellular nitrogen compound metabolic process; TAS:Reactome.
DR GO; GO:0007588; P:excretion; IMP:UniProtKB.
DR GO; GO:0046487; P:glyoxylate metabolic process; TAS:Reactome.
DR GO; GO:0051259; P:protein oligomerization; IDA:UniProtKB.
DR Gene3D; 3.40.50.720; -; 2.
DR InterPro; IPR006139; D-isomer_2_OHA_DH_cat_dom.
DR InterPro; IPR006140; D-isomer_2_OHA_DH_NAD-bd.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR Pfam; PF00389; 2-Hacid_dh; 1.
DR Pfam; PF02826; 2-Hacid_dh_C; 1.
DR PROSITE; PS00065; D_2_HYDROXYACID_DH_1; FALSE_NEG.
DR PROSITE; PS00670; D_2_HYDROXYACID_DH_2; FALSE_NEG.
DR PROSITE; PS00671; D_2_HYDROXYACID_DH_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; NADP; Oxidoreductase; Polymorphism;
KW Reference proteome.
FT CHAIN 1 328 Glyoxylate reductase/hydroxypyruvate
FT reductase.
FT /FTId=PRO_0000075944.
FT NP_BIND 162 164 NADP.
FT NP_BIND 185 188 NADP.
FT REGION 83 84 Substrate binding.
FT REGION 293 296 Substrate binding.
FT ACT_SITE 293 293 Proton donor.
FT BINDING 217 217 NADP.
FT BINDING 243 243 NADP; via carbonyl oxygen.
FT BINDING 245 245 Substrate.
FT BINDING 269 269 Substrate.
FT BINDING 295 295 NADP; via amide nitrogen.
FT SITE 274 274 Raises pKa of active site His.
FT VARIANT 170 170 R -> Q (in dbSNP:rs12002324).
FT /FTId=VAR_032762.
FT STRAND 7 13
FT HELIX 17 25
FT STRAND 29 33
FT STRAND 36 38
FT HELIX 42 49
FT STRAND 53 57
FT HELIX 65 71
FT STRAND 77 83
FT HELIX 90 95
FT STRAND 99 101
FT HELIX 108 123
FT HELIX 126 134
FT STRAND 143 146
FT STRAND 155 159
FT HELIX 163 172
FT HELIX 173 175
FT STRAND 179 186
FT HELIX 189 193
FT TURN 194 196
FT STRAND 197 199
FT HELIX 202 208
FT STRAND 210 214
FT TURN 220 224
FT HELIX 228 233
FT STRAND 239 242
FT HELIX 246 248
FT HELIX 251 259
FT STRAND 262 269
FT STRAND 272 275
FT HELIX 281 284
FT STRAND 288 290
FT HELIX 299 318
SQ SEQUENCE 328 AA; 35668 MW; 68A0E311AA4E5650 CRC64;
MRPVRLMKVF VTRRIPAEGR VALARAADCE VEQWDSDEPI PAKELERGVA GAHGLLCLLS
DHVDKRILDA AGANLKVIST MSVGIDHLAL DEIKKRGIRV GYTPDVLTDT TAELAVSLLL
TTCRRLPEAI EEVKNGGWTS WKPLWLCGYG LTQSTVGIIG LGRIGQAIAR RLKPFGVQRF
LYTGRQPRPE EAAEFQAEFV STPELAAQSD FIVVACSLTP ATEGLCNKDF FQKMKETAVF
INISRGDVVN QDDLYQALAS GKIAAAGLDV TSPEPLPTNH PLLTLKNCVI LPHIGSATHR
TRNTMSLLAA NNLLAGLRGE PMPSELKL
//
ID GRHPR_HUMAN Reviewed; 328 AA.
AC Q9UBQ7; Q5T945; Q9H3E9; Q9UKX1;
DT 10-MAY-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-MAY-2000, sequence version 1.
DT 22-JAN-2014, entry version 126.
DE RecName: Full=Glyoxylate reductase/hydroxypyruvate reductase;
DE EC=1.1.1.79;
DE EC=1.1.1.81;
GN Name=GRHPR; Synonyms=GLXR; ORFNames=MSTP035;
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], AND SUBUNIT.
RC TISSUE=Liver;
RX PubMed=10524214; DOI=10.1016/S0167-4781(99)00105-0;
RA Rumsby G., Cregeen D.P.;
RT "Identification and expression of a cDNA for human
RT hydroxypyruvate/glyoxylate reductase.";
RL Biochim. Biophys. Acta 1446:383-388(1999).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA], AND INVOLVEMENT IN HP2.
RC TISSUE=Liver;
RX PubMed=10484776; DOI=10.1093/hmg/8.11.2063;
RA Cramer S.D., Ferree P.M., Lin K., Milliner D.S., Holmes R.P.;
RT "The gene encoding hydroxypyruvate reductase (GRHPR) is mutated in
RT patients with primary hyperoxaluria type II.";
RL Hum. Mol. Genet. 8:2063-2069(1999).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Aorta;
RA Liu B., Liu Y.Q., Wang X.Y., Zhao B., Sheng H., Zhao X.W., Liu S.,
RA Xu Y.Y., Ye J., Song L., Gao Y., Zhang C.L., Zhang J., Wei Y.J.,
RA Cao H.Q., Zhao Y., Liu L.S., Ding J.F., Gao R.L., Wu Q.Y., Qiang B.Q.,
RA Yuan J.G., Liew C.C., Zhao M.S., Hui R.T.;
RL Submitted (DEC-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Testis;
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 [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164053; DOI=10.1038/nature02465;
RA Humphray S.J., Oliver K., Hunt A.R., Plumb R.W., Loveland J.E.,
RA Howe K.L., Andrews T.D., Searle S., Hunt S.E., Scott C.E., Jones M.C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Ashwell R.I.S.,
RA Babbage A.K., Babbage S., Bagguley C.L., Bailey J., Banerjee R.,
RA Barker D.J., Barlow K.F., Bates K., Beasley H., Beasley O., Bird C.P.,
RA Bray-Allen S., Brown A.J., Brown J.Y., Burford D., Burrill W.,
RA Burton J., Carder C., Carter N.P., Chapman J.C., Chen Y., Clarke G.,
RA Clark S.Y., Clee C.M., Clegg S., Collier R.E., Corby N., Crosier M.,
RA Cummings A.T., Davies J., Dhami P., Dunn M., Dutta I., Dyer L.W.,
RA Earthrowl M.E., Faulkner L., Fleming C.J., Frankish A.,
RA Frankland J.A., French L., Fricker D.G., Garner P., Garnett J.,
RA Ghori J., Gilbert J.G.R., Glison C., Grafham D.V., Gribble S.,
RA Griffiths C., Griffiths-Jones S., Grocock R., Guy J., Hall R.E.,
RA Hammond S., Harley J.L., Harrison E.S.I., Hart E.A., Heath P.D.,
RA Henderson C.D., Hopkins B.L., Howard P.J., Howden P.J., Huckle E.,
RA Johnson C., Johnson D., Joy A.A., Kay M., Keenan S., Kershaw J.K.,
RA Kimberley A.M., King A., Knights A., Laird G.K., Langford C.,
RA Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C., Lloyd D.M.,
RA Lovell J., Martin S., Mashreghi-Mohammadi M., Matthews L., McLaren S.,
RA McLay K.E., McMurray A., Milne S., Nickerson T., Nisbett J.,
RA Nordsiek G., Pearce A.V., Peck A.I., Porter K.M., Pandian R.,
RA Pelan S., Phillimore B., Povey S., Ramsey Y., Rand V., Scharfe M.,
RA Sehra H.K., Shownkeen R., Sims S.K., Skuce C.D., Smith M.,
RA Steward C.A., Swarbreck D., Sycamore N., Tester J., Thorpe A.,
RA Tracey A., Tromans A., Thomas D.W., Wall M., Wallis J.M., West A.P.,
RA Whitehead S.L., Willey D.L., Williams S.A., Wilming L., Wray P.W.,
RA Young L., Ashurst J.L., Coulson A., Blocker H., Durbin R.M.,
RA Sulston J.E., Hubbard T., Jackson M.J., Bentley D.R., Beck S.,
RA Rogers J., Dunham I.;
RT "DNA sequence and analysis of human chromosome 9.";
RL Nature 429:369-374(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Kidney;
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 [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 45-328, AND TISSUE SPECIFICITY.
RX PubMed=10679197; DOI=10.1006/bbrc.2000.2122;
RA Huang T., Yang W., Pereira A.C., Craigen W.J., Shih V.E.;
RT "Cloning and characterization of a putative human D-2-hydroxyacid
RT dehydrogenase in chromosome 9q.";
RL Biochem. Biophys. Res. Commun. 268:298-301(2000).
RN [9]
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 [10]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) IN COMPLEX WITH NADP AND
RP SUBSTRATE, AND SUBUNIT.
RX PubMed=16756993; DOI=10.1016/j.jmb.2006.05.018;
RA Booth M.P.S., Conners R., Rumsby G., Brady R.L.;
RT "Structural basis of substrate specificity in human glyoxylate
RT reductase/hydroxypyruvate reductase.";
RL J. Mol. Biol. 360:178-189(2006).
RN [11]
RP X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) OF 2-328.
RG Center for eukaryotic structural genomics (CESG);
RT "Crystal structure of a glyoxylate/hydroxypyruvate reductase from Homo
RT sapiens.";
RL Submitted (FEB-2009) to the PDB data bank.
CC -!- FUNCTION: Enzyme with hydroxy-pyruvate reductase, glyoxylate
CC reductase and D-glycerate dehydrogenase enzymatic activities.
CC Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate
CC oxidizes D-glycerate to hydroxypyruvate.
CC -!- CATALYTIC ACTIVITY: Glycolate + NADP(+) = glyoxylate + NADPH.
CC -!- CATALYTIC ACTIVITY: D-glycerate + NAD(P)(+) = hydroxypyruvate +
CC NAD(P)H.
CC -!- SUBUNIT: Homodimer.
CC -!- TISSUE SPECIFICITY: Ubiquitous. Most abundantly expressed in the
CC liver.
CC -!- DISEASE: Hyperoxaluria primary 2 (HP2) [MIM:260000]: A disorder
CC characterized by elevated urinary excretion of oxalate and L-
CC glycerate, progressive tissue accumulation of insoluble calcium
CC oxalate, nephrolithiasis, nephrocalcinosis, and end-stage renal
CC disease. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Belongs to the D-isomer specific 2-hydroxyacid
CC dehydrogenase family.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAD54066.1; Type=Frameshift; Positions=109, 137;
CC Sequence=AAG39286.1; Type=Frameshift; Positions=237;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GRHPR";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; AF134895; AAF00111.1; -; mRNA.
DR EMBL; AF146018; AAD45886.1; -; mRNA.
DR EMBL; AF146689; AAD46517.1; -; Genomic_DNA.
DR EMBL; AF113215; AAG39286.1; ALT_FRAME; mRNA.
DR EMBL; AK315690; BAG38053.1; -; mRNA.
DR EMBL; AL158155; CAI13848.1; -; Genomic_DNA.
DR EMBL; CH471071; EAW58284.1; -; Genomic_DNA.
DR EMBL; BC000605; AAH00605.1; -; mRNA.
DR EMBL; AF113251; AAD54066.1; ALT_FRAME; mRNA.
DR PIR; JC7190; JC7190.
DR RefSeq; NP_036335.1; NM_012203.1.
DR UniGene; Hs.155742; -.
DR PDB; 2GCG; X-ray; 2.20 A; A/B/C/D=1-328.
DR PDB; 2H1S; X-ray; 2.45 A; A/B/C/D=2-328.
DR PDB; 2Q50; X-ray; 2.45 A; A/B/C/D=2-328.
DR PDB; 2WWR; X-ray; 2.82 A; A/B/C/D=1-328.
DR PDBsum; 2GCG; -.
DR PDBsum; 2H1S; -.
DR PDBsum; 2Q50; -.
DR PDBsum; 2WWR; -.
DR ProteinModelPortal; Q9UBQ7; -.
DR SMR; Q9UBQ7; 5-328.
DR IntAct; Q9UBQ7; 5.
DR MINT; MINT-5005010; -.
DR STRING; 9606.ENSP00000313432; -.
DR PhosphoSite; Q9UBQ7; -.
DR DMDM; 47116943; -.
DR REPRODUCTION-2DPAGE; IPI00037448; -.
DR UCD-2DPAGE; Q9UBQ7; -.
DR PaxDb; Q9UBQ7; -.
DR PRIDE; Q9UBQ7; -.
DR DNASU; 9380; -.
DR Ensembl; ENST00000318158; ENSP00000313432; ENSG00000137106.
DR GeneID; 9380; -.
DR KEGG; hsa:9380; -.
DR UCSC; uc003zzt.1; human.
DR CTD; 9380; -.
DR GeneCards; GC09P037412; -.
DR HGNC; HGNC:4570; GRHPR.
DR HPA; HPA022971; -.
DR MIM; 260000; phenotype.
DR MIM; 604296; gene.
DR neXtProt; NX_Q9UBQ7; -.
DR Orphanet; 93599; Primary hyperoxaluria type 2.
DR PharmGKB; PA28965; -.
DR eggNOG; COG1052; -.
DR HOVERGEN; HBG051838; -.
DR KO; K00049; -.
DR OMA; ERSMKPS; -.
DR PhylomeDB; Q9UBQ7; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; Q9UBQ7; -.
DR ChiTaRS; GRHPR; human.
DR EvolutionaryTrace; Q9UBQ7; -.
DR GeneWiki; GRHPR; -.
DR GenomeRNAi; 9380; -.
DR NextBio; 35148; -.
DR PRO; PR:Q9UBQ7; -.
DR ArrayExpress; Q9UBQ7; -.
DR Bgee; Q9UBQ7; -.
DR CleanEx; HS_GRHPR; -.
DR Genevestigator; Q9UBQ7; -.
DR GO; GO:0005782; C:peroxisomal matrix; TAS:Reactome.
DR GO; GO:0008465; F:glycerate dehydrogenase activity; IDA:UniProtKB.
DR GO; GO:0030267; F:glyoxylate reductase (NADP) activity; IDA:UniProtKB.
DR GO; GO:0016618; F:hydroxypyruvate reductase activity; IDA:UniProtKB.
DR GO; GO:0051287; F:NAD binding; TAS:UniProtKB.
DR GO; GO:0070402; F:NADPH binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0034641; P:cellular nitrogen compound metabolic process; TAS:Reactome.
DR GO; GO:0007588; P:excretion; IMP:UniProtKB.
DR GO; GO:0046487; P:glyoxylate metabolic process; TAS:Reactome.
DR GO; GO:0051259; P:protein oligomerization; IDA:UniProtKB.
DR Gene3D; 3.40.50.720; -; 2.
DR InterPro; IPR006139; D-isomer_2_OHA_DH_cat_dom.
DR InterPro; IPR006140; D-isomer_2_OHA_DH_NAD-bd.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR Pfam; PF00389; 2-Hacid_dh; 1.
DR Pfam; PF02826; 2-Hacid_dh_C; 1.
DR PROSITE; PS00065; D_2_HYDROXYACID_DH_1; FALSE_NEG.
DR PROSITE; PS00670; D_2_HYDROXYACID_DH_2; FALSE_NEG.
DR PROSITE; PS00671; D_2_HYDROXYACID_DH_3; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Complete proteome; NADP; Oxidoreductase; Polymorphism;
KW Reference proteome.
FT CHAIN 1 328 Glyoxylate reductase/hydroxypyruvate
FT reductase.
FT /FTId=PRO_0000075944.
FT NP_BIND 162 164 NADP.
FT NP_BIND 185 188 NADP.
FT REGION 83 84 Substrate binding.
FT REGION 293 296 Substrate binding.
FT ACT_SITE 293 293 Proton donor.
FT BINDING 217 217 NADP.
FT BINDING 243 243 NADP; via carbonyl oxygen.
FT BINDING 245 245 Substrate.
FT BINDING 269 269 Substrate.
FT BINDING 295 295 NADP; via amide nitrogen.
FT SITE 274 274 Raises pKa of active site His.
FT VARIANT 170 170 R -> Q (in dbSNP:rs12002324).
FT /FTId=VAR_032762.
FT STRAND 7 13
FT HELIX 17 25
FT STRAND 29 33
FT STRAND 36 38
FT HELIX 42 49
FT STRAND 53 57
FT HELIX 65 71
FT STRAND 77 83
FT HELIX 90 95
FT STRAND 99 101
FT HELIX 108 123
FT HELIX 126 134
FT STRAND 143 146
FT STRAND 155 159
FT HELIX 163 172
FT HELIX 173 175
FT STRAND 179 186
FT HELIX 189 193
FT TURN 194 196
FT STRAND 197 199
FT HELIX 202 208
FT STRAND 210 214
FT TURN 220 224
FT HELIX 228 233
FT STRAND 239 242
FT HELIX 246 248
FT HELIX 251 259
FT STRAND 262 269
FT STRAND 272 275
FT HELIX 281 284
FT STRAND 288 290
FT HELIX 299 318
SQ SEQUENCE 328 AA; 35668 MW; 68A0E311AA4E5650 CRC64;
MRPVRLMKVF VTRRIPAEGR VALARAADCE VEQWDSDEPI PAKELERGVA GAHGLLCLLS
DHVDKRILDA AGANLKVIST MSVGIDHLAL DEIKKRGIRV GYTPDVLTDT TAELAVSLLL
TTCRRLPEAI EEVKNGGWTS WKPLWLCGYG LTQSTVGIIG LGRIGQAIAR RLKPFGVQRF
LYTGRQPRPE EAAEFQAEFV STPELAAQSD FIVVACSLTP ATEGLCNKDF FQKMKETAVF
INISRGDVVN QDDLYQALAS GKIAAAGLDV TSPEPLPTNH PLLTLKNCVI LPHIGSATHR
TRNTMSLLAA NNLLAGLRGE PMPSELKL
//
MIM
260000
*RECORD*
*FIELD* NO
260000
*FIELD* TI
#260000 HYPEROXALURIA, PRIMARY, TYPE II; HP2
;;OXALOSIS II;;
GLYCERIC ACIDURIA;;
GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE DEFICIENCY;;
read moreD-GLYCERATE DEHYDROGENASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that type
II primary hyperoxaluria (HP2) can be caused by homozygous mutation in
the glyoxylate reductase/hydroxypyruvate reductase gene (GRHPR; 604296)
on chromosome 9p13.
For a discussion of genetic heterogeneity of primary hyperoxaluria, see
259900.
CLINICAL FEATURES
Williams and Smith (1971) presented evidence that in hyperoxaluria II,
hydroxypyruvate, present in excess because of deficiency in the enzyme
that converts it to D-glycerate, stimulates oxidation of glycolate to
oxalate, and decreases reduction of glyoxylate to glycolate. This is a
novel explanation for the phenotypic consequences of a garrodian inborn
error of metabolism. D-glycerate dehydrogenase also has glyoxylate
reductase activity; Seargeant et al. (1991) quoted the opinion that
deficiency of glyoxylate reductase activity may be responsible for the
hyperoxaluria in this disorder. To the 8 previously reported patients,
they added 8 more who belonged to 3 Saulteaux-Ojibway Canadian Indian
families living in 2 isolated communities in northwestern Ontario. They
demonstrated combined deficiencies of D-glycerate dehydrogenase and
glyoxylate reductase. The 2 activities are attributable to a single
enzyme. Deficiency of D-glycerate dehydrogenase activity presumably
causes accumulation of its substrate, hydroxypyruvate, which is then
converted to L-glycerate by the action of L-lactate dehydrogenase.
Deficiency of glyoxylate reductase activity presumably causes impaired
conversion of glyoxylate to glycolate. Conversion of glyoxylate to
oxalate by L-lactate dehydrogenase would explain the observed
hyperoxaluria. As in type I primary hyperoxaluria, the main clinical
manifestation is calcium oxalate nephrolithiasis. Seven of the 8
previously reported patients had renal calculi between 18 months and 24
years of age. One patient seemed to have had no symptoms and was
identified only because his younger brother had the disorder (Chalmers
et al., 1984). Four of the 8 patients studied by Seargeant et al. (1991)
were free of symptoms and 3 had not had recurrences. Thus, hyperoxaluria
type II may be a much milder disease with a better long-term prognosis
for renal function than is the case in type I. Van Schaftingen et al.
(1989) presented evidence that D-glycerate dehydrogenase should be
considered an NADPH-linked reductase. This property accounts well for
the function of the enzyme, which is to maintain the cytosolic
concentration of hydroxypyruvate and glyoxylate at a very low level,
thus preventing the formation of oxalate.
Kemper et al. (1997) stated that only 24 patients with primary
hyperoxaluria type II had been reported. It should be considered in any
patient presenting with urolithiasis or nephrocalcinosis due to
hyperoxaluria. The metabolic defect is deficiency of D-glycerate
dehydrogenase/glyoxylate reductase leading to characteristic
hyperoxaluria and excretion of L-glycerate, the cornerstone of diagnosis
of this form of primary hyperoxaluria. Although development of terminal
renal failure may be less common than in type I primary hyperoxaluria,
chronic as well as terminal renal insufficiency has been described.
Therefore, specific therapeutic measures should aim at reduction of
urinary calcium oxalate saturation by potassium citrate or pyrophosphate
to reduce the incidence of nephrolithiasis and nephrocalcinosis and thus
improve renal survival. Secondary complications (obstruction, urinary
tract infections, and pyelonephritis) must be avoided. In patients with
terminal renal failure, renal transplantation seems to carry a high risk
of disease recurrence.
MOLECULAR GENETICS
Cramer et al. (1999) found homozygosity for an identical mutation in the
GRHPR gene (604296.0001) in 2 pairs of sibs from unrelated families with
type II primary hyperoxaluria.
*FIELD* SA
Williams and Smith (1978); Yendt and Cohanim (1985)
*FIELD* RF
1. Chalmers, R. A.; Tracey, B. M.; Mistry, J.; Griffiths, K. D.; Green,
A.; Winterborn, M. H.: L-glyceric aciduria (primary hyperoxaluria
type 2) in siblings in two unrelated families. J. Inherit. Metab.
Dis. 7 (suppl. 2): 133-134, 1984.
2. Cramer, S. D.; Ferree, P. M.; Lin, K.; Milliner, D. S.; Holmes,
R. P.: The gene encoding hydroxypyruvate reductase (GRHPR) is mutated
in patients with primary hyperoxaluria type II. Hum. Molec. Genet. 8:
2063-2069, 1999. Note: Erratum: Hum. Molec. Genet. 8: 2574 only, 1999.
3. Kemper, M. J.; Conrad, S.; Muller-Wiefel, D. E.: Primary hyperoxaluria
type 2. Europ. J. Pediat. 156: 509-512, 1997.
4. Seargeant, L. E.; deGroot, G. W.; Dilling, L. A.; Mallory, C. J.;
Haworth, J. C.: Primary oxaluria type 2 (L-glyceric aciduria): a
rare cause of nephrolithiasis in children. J. Pediat. 118: 912-914,
1991.
5. Van Schaftingen, E.; Draye, J.-P.; Van Hoof, F.: Coenzyme specificity
of mammalian liver D-glycerate dehydrogenase. Europ. J. Biochem. 186:
355-359, 1989.
6. Williams, H. E.; Smith, L. H., Jr.: Hyperoxaluria in L-glyceric
aciduria: possible pathogenetic mechanism. Science 171: 390-391,
1971.
7. Williams, H. E.; Smith, L. H., Jr.: Primary hyperoxaluria.In:
Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.: Metabolic
Basis of Inherited Disease. New York: McGraw-Hill (pub.) (4th
ed.): 1978. Pp. 182-204.
8. Yendt, E. R.; Cohanim, M.: Response to a physiologic dose of pyridoxine
in type I primary hyperoxaluria. New Eng. J. Med. 312: 953-957,
1985.
*FIELD* CS
GU:
Calcium oxalate urolithiasis
Lab:
D-glycerate dehydrogenase deficiency;
Hyperoxaluria;
Glyceric aciduria
Misc:
Milder disease with better longterm prognosis for renal function than
in type I
Inheritance:
Autosomal recessive;
two separate loci
*FIELD* CN
Victor A. McKusick - updated: 10/25/1999
Victor A. McKusick - updated: 9/5/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 11/21/2012
terry: 10/4/2012
terry: 4/20/2005
tkritzer: 9/17/2003
mgross: 11/16/1999
mgross: 11/15/1999
terry: 10/25/1999
dkim: 7/24/1998
mark: 9/12/1997
terry: 9/5/1997
davew: 8/19/1994
mimadm: 3/11/1994
supermim: 3/17/1992
carol: 2/22/1992
carol: 2/10/1992
carol: 9/16/1991
*RECORD*
*FIELD* NO
260000
*FIELD* TI
#260000 HYPEROXALURIA, PRIMARY, TYPE II; HP2
;;OXALOSIS II;;
GLYCERIC ACIDURIA;;
GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE DEFICIENCY;;
read moreD-GLYCERATE DEHYDROGENASE DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because of evidence that type
II primary hyperoxaluria (HP2) can be caused by homozygous mutation in
the glyoxylate reductase/hydroxypyruvate reductase gene (GRHPR; 604296)
on chromosome 9p13.
For a discussion of genetic heterogeneity of primary hyperoxaluria, see
259900.
CLINICAL FEATURES
Williams and Smith (1971) presented evidence that in hyperoxaluria II,
hydroxypyruvate, present in excess because of deficiency in the enzyme
that converts it to D-glycerate, stimulates oxidation of glycolate to
oxalate, and decreases reduction of glyoxylate to glycolate. This is a
novel explanation for the phenotypic consequences of a garrodian inborn
error of metabolism. D-glycerate dehydrogenase also has glyoxylate
reductase activity; Seargeant et al. (1991) quoted the opinion that
deficiency of glyoxylate reductase activity may be responsible for the
hyperoxaluria in this disorder. To the 8 previously reported patients,
they added 8 more who belonged to 3 Saulteaux-Ojibway Canadian Indian
families living in 2 isolated communities in northwestern Ontario. They
demonstrated combined deficiencies of D-glycerate dehydrogenase and
glyoxylate reductase. The 2 activities are attributable to a single
enzyme. Deficiency of D-glycerate dehydrogenase activity presumably
causes accumulation of its substrate, hydroxypyruvate, which is then
converted to L-glycerate by the action of L-lactate dehydrogenase.
Deficiency of glyoxylate reductase activity presumably causes impaired
conversion of glyoxylate to glycolate. Conversion of glyoxylate to
oxalate by L-lactate dehydrogenase would explain the observed
hyperoxaluria. As in type I primary hyperoxaluria, the main clinical
manifestation is calcium oxalate nephrolithiasis. Seven of the 8
previously reported patients had renal calculi between 18 months and 24
years of age. One patient seemed to have had no symptoms and was
identified only because his younger brother had the disorder (Chalmers
et al., 1984). Four of the 8 patients studied by Seargeant et al. (1991)
were free of symptoms and 3 had not had recurrences. Thus, hyperoxaluria
type II may be a much milder disease with a better long-term prognosis
for renal function than is the case in type I. Van Schaftingen et al.
(1989) presented evidence that D-glycerate dehydrogenase should be
considered an NADPH-linked reductase. This property accounts well for
the function of the enzyme, which is to maintain the cytosolic
concentration of hydroxypyruvate and glyoxylate at a very low level,
thus preventing the formation of oxalate.
Kemper et al. (1997) stated that only 24 patients with primary
hyperoxaluria type II had been reported. It should be considered in any
patient presenting with urolithiasis or nephrocalcinosis due to
hyperoxaluria. The metabolic defect is deficiency of D-glycerate
dehydrogenase/glyoxylate reductase leading to characteristic
hyperoxaluria and excretion of L-glycerate, the cornerstone of diagnosis
of this form of primary hyperoxaluria. Although development of terminal
renal failure may be less common than in type I primary hyperoxaluria,
chronic as well as terminal renal insufficiency has been described.
Therefore, specific therapeutic measures should aim at reduction of
urinary calcium oxalate saturation by potassium citrate or pyrophosphate
to reduce the incidence of nephrolithiasis and nephrocalcinosis and thus
improve renal survival. Secondary complications (obstruction, urinary
tract infections, and pyelonephritis) must be avoided. In patients with
terminal renal failure, renal transplantation seems to carry a high risk
of disease recurrence.
MOLECULAR GENETICS
Cramer et al. (1999) found homozygosity for an identical mutation in the
GRHPR gene (604296.0001) in 2 pairs of sibs from unrelated families with
type II primary hyperoxaluria.
*FIELD* SA
Williams and Smith (1978); Yendt and Cohanim (1985)
*FIELD* RF
1. Chalmers, R. A.; Tracey, B. M.; Mistry, J.; Griffiths, K. D.; Green,
A.; Winterborn, M. H.: L-glyceric aciduria (primary hyperoxaluria
type 2) in siblings in two unrelated families. J. Inherit. Metab.
Dis. 7 (suppl. 2): 133-134, 1984.
2. Cramer, S. D.; Ferree, P. M.; Lin, K.; Milliner, D. S.; Holmes,
R. P.: The gene encoding hydroxypyruvate reductase (GRHPR) is mutated
in patients with primary hyperoxaluria type II. Hum. Molec. Genet. 8:
2063-2069, 1999. Note: Erratum: Hum. Molec. Genet. 8: 2574 only, 1999.
3. Kemper, M. J.; Conrad, S.; Muller-Wiefel, D. E.: Primary hyperoxaluria
type 2. Europ. J. Pediat. 156: 509-512, 1997.
4. Seargeant, L. E.; deGroot, G. W.; Dilling, L. A.; Mallory, C. J.;
Haworth, J. C.: Primary oxaluria type 2 (L-glyceric aciduria): a
rare cause of nephrolithiasis in children. J. Pediat. 118: 912-914,
1991.
5. Van Schaftingen, E.; Draye, J.-P.; Van Hoof, F.: Coenzyme specificity
of mammalian liver D-glycerate dehydrogenase. Europ. J. Biochem. 186:
355-359, 1989.
6. Williams, H. E.; Smith, L. H., Jr.: Hyperoxaluria in L-glyceric
aciduria: possible pathogenetic mechanism. Science 171: 390-391,
1971.
7. Williams, H. E.; Smith, L. H., Jr.: Primary hyperoxaluria.In:
Stanbury, J. B.; Wyngaarden, J. B.; Fredrickson, D. S.: Metabolic
Basis of Inherited Disease. New York: McGraw-Hill (pub.) (4th
ed.): 1978. Pp. 182-204.
8. Yendt, E. R.; Cohanim, M.: Response to a physiologic dose of pyridoxine
in type I primary hyperoxaluria. New Eng. J. Med. 312: 953-957,
1985.
*FIELD* CS
GU:
Calcium oxalate urolithiasis
Lab:
D-glycerate dehydrogenase deficiency;
Hyperoxaluria;
Glyceric aciduria
Misc:
Milder disease with better longterm prognosis for renal function than
in type I
Inheritance:
Autosomal recessive;
two separate loci
*FIELD* CN
Victor A. McKusick - updated: 10/25/1999
Victor A. McKusick - updated: 9/5/1997
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 11/21/2012
terry: 10/4/2012
terry: 4/20/2005
tkritzer: 9/17/2003
mgross: 11/16/1999
mgross: 11/15/1999
terry: 10/25/1999
dkim: 7/24/1998
mark: 9/12/1997
terry: 9/5/1997
davew: 8/19/1994
mimadm: 3/11/1994
supermim: 3/17/1992
carol: 2/22/1992
carol: 2/10/1992
carol: 9/16/1991
MIM
604296
*RECORD*
*FIELD* NO
604296
*FIELD* TI
*604296 GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE; GRHPR
;;GLXR
*FIELD* TX
CLONING
read more
Cramer et al. (1999) and Rumsby and Cregeen (1999) independently
identified a glyoxylate reductase/hydroxypyruvate reductase (GRHPR; EC
1.1.1.79) cDNA clone from a human liver EST library. The GRHPR gene
encodes a predicted 328-amino acid protein with a calculated molecular
mass of 35.5 kD. By transient transfection of the cDNA clone into COS
cells, Cramer et al. (1999) verified that GRHPR encodes an enzyme with
hydroxypyruvate reductase, glyoxylate reductase, and D-glycerate
dehydrogenase enzymatic activities. Database analysis of human ESTs
revealed widespread tissue expression, indicating that the enzyme may
have a role in metabolism.
GENE STRUCTURE
Cramer et al. (1999) determined that the GRHPR gene contains 9 exons
spanning approximately 9 kb.
MAPPING
Using ESTs, Cramer et al. (1999) found that the GRHPR gene maps
pericentromeric on chromosome 9. Webster et al. (2000) presented
haplotype data indicating that the GRHPR gene is located near the marker
D9S1874.
MOLECULAR GENETICS
In 2 pairs of sibs from 2 unrelated families with type II hyperoxaluria
(260000), Cramer et al. (1999) identified a 1-bp deletion in the GRHPR
gene (103delG; 604296.0001) by SSCP analysis. All 4 patients were
homozygous for the same mutation.
Webster et al. (2000) identified 5 other mutations in patients with type
II hyperoxaluria. Ten of 11 patients that they had genotyped were
homozygous for 1 of the 6 known mutations. In the case of two-thirds of
the patients, the parents were related. Genotyping also showed the
possible presence of a founder effect for the 2 most common mutations:
103delG and arg99 to ter (604296.0002).
*FIELD* AV
.0001
HYPEROXALURIA, PRIMARY, TYPE II
GRHPR, 1-BP DEL, 103G
In 2 pairs of sibs from 2 unrelated families with type II primary
hyperoxaluria (260000), Cramer et al. (1999) identified deletion of the
first nucleotide (G) of codon 35 (103G) of the GRHPR gene, resulting in
a frameshift beginning at codon 35 and predicted to result in a
truncated protein of 44 amino acids. All 4 patients were homozygous for
this mutation.
.0002
HYPEROXALURIA, PRIMARY, TYPE II
GRHPR, ARG99TER
In 4 of 18 alleles of the GRHPR gene in patients with type II primary
hyperoxaluria (260000), Webster et al. (2000) found a 295C-T transition
causing a nonsense arg99-to-ter amino acid substitution.
*FIELD* RF
1. Cramer, S. D.; Ferree, P. M.; Lin, K.; Milliner, D. S.; Holmes,
R. P.: The gene encoding hydroxypyruvate reductase (GRHPR) is mutated
in patients with primary hyperoxaluria type II. Hum. Molec. Genet. 8:
2063-2069, 1999. Note: Erratum: Hum. Molec. Genet. 8: 2574 only, 1999.
2. Rumsby, G.; Cregeen, D. P.: Identification and expression of a
cDNA for human hydroxypyruvate/glyoxylate reductase. Biochim. Biophys.
Acta 1446: 383-388, 1999.
3. Webster, K. E.; Ferree, P. M.; Holmes, R. P.; Cramer, S. D.: Identification
of missense, nonsense, and deletion mutations in the GRHPR gene in
patients with primary hyperoxaluria type II (PH2). Hum. Genet. 107:
176-185, 2000.
*FIELD* CN
Victor A. McKusick - updated: 9/14/2000
*FIELD* CD
Victor A. McKusick: 11/15/1999
*FIELD* ED
terry: 10/04/2012
wwang: 9/22/2009
mcapotos: 10/5/2000
mcapotos: 9/26/2000
terry: 9/14/2000
mgross: 11/23/1999
mgross: 11/15/1999
*RECORD*
*FIELD* NO
604296
*FIELD* TI
*604296 GLYOXYLATE REDUCTASE/HYDROXYPYRUVATE REDUCTASE; GRHPR
;;GLXR
*FIELD* TX
CLONING
read more
Cramer et al. (1999) and Rumsby and Cregeen (1999) independently
identified a glyoxylate reductase/hydroxypyruvate reductase (GRHPR; EC
1.1.1.79) cDNA clone from a human liver EST library. The GRHPR gene
encodes a predicted 328-amino acid protein with a calculated molecular
mass of 35.5 kD. By transient transfection of the cDNA clone into COS
cells, Cramer et al. (1999) verified that GRHPR encodes an enzyme with
hydroxypyruvate reductase, glyoxylate reductase, and D-glycerate
dehydrogenase enzymatic activities. Database analysis of human ESTs
revealed widespread tissue expression, indicating that the enzyme may
have a role in metabolism.
GENE STRUCTURE
Cramer et al. (1999) determined that the GRHPR gene contains 9 exons
spanning approximately 9 kb.
MAPPING
Using ESTs, Cramer et al. (1999) found that the GRHPR gene maps
pericentromeric on chromosome 9. Webster et al. (2000) presented
haplotype data indicating that the GRHPR gene is located near the marker
D9S1874.
MOLECULAR GENETICS
In 2 pairs of sibs from 2 unrelated families with type II hyperoxaluria
(260000), Cramer et al. (1999) identified a 1-bp deletion in the GRHPR
gene (103delG; 604296.0001) by SSCP analysis. All 4 patients were
homozygous for the same mutation.
Webster et al. (2000) identified 5 other mutations in patients with type
II hyperoxaluria. Ten of 11 patients that they had genotyped were
homozygous for 1 of the 6 known mutations. In the case of two-thirds of
the patients, the parents were related. Genotyping also showed the
possible presence of a founder effect for the 2 most common mutations:
103delG and arg99 to ter (604296.0002).
*FIELD* AV
.0001
HYPEROXALURIA, PRIMARY, TYPE II
GRHPR, 1-BP DEL, 103G
In 2 pairs of sibs from 2 unrelated families with type II primary
hyperoxaluria (260000), Cramer et al. (1999) identified deletion of the
first nucleotide (G) of codon 35 (103G) of the GRHPR gene, resulting in
a frameshift beginning at codon 35 and predicted to result in a
truncated protein of 44 amino acids. All 4 patients were homozygous for
this mutation.
.0002
HYPEROXALURIA, PRIMARY, TYPE II
GRHPR, ARG99TER
In 4 of 18 alleles of the GRHPR gene in patients with type II primary
hyperoxaluria (260000), Webster et al. (2000) found a 295C-T transition
causing a nonsense arg99-to-ter amino acid substitution.
*FIELD* RF
1. Cramer, S. D.; Ferree, P. M.; Lin, K.; Milliner, D. S.; Holmes,
R. P.: The gene encoding hydroxypyruvate reductase (GRHPR) is mutated
in patients with primary hyperoxaluria type II. Hum. Molec. Genet. 8:
2063-2069, 1999. Note: Erratum: Hum. Molec. Genet. 8: 2574 only, 1999.
2. Rumsby, G.; Cregeen, D. P.: Identification and expression of a
cDNA for human hydroxypyruvate/glyoxylate reductase. Biochim. Biophys.
Acta 1446: 383-388, 1999.
3. Webster, K. E.; Ferree, P. M.; Holmes, R. P.; Cramer, S. D.: Identification
of missense, nonsense, and deletion mutations in the GRHPR gene in
patients with primary hyperoxaluria type II (PH2). Hum. Genet. 107:
176-185, 2000.
*FIELD* CN
Victor A. McKusick - updated: 9/14/2000
*FIELD* CD
Victor A. McKusick: 11/15/1999
*FIELD* ED
terry: 10/04/2012
wwang: 9/22/2009
mcapotos: 10/5/2000
mcapotos: 9/26/2000
terry: 9/14/2000
mgross: 11/23/1999
mgross: 11/15/1999