Full text data of GSS
GSS
[Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Glutathione synthetase; GSH synthetase; GSH-S; 6.3.2.3 (Glutathione synthase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Glutathione synthetase; GSH synthetase; GSH-S; 6.3.2.3 (Glutathione synthase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
hRBCD
IPI00010706
IPI00010706 Glutathione synthetase ATP + gamma-L-glutamyl-L-cysteine + glycine = ADP + phosphate + glutathione, glutathione synthase activity, amino acid metabolism, response to oxidative stress soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
IPI00010706 Glutathione synthetase ATP + gamma-L-glutamyl-L-cysteine + glycine = ADP + phosphate + glutathione, glutathione synthase activity, amino acid metabolism, response to oxidative stress soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic n/a found at its expected molecular weight found at molecular weight
UniProt
P48637
ID GSHB_HUMAN Reviewed; 474 AA.
AC P48637; B2R697; B6F210; E1P5P9; Q4TTD9;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 1.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Glutathione synthetase;
DE Short=GSH synthetase;
DE Short=GSH-S;
DE EC=6.3.2.3;
DE AltName: Full=Glutathione synthase;
GN Name=GSS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=7646467;
RA Gali R.R., Board P.G.;
RT "Sequencing and expression of a cDNA for human glutathione
RT synthetase.";
RL Biochem. J. 310:353-358(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=19672693; DOI=10.1007/s11033-009-9675-3;
RA Uchida M., Sugaya M., Kanamaru T., Hisatomi H.;
RT "Alternative RNA splicing in expression of the glutathione synthetase
RT gene in human cells.";
RL Mol. Biol. Rep. 37:2105-2109(2010).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RA Shi Z.-Z., Galang R.L., Habib G.M., Lebovitz R.M., Lieberman M.W.;
RL Submitted (AUG-1995) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP GLU-437.
RC TISSUE=Substantia nigra;
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 [GENOMIC DNA], AND VARIANTS GLN-236 AND GLU-437.
RG NIEHS SNPs program;
RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [7]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
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 [9]
RP PROTEIN SEQUENCE OF 26-34; 113-125; 142-158; 222-230; 254-267;
RP 274-283; 294-305; 419-434 AND 453-474, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
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 [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 1-474 IN COMPLEX WITH ADP
RP AND GLUTATHIONE, COFACTOR, AND SUBUNIT.
RX PubMed=10369661; DOI=10.1093/emboj/18.12.3204;
RA Polekhina G., Board P.G., Gali R.R., Rossjohn J., Parker M.W.;
RT "Molecular basis of glutathione synthetase deficiency and a rare gene
RT permutation event.";
RL EMBO J. 18:3204-3213(1999).
RN [14]
RP VARIANTS GSS DEFICIENCY GLY-219; TRP-267 AND CYS-283.
RX PubMed=8896573; DOI=10.1038/ng1196-361;
RA Shi Z.-Z., Habib G.M., Rhead W.J., Gahl W.A., He X., Sazer S.,
RA Lieberman M.W.;
RT "Mutations in the glutathione synthetase gene cause 5-oxoprolinuria.";
RL Nat. Genet. 14:361-365(1996).
RN [15]
RP VARIANTS GSS DEFICIENCY.
RX PubMed=9215686; DOI=10.1093/hmg/6.7.1147;
RA Dahl N., Pigg M., Ristoff E., Gali R., Carlsson B., Mannervik B.,
RA Larsson A., Board P.;
RT "Missense mutations in the human glutathione synthetase gene result in
RT severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and
RT neurological dysfunction.";
RL Hum. Mol. Genet. 6:1147-1152(1997).
CC -!- CATALYTIC ACTIVITY: ATP + gamma-L-glutamyl-L-cysteine + glycine =
CC ADP + phosphate + glutathione.
CC -!- COFACTOR: Binds 1 magnesium ion per subunit.
CC -!- PATHWAY: Sulfur metabolism; glutathione biosynthesis; glutathione
CC from L-cysteine and L-glutamate: step 2/2.
CC -!- SUBUNIT: Homodimer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P48637-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P48637-2; Sequence=VSP_047617;
CC Note=Detected in colon, kidney, lung, liver, placenta,
CC peripheral blood and uterus, but not in heart, skeletal muscle
CC and spleen;
CC -!- DISEASE: Glutathione synthetase deficiency (GSS deficiency)
CC [MIM:266130]: Severe form characterized by an increased rate of
CC hemolysis and defective function of the central nervous system.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Glutathione synthetase deficiency of erythrocytes
CC (GLUSYNDE) [MIM:231900]: Mild form causing hemolytic anemia.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the eukaryotic GSH synthase family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GSS";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/gss/";
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DR EMBL; L42531; AAA69492.1; -; mRNA.
DR EMBL; AB459500; BAG75452.1; -; mRNA.
DR EMBL; U34683; AAB62390.1; -; mRNA.
DR EMBL; AK312492; BAG35394.1; -; mRNA.
DR EMBL; DQ074975; AAY57328.1; -; Genomic_DNA.
DR EMBL; AL133324; CAB93423.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW76239.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW76240.1; -; Genomic_DNA.
DR EMBL; BC007927; AAH07927.1; -; mRNA.
DR PIR; S56748; S56748.
DR RefSeq; NP_000169.1; NM_000178.2.
DR RefSeq; XP_005260462.1; XM_005260405.1.
DR RefSeq; XP_005260463.1; XM_005260406.1.
DR UniGene; Hs.82327; -.
DR PDB; 2HGS; X-ray; 2.10 A; A=1-474.
DR PDBsum; 2HGS; -.
DR ProteinModelPortal; P48637; -.
DR SMR; P48637; 3-474.
DR IntAct; P48637; 2.
DR MINT; MINT-5001027; -.
DR STRING; 9606.ENSP00000216951; -.
DR DrugBank; DB00143; Glutathione.
DR DrugBank; DB00145; Glycine.
DR DrugBank; DB00151; L-Cysteine.
DR PhosphoSite; P48637; -.
DR DMDM; 1346191; -.
DR OGP; P48637; -.
DR REPRODUCTION-2DPAGE; IPI00010706; -.
DR PaxDb; P48637; -.
DR PeptideAtlas; P48637; -.
DR PRIDE; P48637; -.
DR DNASU; 2937; -.
DR Ensembl; ENST00000216951; ENSP00000216951; ENSG00000100983.
DR Ensembl; ENST00000451957; ENSP00000407517; ENSG00000100983.
DR GeneID; 2937; -.
DR KEGG; hsa:2937; -.
DR UCSC; uc010zuo.2; human.
DR CTD; 2937; -.
DR GeneCards; GC20M033517; -.
DR HGNC; HGNC:4624; GSS.
DR HPA; HPA054508; -.
DR MIM; 231900; phenotype.
DR MIM; 266130; phenotype.
DR MIM; 601002; gene.
DR neXtProt; NX_P48637; -.
DR Orphanet; 289846; Glutathione synthetase deficiency with 5-oxoprolinuria.
DR Orphanet; 289849; Glutathione synthetase deficiency without 5-oxoprolinuria.
DR PharmGKB; PA29015; -.
DR eggNOG; NOG329040; -.
DR HOGENOM; HOG000172641; -.
DR HOVERGEN; HBG002458; -.
DR InParanoid; P48637; -.
DR KO; K01920; -.
DR OMA; FENCLLR; -.
DR OrthoDB; EOG757CXD; -.
DR PhylomeDB; P48637; -.
DR BioCyc; MetaCyc:HS02174-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P48637; -.
DR UniPathway; UPA00142; UER00210.
DR ChiTaRS; GSS; human.
DR EvolutionaryTrace; P48637; -.
DR GenomeRNAi; 2937; -.
DR NextBio; 11639; -.
DR PRO; PR:P48637; -.
DR ArrayExpress; P48637; -.
DR Bgee; P48637; -.
DR CleanEx; HS_GSS; -.
DR Genevestigator; P48637; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0043295; F:glutathione binding; IDA:UniProtKB.
DR GO; GO:0004363; F:glutathione synthase activity; TAS:Reactome.
DR GO; GO:0016594; F:glycine binding; IEA:Ensembl.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:1901687; P:glutathione derivative biosynthetic process; TAS:Reactome.
DR GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR GO; GO:0043200; P:response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; TAS:ProtInc.
DR GO; GO:0034612; P:response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR Gene3D; 1.10.1080.10; -; 2.
DR Gene3D; 3.30.1490.50; -; 1.
DR Gene3D; 3.30.1490.80; -; 2.
DR Gene3D; 3.40.50.1760; -; 1.
DR InterPro; IPR004887; Glutathione_synth_subst-bd_euk.
DR InterPro; IPR014042; Glutathione_synthase_a-hlx_euk.
DR InterPro; IPR014709; Glutathione_synthase_dom.
DR InterPro; IPR005615; Glutathione_synthase_euk.
DR InterPro; IPR014049; Glutathione_synthase_N_euk.
DR InterPro; IPR016185; PreATP-grasp_dom.
DR PANTHER; PTHR11130; PTHR11130; 1.
DR Pfam; PF03917; GSH_synth_ATP; 1.
DR Pfam; PF03199; GSH_synthase; 1.
DR PIRSF; PIRSF001558; GSHase; 1.
DR SUPFAM; SSF52440; SSF52440; 1.
DR TIGRFAMs; TIGR01986; glut_syn_euk; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Glutathione biosynthesis; Hereditary hemolytic anemia; Ligase;
KW Magnesium; Metal-binding; Nucleotide-binding; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 474 Glutathione synthetase.
FT /FTId=PRO_0000211260.
FT NP_BIND 364 373 ATP.
FT NP_BIND 398 401 ATP.
FT REGION 148 151 Substrate binding.
FT REGION 214 216 Substrate binding.
FT REGION 267 270 Substrate binding.
FT REGION 461 462 Substrate binding.
FT METAL 144 144 Magnesium.
FT METAL 146 146 Magnesium.
FT METAL 368 368 Magnesium.
FT BINDING 125 125 Substrate.
FT BINDING 144 144 ATP.
FT BINDING 220 220 Substrate.
FT BINDING 305 305 ATP.
FT BINDING 375 375 ATP.
FT BINDING 425 425 ATP.
FT BINDING 450 450 Substrate.
FT BINDING 452 452 ATP.
FT BINDING 458 458 ATP; via carbonyl oxygen.
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 93 203 Missing (in isoform 2).
FT /FTId=VSP_047617.
FT VARIANT 26 26 A -> D (in GSS deficiency).
FT /FTId=VAR_003602.
FT VARIANT 188 188 L -> P (in GSS deficiency; 100-fold
FT reduction of activity).
FT /FTId=VAR_003603.
FT VARIANT 219 219 D -> A (in GSS deficiency).
FT /FTId=VAR_003604.
FT VARIANT 219 219 D -> G (in GSS deficiency;
FT dbSNP:rs28938472).
FT /FTId=VAR_003605.
FT VARIANT 236 236 R -> Q (in dbSNP:rs34239729).
FT /FTId=VAR_025047.
FT VARIANT 254 254 L -> R (in GSS deficiency).
FT /FTId=VAR_003606.
FT VARIANT 267 267 R -> W (in GSS deficiency).
FT /FTId=VAR_003607.
FT VARIANT 270 270 Y -> C (in GSS deficiency; 100-fold
FT reduction of activity).
FT /FTId=VAR_003608.
FT VARIANT 270 270 Y -> H (in GSS deficiency; 100-fold
FT reduction of activity).
FT /FTId=VAR_003609.
FT VARIANT 283 283 R -> C (in GSS deficiency; 10-fold
FT reduction of activity).
FT /FTId=VAR_003610.
FT VARIANT 286 286 L -> Q (in GSS deficiency).
FT /FTId=VAR_003611.
FT VARIANT 330 330 R -> C (in GSS deficiency;
FT dbSNP:rs148640446).
FT /FTId=VAR_003612.
FT VARIANT 437 437 K -> E (in dbSNP:rs34852238).
FT /FTId=VAR_025048.
FT VARIANT 464 464 G -> V (in GSS deficiency).
FT /FTId=VAR_003613.
FT VARIANT 469 469 D -> E (in GSS deficiency).
FT /FTId=VAR_003614.
FT HELIX 6 9
FT HELIX 12 28
FT STRAND 32 34
FT STRAND 43 47
FT STRAND 50 53
FT STRAND 56 58
FT HELIX 59 67
FT HELIX 69 81
FT HELIX 83 91
FT HELIX 93 96
FT HELIX 98 113
FT STRAND 119 132
FT STRAND 134 136
FT STRAND 138 146
FT HELIX 153 158
FT HELIX 160 169
FT HELIX 173 176
FT HELIX 184 199
FT STRAND 205 209
FT HELIX 217 228
FT TURN 229 231
FT STRAND 234 237
FT HELIX 239 245
FT STRAND 246 248
FT STRAND 254 256
FT STRAND 259 268
FT HELIX 272 274
FT HELIX 277 288
FT STRAND 289 295
FT HELIX 297 301
FT HELIX 305 310
FT HELIX 316 320
FT HELIX 325 333
FT STRAND 338 340
FT STRAND 342 344
FT HELIX 345 356
FT HELIX 358 360
FT STRAND 361 366
FT STRAND 369 371
FT HELIX 376 386
FT HELIX 390 394
FT STRAND 395 399
FT STRAND 406 411
FT STRAND 418 435
FT STRAND 438 453
FT TURN 461 464
FT STRAND 467 469
FT STRAND 472 474
SQ SEQUENCE 474 AA; 52385 MW; 3C25EF7072EFE058 CRC64;
MATNWGSLLQ DKQQLEELAR QAVDRALAEG VLLRTSQEPT SSEVVSYAPF TLFPSLVPSA
LLEQAYAVQM DFNLLVDAVS QNAAFLEQTL SSTIKQDDFT ARLFDIHKQV LKEGIAQTVF
LGLNRSDYMF QRSADGSPAL KQIEINTISA SFGGLASRTP AVHRHVLSVL SKTKEAGKIL
SNNPSKGLAL GIAKAWELYG SPNALVLLIA QEKERNIFDQ RAIENELLAR NIHVIRRTFE
DISEKGSLDQ DRRLFVDGQE IAVVYFRDGY MPRQYSLQNW EARLLLERSH AAKCPDIATQ
LAGTKKVQQE LSRPGMLEML LPGQPEAVAR LRATFAGLYS LDVGEEGDQA IAEALAAPSR
FVLKPQREGG GNNLYGEEMV QALKQLKDSE ERASYILMEK IEPEPFENCL LRPGSPARVV
QCISELGIFG VYVRQEKTLV MNKHVGHLLR TKAIEHADGG VAAGVAVLDN PYPV
//
ID GSHB_HUMAN Reviewed; 474 AA.
AC P48637; B2R697; B6F210; E1P5P9; Q4TTD9;
DT 01-FEB-1996, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-FEB-1996, sequence version 1.
DT 22-JAN-2014, entry version 145.
DE RecName: Full=Glutathione synthetase;
DE Short=GSH synthetase;
DE Short=GSH-S;
DE EC=6.3.2.3;
DE AltName: Full=Glutathione synthase;
GN Name=GSS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=7646467;
RA Gali R.R., Board P.G.;
RT "Sequencing and expression of a cDNA for human glutathione
RT synthetase.";
RL Biochem. J. 310:353-358(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RX PubMed=19672693; DOI=10.1007/s11033-009-9675-3;
RA Uchida M., Sugaya M., Kanamaru T., Hisatomi H.;
RT "Alternative RNA splicing in expression of the glutathione synthetase
RT gene in human cells.";
RL Mol. Biol. Rep. 37:2105-2109(2010).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Kidney;
RA Shi Z.-Z., Galang R.L., Habib G.M., Lebovitz R.M., Lieberman M.W.;
RL Submitted (AUG-1995) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT
RP GLU-437.
RC TISSUE=Substantia nigra;
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 [GENOMIC DNA], AND VARIANTS GLN-236 AND GLU-437.
RG NIEHS SNPs program;
RL Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=11780052; DOI=10.1038/414865a;
RA Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R.,
RA Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L.,
RA Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M.,
RA Beasley O.P., Bird C.P., Blakey S.E., Bridgeman A.M., Brown A.J.,
RA Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P.,
RA Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M.,
RA Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R.,
RA Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M.,
RA Ellington A.G., Frankland J.A., Fraser A., French L., Garner P.,
RA Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E.,
RA Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J.,
RA Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D.,
RA Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S.,
RA Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D.,
RA Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A.,
RA Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T.,
RA Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I.,
RA Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H.,
RA Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S.,
RA Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E.,
RA Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A.,
RA Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M.,
RA Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A.,
RA Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S.,
RA Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 20.";
RL Nature 414:865-871(2001).
RN [7]
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 (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Lung;
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 [9]
RP PROTEIN SEQUENCE OF 26-34; 113-125; 142-158; 222-230; 254-267;
RP 274-283; 294-305; 419-434 AND 453-474, AND MASS SPECTROMETRY.
RC TISSUE=Fetal brain cortex;
RA Lubec G., Chen W.-Q., Sun Y.;
RL Submitted (DEC-2008) to UniProtKB.
RN [10]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT ALA-2, MASS SPECTROMETRY, AND
RP CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=19413330; DOI=10.1021/ac9004309;
RA Gauci S., Helbig A.O., Slijper M., Krijgsveld J., Heck A.J.,
RA Mohammed S.;
RT "Lys-N and trypsin cover complementary parts of the phosphoproteome in
RT a refined SCX-based approach.";
RL Anal. Chem. 81:4493-4501(2009).
RN [11]
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 [12]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22814378; DOI=10.1073/pnas.1210303109;
RA Van Damme P., Lasa M., Polevoda B., Gazquez C., Elosegui-Artola A.,
RA Kim D.S., De Juan-Pardo E., Demeyer K., Hole K., Larrea E.,
RA Timmerman E., Prieto J., Arnesen T., Sherman F., Gevaert K.,
RA Aldabe R.;
RT "N-terminal acetylome analyses and functional insights of the N-
RT terminal acetyltransferase NatB.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:12449-12454(2012).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) OF 1-474 IN COMPLEX WITH ADP
RP AND GLUTATHIONE, COFACTOR, AND SUBUNIT.
RX PubMed=10369661; DOI=10.1093/emboj/18.12.3204;
RA Polekhina G., Board P.G., Gali R.R., Rossjohn J., Parker M.W.;
RT "Molecular basis of glutathione synthetase deficiency and a rare gene
RT permutation event.";
RL EMBO J. 18:3204-3213(1999).
RN [14]
RP VARIANTS GSS DEFICIENCY GLY-219; TRP-267 AND CYS-283.
RX PubMed=8896573; DOI=10.1038/ng1196-361;
RA Shi Z.-Z., Habib G.M., Rhead W.J., Gahl W.A., He X., Sazer S.,
RA Lieberman M.W.;
RT "Mutations in the glutathione synthetase gene cause 5-oxoprolinuria.";
RL Nat. Genet. 14:361-365(1996).
RN [15]
RP VARIANTS GSS DEFICIENCY.
RX PubMed=9215686; DOI=10.1093/hmg/6.7.1147;
RA Dahl N., Pigg M., Ristoff E., Gali R., Carlsson B., Mannervik B.,
RA Larsson A., Board P.;
RT "Missense mutations in the human glutathione synthetase gene result in
RT severe metabolic acidosis, 5-oxoprolinuria, hemolytic anemia and
RT neurological dysfunction.";
RL Hum. Mol. Genet. 6:1147-1152(1997).
CC -!- CATALYTIC ACTIVITY: ATP + gamma-L-glutamyl-L-cysteine + glycine =
CC ADP + phosphate + glutathione.
CC -!- COFACTOR: Binds 1 magnesium ion per subunit.
CC -!- PATHWAY: Sulfur metabolism; glutathione biosynthesis; glutathione
CC from L-cysteine and L-glutamate: step 2/2.
CC -!- SUBUNIT: Homodimer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=P48637-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P48637-2; Sequence=VSP_047617;
CC Note=Detected in colon, kidney, lung, liver, placenta,
CC peripheral blood and uterus, but not in heart, skeletal muscle
CC and spleen;
CC -!- DISEASE: Glutathione synthetase deficiency (GSS deficiency)
CC [MIM:266130]: Severe form characterized by an increased rate of
CC hemolysis and defective function of the central nervous system.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Glutathione synthetase deficiency of erythrocytes
CC (GLUSYNDE) [MIM:231900]: Mild form causing hemolytic anemia.
CC Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the eukaryotic GSH synthase family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GSS";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/gss/";
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DR EMBL; L42531; AAA69492.1; -; mRNA.
DR EMBL; AB459500; BAG75452.1; -; mRNA.
DR EMBL; U34683; AAB62390.1; -; mRNA.
DR EMBL; AK312492; BAG35394.1; -; mRNA.
DR EMBL; DQ074975; AAY57328.1; -; Genomic_DNA.
DR EMBL; AL133324; CAB93423.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW76239.1; -; Genomic_DNA.
DR EMBL; CH471077; EAW76240.1; -; Genomic_DNA.
DR EMBL; BC007927; AAH07927.1; -; mRNA.
DR PIR; S56748; S56748.
DR RefSeq; NP_000169.1; NM_000178.2.
DR RefSeq; XP_005260462.1; XM_005260405.1.
DR RefSeq; XP_005260463.1; XM_005260406.1.
DR UniGene; Hs.82327; -.
DR PDB; 2HGS; X-ray; 2.10 A; A=1-474.
DR PDBsum; 2HGS; -.
DR ProteinModelPortal; P48637; -.
DR SMR; P48637; 3-474.
DR IntAct; P48637; 2.
DR MINT; MINT-5001027; -.
DR STRING; 9606.ENSP00000216951; -.
DR DrugBank; DB00143; Glutathione.
DR DrugBank; DB00145; Glycine.
DR DrugBank; DB00151; L-Cysteine.
DR PhosphoSite; P48637; -.
DR DMDM; 1346191; -.
DR OGP; P48637; -.
DR REPRODUCTION-2DPAGE; IPI00010706; -.
DR PaxDb; P48637; -.
DR PeptideAtlas; P48637; -.
DR PRIDE; P48637; -.
DR DNASU; 2937; -.
DR Ensembl; ENST00000216951; ENSP00000216951; ENSG00000100983.
DR Ensembl; ENST00000451957; ENSP00000407517; ENSG00000100983.
DR GeneID; 2937; -.
DR KEGG; hsa:2937; -.
DR UCSC; uc010zuo.2; human.
DR CTD; 2937; -.
DR GeneCards; GC20M033517; -.
DR HGNC; HGNC:4624; GSS.
DR HPA; HPA054508; -.
DR MIM; 231900; phenotype.
DR MIM; 266130; phenotype.
DR MIM; 601002; gene.
DR neXtProt; NX_P48637; -.
DR Orphanet; 289846; Glutathione synthetase deficiency with 5-oxoprolinuria.
DR Orphanet; 289849; Glutathione synthetase deficiency without 5-oxoprolinuria.
DR PharmGKB; PA29015; -.
DR eggNOG; NOG329040; -.
DR HOGENOM; HOG000172641; -.
DR HOVERGEN; HBG002458; -.
DR InParanoid; P48637; -.
DR KO; K01920; -.
DR OMA; FENCLLR; -.
DR OrthoDB; EOG757CXD; -.
DR PhylomeDB; P48637; -.
DR BioCyc; MetaCyc:HS02174-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P48637; -.
DR UniPathway; UPA00142; UER00210.
DR ChiTaRS; GSS; human.
DR EvolutionaryTrace; P48637; -.
DR GenomeRNAi; 2937; -.
DR NextBio; 11639; -.
DR PRO; PR:P48637; -.
DR ArrayExpress; P48637; -.
DR Bgee; P48637; -.
DR CleanEx; HS_GSS; -.
DR Genevestigator; P48637; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IDA:UniProtKB.
DR GO; GO:0043295; F:glutathione binding; IDA:UniProtKB.
DR GO; GO:0004363; F:glutathione synthase activity; TAS:Reactome.
DR GO; GO:0016594; F:glycine binding; IEA:Ensembl.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0007568; P:aging; IEA:Ensembl.
DR GO; GO:1901687; P:glutathione derivative biosynthetic process; TAS:Reactome.
DR GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR GO; GO:0043200; P:response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0046686; P:response to cadmium ion; IEA:Ensembl.
DR GO; GO:0031667; P:response to nutrient levels; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; TAS:ProtInc.
DR GO; GO:0034612; P:response to tumor necrosis factor; IEA:Ensembl.
DR GO; GO:0006805; P:xenobiotic metabolic process; TAS:Reactome.
DR Gene3D; 1.10.1080.10; -; 2.
DR Gene3D; 3.30.1490.50; -; 1.
DR Gene3D; 3.30.1490.80; -; 2.
DR Gene3D; 3.40.50.1760; -; 1.
DR InterPro; IPR004887; Glutathione_synth_subst-bd_euk.
DR InterPro; IPR014042; Glutathione_synthase_a-hlx_euk.
DR InterPro; IPR014709; Glutathione_synthase_dom.
DR InterPro; IPR005615; Glutathione_synthase_euk.
DR InterPro; IPR014049; Glutathione_synthase_N_euk.
DR InterPro; IPR016185; PreATP-grasp_dom.
DR PANTHER; PTHR11130; PTHR11130; 1.
DR Pfam; PF03917; GSH_synth_ATP; 1.
DR Pfam; PF03199; GSH_synthase; 1.
DR PIRSF; PIRSF001558; GSHase; 1.
DR SUPFAM; SSF52440; SSF52440; 1.
DR TIGRFAMs; TIGR01986; glut_syn_euk; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Alternative splicing; ATP-binding;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Glutathione biosynthesis; Hereditary hemolytic anemia; Ligase;
KW Magnesium; Metal-binding; Nucleotide-binding; Polymorphism;
KW Reference proteome.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 474 Glutathione synthetase.
FT /FTId=PRO_0000211260.
FT NP_BIND 364 373 ATP.
FT NP_BIND 398 401 ATP.
FT REGION 148 151 Substrate binding.
FT REGION 214 216 Substrate binding.
FT REGION 267 270 Substrate binding.
FT REGION 461 462 Substrate binding.
FT METAL 144 144 Magnesium.
FT METAL 146 146 Magnesium.
FT METAL 368 368 Magnesium.
FT BINDING 125 125 Substrate.
FT BINDING 144 144 ATP.
FT BINDING 220 220 Substrate.
FT BINDING 305 305 ATP.
FT BINDING 375 375 ATP.
FT BINDING 425 425 ATP.
FT BINDING 450 450 Substrate.
FT BINDING 452 452 ATP.
FT BINDING 458 458 ATP; via carbonyl oxygen.
FT MOD_RES 2 2 N-acetylalanine.
FT VAR_SEQ 93 203 Missing (in isoform 2).
FT /FTId=VSP_047617.
FT VARIANT 26 26 A -> D (in GSS deficiency).
FT /FTId=VAR_003602.
FT VARIANT 188 188 L -> P (in GSS deficiency; 100-fold
FT reduction of activity).
FT /FTId=VAR_003603.
FT VARIANT 219 219 D -> A (in GSS deficiency).
FT /FTId=VAR_003604.
FT VARIANT 219 219 D -> G (in GSS deficiency;
FT dbSNP:rs28938472).
FT /FTId=VAR_003605.
FT VARIANT 236 236 R -> Q (in dbSNP:rs34239729).
FT /FTId=VAR_025047.
FT VARIANT 254 254 L -> R (in GSS deficiency).
FT /FTId=VAR_003606.
FT VARIANT 267 267 R -> W (in GSS deficiency).
FT /FTId=VAR_003607.
FT VARIANT 270 270 Y -> C (in GSS deficiency; 100-fold
FT reduction of activity).
FT /FTId=VAR_003608.
FT VARIANT 270 270 Y -> H (in GSS deficiency; 100-fold
FT reduction of activity).
FT /FTId=VAR_003609.
FT VARIANT 283 283 R -> C (in GSS deficiency; 10-fold
FT reduction of activity).
FT /FTId=VAR_003610.
FT VARIANT 286 286 L -> Q (in GSS deficiency).
FT /FTId=VAR_003611.
FT VARIANT 330 330 R -> C (in GSS deficiency;
FT dbSNP:rs148640446).
FT /FTId=VAR_003612.
FT VARIANT 437 437 K -> E (in dbSNP:rs34852238).
FT /FTId=VAR_025048.
FT VARIANT 464 464 G -> V (in GSS deficiency).
FT /FTId=VAR_003613.
FT VARIANT 469 469 D -> E (in GSS deficiency).
FT /FTId=VAR_003614.
FT HELIX 6 9
FT HELIX 12 28
FT STRAND 32 34
FT STRAND 43 47
FT STRAND 50 53
FT STRAND 56 58
FT HELIX 59 67
FT HELIX 69 81
FT HELIX 83 91
FT HELIX 93 96
FT HELIX 98 113
FT STRAND 119 132
FT STRAND 134 136
FT STRAND 138 146
FT HELIX 153 158
FT HELIX 160 169
FT HELIX 173 176
FT HELIX 184 199
FT STRAND 205 209
FT HELIX 217 228
FT TURN 229 231
FT STRAND 234 237
FT HELIX 239 245
FT STRAND 246 248
FT STRAND 254 256
FT STRAND 259 268
FT HELIX 272 274
FT HELIX 277 288
FT STRAND 289 295
FT HELIX 297 301
FT HELIX 305 310
FT HELIX 316 320
FT HELIX 325 333
FT STRAND 338 340
FT STRAND 342 344
FT HELIX 345 356
FT HELIX 358 360
FT STRAND 361 366
FT STRAND 369 371
FT HELIX 376 386
FT HELIX 390 394
FT STRAND 395 399
FT STRAND 406 411
FT STRAND 418 435
FT STRAND 438 453
FT TURN 461 464
FT STRAND 467 469
FT STRAND 472 474
SQ SEQUENCE 474 AA; 52385 MW; 3C25EF7072EFE058 CRC64;
MATNWGSLLQ DKQQLEELAR QAVDRALAEG VLLRTSQEPT SSEVVSYAPF TLFPSLVPSA
LLEQAYAVQM DFNLLVDAVS QNAAFLEQTL SSTIKQDDFT ARLFDIHKQV LKEGIAQTVF
LGLNRSDYMF QRSADGSPAL KQIEINTISA SFGGLASRTP AVHRHVLSVL SKTKEAGKIL
SNNPSKGLAL GIAKAWELYG SPNALVLLIA QEKERNIFDQ RAIENELLAR NIHVIRRTFE
DISEKGSLDQ DRRLFVDGQE IAVVYFRDGY MPRQYSLQNW EARLLLERSH AAKCPDIATQ
LAGTKKVQQE LSRPGMLEML LPGQPEAVAR LRATFAGLYS LDVGEEGDQA IAEALAAPSR
FVLKPQREGG GNNLYGEEMV QALKQLKDSE ERASYILMEK IEPEPFENCL LRPGSPARVV
QCISELGIFG VYVRQEKTLV MNKHVGHLLR TKAIEHADGG VAAGVAVLDN PYPV
//
MIM
231900
*RECORD*
*FIELD* NO
231900
*FIELD* TI
#231900 GLUTATHIONE SYNTHETASE DEFICIENCY OF ERYTHROCYTES, HEMOLYTIC ANEMIA
DUE TO; GSSDE
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence hemolytic
anemia due to glutathione synthetase deficiency of erythrocytes (GSSDE)
can be caused by homozygous mutation in the gene encoding glutathione
synthetase (GSS; 601002), on chromosome 20q11. The same gene is mutant
in 5-oxoprolinuria (266130).
DESCRIPTION
Two forms of glutathione synthetase deficiency have been described; a
mild form, referred to as glutathione synthetase deficiency of
erythrocytes, causing hemolytic anemia, and a more severe form causing
5-oxoprolinuria with secondary neurologic involvement (266130).
CLINICAL FEATURES
Mohler et al. (1970) described a man of Scottish extraction with
hemolytic anemia due to deficiency of glutathione synthetase. Four
children of the proband, 1 of 3 of his sibs, and both parents had
intermediate levels of enzyme. Presumably, the families of Oort et al.
(1961) and of Boivin et al. (1966) had the same condition. In the family
reported by Prins et al. (1966), 3 of 12 sibs from second-cousin parents
had absence of glutathione in the erythrocytes. The clinical picture was
that of nonspherocytic hemolytic anemia. Glyoxalase activity, which is
dependent on glutathione as a cofactor, was also deficient. Other
enzymes were increased, presumably due to the younger average age of
erythrocytes. In a later report on the kindred, 5 cases in 2 sibships,
with all 4 parents traced to a common ancestral couple, were described.
Glutathione (gamma-glutamyl-cysteinyl-glycine) was less than 10% of
normal in presumed homozygotes.
Spielberg et al. (1978) showed an enzymatic difference between
5-oxoprolinuria (pyroglutamic aciduria) and isolated hemolytic anemia
due to glutathione synthetase deficiency. In the former all cell types
examined have grossly deficient enzyme activity and glutathione content.
In contrast, in the nonoxoprolinuric variant, red cells have reduced
enzyme and glutathione, but nucleated cells are normal. The enzyme from
the latter type is unstable in vitro and shows shortened survival in
intact erythrocytes. Nucleated cells are apparently able to maintain
sufficient enzyme activity and glutathione content to suppress
overproduction of 5-oxoproline.
Beutler et al. (1986) described 2 sibs with hemolytic anemia. Their red
cells lacked GSH and were severely deficient in GSH-S. No neurologic
abnormalities or 5-oxoprolinuria were present. A concurrent
glutathione-S-transferase (GST; see 138350) deficiency was also found in
red cells. The GSH-S activity was one-half normal in the parents, but
GST was normal, indicating that GSH-S deficiency is the primary defect.
Glutathione stabilizes GST.
CLINICAL MANAGEMENT
Ristoff et al. (2001) studied 28 patients with GSS deficiency, which
they classified into 3 types based on severity of clinical signs: mild
(hemolytic anemia only), moderate (neonatal acidosis), and severe
(neurologic involvement). They concluded that early supplementation with
vitamins C and E may improve the long-term clinical outcome of these
patients.
MAPPING
By analysis of somatic cell hybrids and FISH, Webb et al. (1995) mapped
the GSS gene to chromosome 20q11.2.
MOLECULAR GENETICS
In the patient with GSS deficiency reported by Mohler et al. (1970), Shi
et al. (1996) identified a homozygous missense mutation in the GSS gene
(601002.0007).
*FIELD* SA
Zurcher (1967)
*FIELD* RF
1. Beutler, E.; Gelbart, T.; Pegelow, C.: Erythrocyte glutathione
synthetase deficiency leads not only to glutathione but also to glutathione-S-transferase
deficiency. J. Clin. Invest. 77: 38-41, 1986.
2. Boivin, P.; Galand, C.; Andre, R.; Debray, J.: Anemies hemolytiques
congenitales avec deficit isole en glutathion reduit par deficit en
glutathion synthetase. Nouv. Rev. Franc. Hemat. 6: 859-865, 1966.
3. Mohler, D. N.; Majerus, P. W.; Minnich, V.; Hess, C. E.; Garrick,
M. D.: Glutathione synthetase deficiency as a cause of hereditary
hemolytic disease. New Eng. J. Med. 283: 1253-1257, 1970.
4. Oort, M.; Loos, J. A.; Prins, H. K.: Hereditary absence of reduced
glutathione in the erythrocytes--a new clinical and biochemical entity. Vox
Sang. 6: 370-373, 1961.
5. Prins, H. K.; Oort, M.; Loos, J. A.; Zurcher, C.; Beckers, T.:
Congenital nonspherocytic hemolytic anemia, associated with glutathione
deficiency of the erythrocytes. Hematologic, biochemical and genetic
studies. Blood 27: 145-166, 1966.
6. Ristoff, E.; Mayatepek, E.; Larsson, A.: Long-term clinical outcome
in patients with glutathione synthetase deficiency. J. Pediat. 139:
79-84, 2001.
7. Shi, Z.-Z.; Habib, G. M.; Rhead, W. J.; Gahl, W. A.; He, X.; Sazer,
S.; Lieberman, M. W.: Mutations in the glutathione synthetase gene
cause 5-oxoprolinuria. Nature Genet. 14: 361-365, 1996.
8. Spielberg, S. P.; Garrick, M. D.; Corash, L. M.; Butler, J. B.;
Tietze, F.; Rogers, L.; Schulman, J. D.: Biochemical heterogeneity
in glutathione synthetase deficiency. J. Clin. Invest. 61: 1417-1420,
1978.
9. Webb, G. C.; Vaska, V. L.; Gali, R. R.; Ford, J. H.; Board, P.
G.: The gene encoding human glutathione synthetase (GSS) maps to
the long arm of chromosome 20 at band 11.2. Genomics 30: 617-619,
1995.
10. Zurcher, C.: Glutathione deficiency.In: Beutler, E.: Hereditary
Disorders of Erythrocyte Metabolism. New York: Grune and Stratton
(pub.) 1967.
*FIELD* CS
Heme:
Hemolytic anemia
Lab:
Glutathione synthetase deficiency;
Glyoxalase deficiency;
Glutathione low
Inheritance:
Autosomal recessive
*FIELD* CN
Carol A. Bocchini - reorganized: 10/4/2001
Deborah L. Stone - updated: 10/4/2001
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 01/24/2013
terry: 4/20/2005
alopez: 5/1/2003
carol: 10/4/2001
terry: 10/28/1996
mark: 1/21/1996
terry: 1/18/1996
mimadm: 2/19/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 3/8/1989
marie: 3/25/1988
*RECORD*
*FIELD* NO
231900
*FIELD* TI
#231900 GLUTATHIONE SYNTHETASE DEFICIENCY OF ERYTHROCYTES, HEMOLYTIC ANEMIA
DUE TO; GSSDE
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence hemolytic
anemia due to glutathione synthetase deficiency of erythrocytes (GSSDE)
can be caused by homozygous mutation in the gene encoding glutathione
synthetase (GSS; 601002), on chromosome 20q11. The same gene is mutant
in 5-oxoprolinuria (266130).
DESCRIPTION
Two forms of glutathione synthetase deficiency have been described; a
mild form, referred to as glutathione synthetase deficiency of
erythrocytes, causing hemolytic anemia, and a more severe form causing
5-oxoprolinuria with secondary neurologic involvement (266130).
CLINICAL FEATURES
Mohler et al. (1970) described a man of Scottish extraction with
hemolytic anemia due to deficiency of glutathione synthetase. Four
children of the proband, 1 of 3 of his sibs, and both parents had
intermediate levels of enzyme. Presumably, the families of Oort et al.
(1961) and of Boivin et al. (1966) had the same condition. In the family
reported by Prins et al. (1966), 3 of 12 sibs from second-cousin parents
had absence of glutathione in the erythrocytes. The clinical picture was
that of nonspherocytic hemolytic anemia. Glyoxalase activity, which is
dependent on glutathione as a cofactor, was also deficient. Other
enzymes were increased, presumably due to the younger average age of
erythrocytes. In a later report on the kindred, 5 cases in 2 sibships,
with all 4 parents traced to a common ancestral couple, were described.
Glutathione (gamma-glutamyl-cysteinyl-glycine) was less than 10% of
normal in presumed homozygotes.
Spielberg et al. (1978) showed an enzymatic difference between
5-oxoprolinuria (pyroglutamic aciduria) and isolated hemolytic anemia
due to glutathione synthetase deficiency. In the former all cell types
examined have grossly deficient enzyme activity and glutathione content.
In contrast, in the nonoxoprolinuric variant, red cells have reduced
enzyme and glutathione, but nucleated cells are normal. The enzyme from
the latter type is unstable in vitro and shows shortened survival in
intact erythrocytes. Nucleated cells are apparently able to maintain
sufficient enzyme activity and glutathione content to suppress
overproduction of 5-oxoproline.
Beutler et al. (1986) described 2 sibs with hemolytic anemia. Their red
cells lacked GSH and were severely deficient in GSH-S. No neurologic
abnormalities or 5-oxoprolinuria were present. A concurrent
glutathione-S-transferase (GST; see 138350) deficiency was also found in
red cells. The GSH-S activity was one-half normal in the parents, but
GST was normal, indicating that GSH-S deficiency is the primary defect.
Glutathione stabilizes GST.
CLINICAL MANAGEMENT
Ristoff et al. (2001) studied 28 patients with GSS deficiency, which
they classified into 3 types based on severity of clinical signs: mild
(hemolytic anemia only), moderate (neonatal acidosis), and severe
(neurologic involvement). They concluded that early supplementation with
vitamins C and E may improve the long-term clinical outcome of these
patients.
MAPPING
By analysis of somatic cell hybrids and FISH, Webb et al. (1995) mapped
the GSS gene to chromosome 20q11.2.
MOLECULAR GENETICS
In the patient with GSS deficiency reported by Mohler et al. (1970), Shi
et al. (1996) identified a homozygous missense mutation in the GSS gene
(601002.0007).
*FIELD* SA
Zurcher (1967)
*FIELD* RF
1. Beutler, E.; Gelbart, T.; Pegelow, C.: Erythrocyte glutathione
synthetase deficiency leads not only to glutathione but also to glutathione-S-transferase
deficiency. J. Clin. Invest. 77: 38-41, 1986.
2. Boivin, P.; Galand, C.; Andre, R.; Debray, J.: Anemies hemolytiques
congenitales avec deficit isole en glutathion reduit par deficit en
glutathion synthetase. Nouv. Rev. Franc. Hemat. 6: 859-865, 1966.
3. Mohler, D. N.; Majerus, P. W.; Minnich, V.; Hess, C. E.; Garrick,
M. D.: Glutathione synthetase deficiency as a cause of hereditary
hemolytic disease. New Eng. J. Med. 283: 1253-1257, 1970.
4. Oort, M.; Loos, J. A.; Prins, H. K.: Hereditary absence of reduced
glutathione in the erythrocytes--a new clinical and biochemical entity. Vox
Sang. 6: 370-373, 1961.
5. Prins, H. K.; Oort, M.; Loos, J. A.; Zurcher, C.; Beckers, T.:
Congenital nonspherocytic hemolytic anemia, associated with glutathione
deficiency of the erythrocytes. Hematologic, biochemical and genetic
studies. Blood 27: 145-166, 1966.
6. Ristoff, E.; Mayatepek, E.; Larsson, A.: Long-term clinical outcome
in patients with glutathione synthetase deficiency. J. Pediat. 139:
79-84, 2001.
7. Shi, Z.-Z.; Habib, G. M.; Rhead, W. J.; Gahl, W. A.; He, X.; Sazer,
S.; Lieberman, M. W.: Mutations in the glutathione synthetase gene
cause 5-oxoprolinuria. Nature Genet. 14: 361-365, 1996.
8. Spielberg, S. P.; Garrick, M. D.; Corash, L. M.; Butler, J. B.;
Tietze, F.; Rogers, L.; Schulman, J. D.: Biochemical heterogeneity
in glutathione synthetase deficiency. J. Clin. Invest. 61: 1417-1420,
1978.
9. Webb, G. C.; Vaska, V. L.; Gali, R. R.; Ford, J. H.; Board, P.
G.: The gene encoding human glutathione synthetase (GSS) maps to
the long arm of chromosome 20 at band 11.2. Genomics 30: 617-619,
1995.
10. Zurcher, C.: Glutathione deficiency.In: Beutler, E.: Hereditary
Disorders of Erythrocyte Metabolism. New York: Grune and Stratton
(pub.) 1967.
*FIELD* CS
Heme:
Hemolytic anemia
Lab:
Glutathione synthetase deficiency;
Glyoxalase deficiency;
Glutathione low
Inheritance:
Autosomal recessive
*FIELD* CN
Carol A. Bocchini - reorganized: 10/4/2001
Deborah L. Stone - updated: 10/4/2001
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 01/24/2013
terry: 4/20/2005
alopez: 5/1/2003
carol: 10/4/2001
terry: 10/28/1996
mark: 1/21/1996
terry: 1/18/1996
mimadm: 2/19/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/26/1989
root: 3/8/1989
marie: 3/25/1988
MIM
266130
*RECORD*
*FIELD* NO
266130
*FIELD* TI
#266130 GLUTATHIONE SYNTHETASE DEFICIENCY; GSSD
;;5-@OXOPROLINURIA;;
PYROGLUTAMIC ACIDURIA
read more*FIELD* TX
A number sign (#) is used with this entry because glutathione synthetase
deficiency, or 5-oxoprolinuria, is caused by homozygous or compound
heterozygous mutation in the gene encoding glutathione synthetase (GSS;
601002) on chromosome 20q11. The same gene is mutant in hemolytic anemia
due to glutathione synthetase deficiency of erythrocytes (231900).
Also see 5-oxoprolinuria due to oxoprolinase deficiency (260005).
DESCRIPTION
Glutathione synthetase deficiency, or 5-oxoprolinuria, is an autosomal
recessive disorder characterized, in its severe form, by massive urinary
excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and
central nervous system damage. The metabolic defect results in decreased
levels of cellular glutathione, which overstimulates the synthesis of
gamma-glutamylcysteine and its subsequent conversion to 5-oxoproline
(Larsson and Anderson, 2001).
CLINICAL FEATURES
Jellum et al. (1970) discovered large amounts of pyroglutamic acid in
the urine and plasma of a 19-year-old retarded Norwegian male. The
chemical search was initiated because of unexplained chronic metabolic
acidosis. Pyroglutamic acid was isolated by gas chromatography and
identified by mass spectrometry; it is ninhydrin-negative. The patient
showed spastic tetraparesis and a cerebellar disorder with intention
tremor and dysarthria. Deficiency of 5-oxoprolinase in the kidney was
suspected but not proved. Larsson et al. (1974) described 2 sisters, a
neonate and a 3 year old, with pyroglutamic aciduria. Both had chronic
metabolic acidosis requiring therapy with bicarbonate. Both showed
increased hemolysis and marked decrease in glutathione in erythrocytes.
Psychologic and somatic development of the 3 year old was normal, and
she had no signs of neurologic damage. Marstein et al. (1976) studied a
24-year-old mentally retarded man who had demonstrated neurologic
deterioration during the previous few years. Ataxia prevented his
walking unaided. He developed epileptic seizures. Erythrocytes contained
no detectable glutathione, and his glutathione synthetase activity was
less than 2% of normal. The overproduction of pyroglutamate is probably
caused by increased in vivo activity of gamma-glutamyl-cysteine
synthetase, which in turn is caused by absence of normal feedback
inhibition by glutathione with resulting superabundance of substrates
available for gamma-glutamyl cyclotransferase. Lack of glutathione in
the erythrocytes is apparently tolerable, but in nonrenewable neurons
leads to serious neurologic problems of progressive nature.
Because of the observation of several episodes of neutropenia in a child
with 5-oxoprolinuria, Spielberg et al. (1979) examined the response of
neutrophils to oxidative stress associated with phagocytosis. Following
ingestion of particles, the cells accumulated excess hydrogen peroxide
compared with normal cells and showed impaired protein iodination and
bacterial killing.
Robertson et al. (1991) described a 12-year-old girl with chronic
metabolic acidosis, mental retardation, and psychotic behavior, as well
as mild hemolytic anemia and peripheral retinal pigmentation
abnormalities. A urine metabolic screen demonstrated 5-oxoprolinuria and
further studies showed glutathione synthetase deficiency. The acidosis
in the newborn period had been labeled renal tubular acidosis and
treated with bicarbonate.
Divry et al. (1991) described a patient with a very severe neurologic
presentation leading to fatal outcome in the first hours of life.
Manning et al. (1994) stated that approximately 20 cases of glutathione
synthase deficiency had been reported and another 10 were known. The
usual presentation had been neonatal acidosis and hemolysis with or
without signs of neurologic damage. Some cases had not been diagnosed
until adult life, however, reflecting a less severe form of the
condition.
CLINICAL MANAGEMENT
Boxer et al. (1979) reported that vitamin E (alpha-tocopherol), 400
IU/day, increased red cell survival, corrected both the bactericidal and
the iodination defects, and eliminated the neutropenia that accompanied
intercurrent illnesses.
Martensson et al. (1989) concluded that N-acetylcysteine may be of value
in increasing the low intracellular glutathione concentrations and
cysteine availability in patients with this disorder.
Ristoff et al. (2001) studied 28 patients with glutathione synthetase
deficiency, which they classified into 3 types based on severity of
clinical signs: mild (hemolytic anemia only), moderate (neonatal
acidosis), and severe (neurologic involvement). They concluded that
early supplementation with vitamins C and E may improve the long-term
clinical outcome of these patients.
DIAGNOSIS
- Prenatal Diagnosis
Erasmus et al. (1993) described a family in which an affected girl died
at the age of 6 weeks. Both parents and the maternal grandmother had
erythrocyte glutathione synthetase activity in the heterozygote range.
Two later pregnancies were monitored with the measurement of
5-oxoproline in the amniotic fluid and in the latter of the 2
pregnancies by glutathione synthetase activity measurements. Both tests
suggested that the infants were not affected and such was proved to be
the case after delivery. Since accumulation of 5-oxoproline in body
fluids, including urine, is characteristic of this disorder and since
the amniotic fluid from the second trimester consists mostly of fetal
urine, prenatal diagnosis by amniocentesis should be possible.
Manning et al. (1994) studied 2 pregnancies of an at-risk couple at 16
weeks' gestation. The levels of 5-oxoproline in both pregnancies was 25
to 30 times normal. The pregnancies were terminated and the diagnosis in
one case was subsequently confirmed by assay of glutathione synthase in
cultured fetal fibroblasts. In the other case, postmortem tissue samples
failed to grow.
MOLECULAR GENETICS
In 3 families with glutathione synthetase deficiency, Shi et al. (1996)
identified 7 mutations in the GSS gene on 6 alleles
(601002.0001-601002.0006).
In 41 patients (33 previously reported) with glutathione synthetase
deficiency from 33 families, Njalsson et al. (2005) evaluated genotype,
enzyme activity, metabolite levels, and clinical phenotype. They
identified 27 different mutations; 23 patients were homozygotes and 18
were compound heterozygotes. The moderate and severe clinical phenotypes
could not be distinguished based on enzyme activity or glutathione or
gamma-glutamylcysteine levels in cultured fibroblasts. All mutations
causing frameshifts, premature stop codons, or aberrant splicing were
associated with moderate or severe clinical phenotypes. Njalsson et al.
(2005) concluded that additional genetic or environmental factors modify
at least the moderate and severe phenotypes and that the clinical
classification given to patients may be influenced by variation in
follow-up.
*FIELD* SA
Meister (1978); Porath and Schreier (1978); Spielberg et al. (1977);
Wellner et al. (1974)
*FIELD* RF
1. Boxer, L. A.; Oliver, J. M.; Spielberg, S. P.; Allen, J. M.; Schulman,
J. D.: Protection of granulocytes by vitamin E in glutathione synthetase
deficiency. New Eng. J. Med. 301: 901-905, 1979.
2. Divry, P.; Roulaud-Parrot, F.; Dorche, C.; Zabot, M. T.; Contraire,
B.; Hagenfeldt, L.; Larsson, A.: 5-Oxoprolinuria (glutathione synthetase
deficiency): a case with neonatal presentation and rapid fatal outcome. J.
Inherit. Metab. Dis. 14: 341-344, 1991.
3. Erasmus, E.; Mienie, L. J.; de Vries, W. N.; de Wet, W. J.; Carlsson,
B.; Larsson, A.: Prenatal analysis in two suspected cases of glutathione
synthetase deficiency. J. Inherit. Metab. Dis. 16: 837-843, 1993.
4. Jellum, E.; Kluge, T.; Borresen, H. C.; Stokke, O.; Eldjarn, L.
: Pyroglutamic acidosis--a new inborn error of metabolism. Scand.
J. Clin. Lab. Invest. 26: 327-335, 1970.
5. Larsson, A.; Anderson, M. E.: Glutathione synthetase deficiency
and other disorders of the gamma-glutamyl cycle.In: Scriver, C. R.;
Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. 2 (8th ed.) New York: McGraw-Hill
2001. Pp. 2205-2216.
6. Larsson, A.; Zetterstrom, R.; Hagenfeldt, L.; Andersson, R.; Dreborg,
S.; Hornell, H.: Pyroglutamic aciduria (5-oxoprolinuria), an inborn
error in glutathione metabolism. Pediat. Res. 8: 852-856, 1974.
7. Manning, N. J.; Davies, N. P.; Olpin, S. E.; Carpenter, K. H.;
Smith, M. F.; Pollitt, R. J.; Duncan, S. L. B.; Larsson, A.; Carlsson,
B.: Prenatal diagnosis of glutathione synthase deficiency. Prenatal
Diag. 14: 475-478, 1994.
8. Marstein, S.; Jellum, E.; Halpern, B.; Eldjarn, L.; Perry, T. L.
: Biochemical studies of erythrocytes in a patient with pyroglutamic
acidemia (5-oxoprolinemia). New Eng. J. Med. 295: 406-412, 1976.
9. Martensson, J.; Gustafsson, J.; Larsson, A.: A therapeutic trial
with N-acetylcysteine in subjects with hereditary glutathione synthetase
deficiency (5-oxoprolinuria). J. Inherit. Metab. Dis. 12: 120-130,
1989.
10. Meister, A.: 5-Oxoprolinuria (pyroglutamic aciduria) and other
disorders of glutathione biosynthesis.In: Stanbury, J. B.; Wyngaarden,
J. B.; Fredrickson, D. S.: Metabolic Basis of Inherited Disease.
New York: McGraw-Hill (pub.) (4th ed.): 1978. Pp. 328-335.
11. Njalsson, R.; Ristoff, E.; Carlsson, K.; Winkler, A.; Larsson,
A.; Norgren, S.: Genotype, enzyme activity, glutathione level, and
clinical phenotype in patients with glutathione synthetase deficiency. Hum.
Genet. 116: 384-389, 2005.
12. Porath, U.; Schreier, K.: Eine Familie mit Pyroglutaminacidurie. Dtsch.
Med. Wschr. 103: 939-942, 1978.
13. Ristoff, E.; Mayatepek, E.; Larsson, A.: Long-term clinical outcome
in patients with glutathione synthetase deficiency. J. Pediat. 139:
79-84, 2001.
14. Robertson, P. L.; Buchanan, D. N.; Muenzer, J.: 5-Oxoprolinuria
in an adolescent with chronic metabolic acidosis, mental retardation,
and psychosis. J. Pediat. 118: 92-95, 1991.
15. Shi, Z.-Z.; Habib, G. M.; Rhead, W. J.; Gahl, W. A.; He, X.; Sazer,
S.; Lieberman, M. W.: Mutations in the glutathione synthetase gene
cause 5-oxoprolinuria. Nature Genet. 14: 361-365, 1996.
16. Spielberg, S. P.; Boxer, L. A.; Oliver, J. M.; Allen, J. M.; Schulman,
J. D.: Oxidative damage to neutrophils in glutathione synthetase
deficiency. Brit. J. Haemat. 42: 215-223, 1979.
17. Spielberg, S. P.; Kramer, L. I.; Goodman, S. I.; Butler, J.; Tietze,
F.; Quinn, P.; Schulman, J. D.: 5-Oxoprolinuria: biochemical observations
and case report. J. Pediat. 91: 237-241, 1977.
18. Wellner, V. P.; Sekura, R.; Meister, A.; Larsson, A.: Glutathione
synthetase deficiency, an inborn error of metabolism involving the
gamma-glutamyl cycle in patients with 5-oxoprolinuria. Proc. Nat.
Acad. Sci. 71: 2505-2509, 1974.
*FIELD* CS
Neuro:
Mental retardation;
Ataxia;
Seizures;
Spastic tetraparesis;
Intention tremor;
Dysarthria;
Psychotic behavior
Eyes:
Peripheral retinal pigmentation abnormalities
Metabolic:
Chronic metabolic acidosis
Heme:
Increased hemolysis;
Mild hemolytic anemia;
Episodic neutropenia
Lab:
Pyroglutamic acidemia;
Pyroglutamic aciduria;
Decreased erythrocyte glutathione;
Glutathione synthetase deficiency;
Increased gamma-glutamyl-cysteine synthetase;
Neutrophil bactericidal and iodination defects responsive to vitamin
E (alpha-tocopherol)
Inheritance:
Autosomal recessive
*FIELD* CN
Marla J. F. O'Neill - updated: 6/21/2005
Carol A. Bocchini - reorganized: 10/4/2001
Deborah L. Stone - updated: 10/4/2001
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 01/24/2013
wwang: 7/1/2005
terry: 6/21/2005
terry: 4/21/2005
carol: 10/4/2001
terry: 10/29/1996
mark: 1/21/1996
terry: 1/18/1996
carol: 9/21/1994
davew: 8/19/1994
mimadm: 3/12/1994
carol: 12/13/1993
supermim: 3/17/1992
carol: 9/13/1991
*RECORD*
*FIELD* NO
266130
*FIELD* TI
#266130 GLUTATHIONE SYNTHETASE DEFICIENCY; GSSD
;;5-@OXOPROLINURIA;;
PYROGLUTAMIC ACIDURIA
read more*FIELD* TX
A number sign (#) is used with this entry because glutathione synthetase
deficiency, or 5-oxoprolinuria, is caused by homozygous or compound
heterozygous mutation in the gene encoding glutathione synthetase (GSS;
601002) on chromosome 20q11. The same gene is mutant in hemolytic anemia
due to glutathione synthetase deficiency of erythrocytes (231900).
Also see 5-oxoprolinuria due to oxoprolinase deficiency (260005).
DESCRIPTION
Glutathione synthetase deficiency, or 5-oxoprolinuria, is an autosomal
recessive disorder characterized, in its severe form, by massive urinary
excretion of 5-oxoproline, metabolic acidosis, hemolytic anemia, and
central nervous system damage. The metabolic defect results in decreased
levels of cellular glutathione, which overstimulates the synthesis of
gamma-glutamylcysteine and its subsequent conversion to 5-oxoproline
(Larsson and Anderson, 2001).
CLINICAL FEATURES
Jellum et al. (1970) discovered large amounts of pyroglutamic acid in
the urine and plasma of a 19-year-old retarded Norwegian male. The
chemical search was initiated because of unexplained chronic metabolic
acidosis. Pyroglutamic acid was isolated by gas chromatography and
identified by mass spectrometry; it is ninhydrin-negative. The patient
showed spastic tetraparesis and a cerebellar disorder with intention
tremor and dysarthria. Deficiency of 5-oxoprolinase in the kidney was
suspected but not proved. Larsson et al. (1974) described 2 sisters, a
neonate and a 3 year old, with pyroglutamic aciduria. Both had chronic
metabolic acidosis requiring therapy with bicarbonate. Both showed
increased hemolysis and marked decrease in glutathione in erythrocytes.
Psychologic and somatic development of the 3 year old was normal, and
she had no signs of neurologic damage. Marstein et al. (1976) studied a
24-year-old mentally retarded man who had demonstrated neurologic
deterioration during the previous few years. Ataxia prevented his
walking unaided. He developed epileptic seizures. Erythrocytes contained
no detectable glutathione, and his glutathione synthetase activity was
less than 2% of normal. The overproduction of pyroglutamate is probably
caused by increased in vivo activity of gamma-glutamyl-cysteine
synthetase, which in turn is caused by absence of normal feedback
inhibition by glutathione with resulting superabundance of substrates
available for gamma-glutamyl cyclotransferase. Lack of glutathione in
the erythrocytes is apparently tolerable, but in nonrenewable neurons
leads to serious neurologic problems of progressive nature.
Because of the observation of several episodes of neutropenia in a child
with 5-oxoprolinuria, Spielberg et al. (1979) examined the response of
neutrophils to oxidative stress associated with phagocytosis. Following
ingestion of particles, the cells accumulated excess hydrogen peroxide
compared with normal cells and showed impaired protein iodination and
bacterial killing.
Robertson et al. (1991) described a 12-year-old girl with chronic
metabolic acidosis, mental retardation, and psychotic behavior, as well
as mild hemolytic anemia and peripheral retinal pigmentation
abnormalities. A urine metabolic screen demonstrated 5-oxoprolinuria and
further studies showed glutathione synthetase deficiency. The acidosis
in the newborn period had been labeled renal tubular acidosis and
treated with bicarbonate.
Divry et al. (1991) described a patient with a very severe neurologic
presentation leading to fatal outcome in the first hours of life.
Manning et al. (1994) stated that approximately 20 cases of glutathione
synthase deficiency had been reported and another 10 were known. The
usual presentation had been neonatal acidosis and hemolysis with or
without signs of neurologic damage. Some cases had not been diagnosed
until adult life, however, reflecting a less severe form of the
condition.
CLINICAL MANAGEMENT
Boxer et al. (1979) reported that vitamin E (alpha-tocopherol), 400
IU/day, increased red cell survival, corrected both the bactericidal and
the iodination defects, and eliminated the neutropenia that accompanied
intercurrent illnesses.
Martensson et al. (1989) concluded that N-acetylcysteine may be of value
in increasing the low intracellular glutathione concentrations and
cysteine availability in patients with this disorder.
Ristoff et al. (2001) studied 28 patients with glutathione synthetase
deficiency, which they classified into 3 types based on severity of
clinical signs: mild (hemolytic anemia only), moderate (neonatal
acidosis), and severe (neurologic involvement). They concluded that
early supplementation with vitamins C and E may improve the long-term
clinical outcome of these patients.
DIAGNOSIS
- Prenatal Diagnosis
Erasmus et al. (1993) described a family in which an affected girl died
at the age of 6 weeks. Both parents and the maternal grandmother had
erythrocyte glutathione synthetase activity in the heterozygote range.
Two later pregnancies were monitored with the measurement of
5-oxoproline in the amniotic fluid and in the latter of the 2
pregnancies by glutathione synthetase activity measurements. Both tests
suggested that the infants were not affected and such was proved to be
the case after delivery. Since accumulation of 5-oxoproline in body
fluids, including urine, is characteristic of this disorder and since
the amniotic fluid from the second trimester consists mostly of fetal
urine, prenatal diagnosis by amniocentesis should be possible.
Manning et al. (1994) studied 2 pregnancies of an at-risk couple at 16
weeks' gestation. The levels of 5-oxoproline in both pregnancies was 25
to 30 times normal. The pregnancies were terminated and the diagnosis in
one case was subsequently confirmed by assay of glutathione synthase in
cultured fetal fibroblasts. In the other case, postmortem tissue samples
failed to grow.
MOLECULAR GENETICS
In 3 families with glutathione synthetase deficiency, Shi et al. (1996)
identified 7 mutations in the GSS gene on 6 alleles
(601002.0001-601002.0006).
In 41 patients (33 previously reported) with glutathione synthetase
deficiency from 33 families, Njalsson et al. (2005) evaluated genotype,
enzyme activity, metabolite levels, and clinical phenotype. They
identified 27 different mutations; 23 patients were homozygotes and 18
were compound heterozygotes. The moderate and severe clinical phenotypes
could not be distinguished based on enzyme activity or glutathione or
gamma-glutamylcysteine levels in cultured fibroblasts. All mutations
causing frameshifts, premature stop codons, or aberrant splicing were
associated with moderate or severe clinical phenotypes. Njalsson et al.
(2005) concluded that additional genetic or environmental factors modify
at least the moderate and severe phenotypes and that the clinical
classification given to patients may be influenced by variation in
follow-up.
*FIELD* SA
Meister (1978); Porath and Schreier (1978); Spielberg et al. (1977);
Wellner et al. (1974)
*FIELD* RF
1. Boxer, L. A.; Oliver, J. M.; Spielberg, S. P.; Allen, J. M.; Schulman,
J. D.: Protection of granulocytes by vitamin E in glutathione synthetase
deficiency. New Eng. J. Med. 301: 901-905, 1979.
2. Divry, P.; Roulaud-Parrot, F.; Dorche, C.; Zabot, M. T.; Contraire,
B.; Hagenfeldt, L.; Larsson, A.: 5-Oxoprolinuria (glutathione synthetase
deficiency): a case with neonatal presentation and rapid fatal outcome. J.
Inherit. Metab. Dis. 14: 341-344, 1991.
3. Erasmus, E.; Mienie, L. J.; de Vries, W. N.; de Wet, W. J.; Carlsson,
B.; Larsson, A.: Prenatal analysis in two suspected cases of glutathione
synthetase deficiency. J. Inherit. Metab. Dis. 16: 837-843, 1993.
4. Jellum, E.; Kluge, T.; Borresen, H. C.; Stokke, O.; Eldjarn, L.
: Pyroglutamic acidosis--a new inborn error of metabolism. Scand.
J. Clin. Lab. Invest. 26: 327-335, 1970.
5. Larsson, A.; Anderson, M. E.: Glutathione synthetase deficiency
and other disorders of the gamma-glutamyl cycle.In: Scriver, C. R.;
Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular
Bases of Inherited Disease. Vol. 2 (8th ed.) New York: McGraw-Hill
2001. Pp. 2205-2216.
6. Larsson, A.; Zetterstrom, R.; Hagenfeldt, L.; Andersson, R.; Dreborg,
S.; Hornell, H.: Pyroglutamic aciduria (5-oxoprolinuria), an inborn
error in glutathione metabolism. Pediat. Res. 8: 852-856, 1974.
7. Manning, N. J.; Davies, N. P.; Olpin, S. E.; Carpenter, K. H.;
Smith, M. F.; Pollitt, R. J.; Duncan, S. L. B.; Larsson, A.; Carlsson,
B.: Prenatal diagnosis of glutathione synthase deficiency. Prenatal
Diag. 14: 475-478, 1994.
8. Marstein, S.; Jellum, E.; Halpern, B.; Eldjarn, L.; Perry, T. L.
: Biochemical studies of erythrocytes in a patient with pyroglutamic
acidemia (5-oxoprolinemia). New Eng. J. Med. 295: 406-412, 1976.
9. Martensson, J.; Gustafsson, J.; Larsson, A.: A therapeutic trial
with N-acetylcysteine in subjects with hereditary glutathione synthetase
deficiency (5-oxoprolinuria). J. Inherit. Metab. Dis. 12: 120-130,
1989.
10. Meister, A.: 5-Oxoprolinuria (pyroglutamic aciduria) and other
disorders of glutathione biosynthesis.In: Stanbury, J. B.; Wyngaarden,
J. B.; Fredrickson, D. S.: Metabolic Basis of Inherited Disease.
New York: McGraw-Hill (pub.) (4th ed.): 1978. Pp. 328-335.
11. Njalsson, R.; Ristoff, E.; Carlsson, K.; Winkler, A.; Larsson,
A.; Norgren, S.: Genotype, enzyme activity, glutathione level, and
clinical phenotype in patients with glutathione synthetase deficiency. Hum.
Genet. 116: 384-389, 2005.
12. Porath, U.; Schreier, K.: Eine Familie mit Pyroglutaminacidurie. Dtsch.
Med. Wschr. 103: 939-942, 1978.
13. Ristoff, E.; Mayatepek, E.; Larsson, A.: Long-term clinical outcome
in patients with glutathione synthetase deficiency. J. Pediat. 139:
79-84, 2001.
14. Robertson, P. L.; Buchanan, D. N.; Muenzer, J.: 5-Oxoprolinuria
in an adolescent with chronic metabolic acidosis, mental retardation,
and psychosis. J. Pediat. 118: 92-95, 1991.
15. Shi, Z.-Z.; Habib, G. M.; Rhead, W. J.; Gahl, W. A.; He, X.; Sazer,
S.; Lieberman, M. W.: Mutations in the glutathione synthetase gene
cause 5-oxoprolinuria. Nature Genet. 14: 361-365, 1996.
16. Spielberg, S. P.; Boxer, L. A.; Oliver, J. M.; Allen, J. M.; Schulman,
J. D.: Oxidative damage to neutrophils in glutathione synthetase
deficiency. Brit. J. Haemat. 42: 215-223, 1979.
17. Spielberg, S. P.; Kramer, L. I.; Goodman, S. I.; Butler, J.; Tietze,
F.; Quinn, P.; Schulman, J. D.: 5-Oxoprolinuria: biochemical observations
and case report. J. Pediat. 91: 237-241, 1977.
18. Wellner, V. P.; Sekura, R.; Meister, A.; Larsson, A.: Glutathione
synthetase deficiency, an inborn error of metabolism involving the
gamma-glutamyl cycle in patients with 5-oxoprolinuria. Proc. Nat.
Acad. Sci. 71: 2505-2509, 1974.
*FIELD* CS
Neuro:
Mental retardation;
Ataxia;
Seizures;
Spastic tetraparesis;
Intention tremor;
Dysarthria;
Psychotic behavior
Eyes:
Peripheral retinal pigmentation abnormalities
Metabolic:
Chronic metabolic acidosis
Heme:
Increased hemolysis;
Mild hemolytic anemia;
Episodic neutropenia
Lab:
Pyroglutamic acidemia;
Pyroglutamic aciduria;
Decreased erythrocyte glutathione;
Glutathione synthetase deficiency;
Increased gamma-glutamyl-cysteine synthetase;
Neutrophil bactericidal and iodination defects responsive to vitamin
E (alpha-tocopherol)
Inheritance:
Autosomal recessive
*FIELD* CN
Marla J. F. O'Neill - updated: 6/21/2005
Carol A. Bocchini - reorganized: 10/4/2001
Deborah L. Stone - updated: 10/4/2001
*FIELD* CD
Victor A. McKusick: 6/4/1986
*FIELD* ED
carol: 01/24/2013
wwang: 7/1/2005
terry: 6/21/2005
terry: 4/21/2005
carol: 10/4/2001
terry: 10/29/1996
mark: 1/21/1996
terry: 1/18/1996
carol: 9/21/1994
davew: 8/19/1994
mimadm: 3/12/1994
carol: 12/13/1993
supermim: 3/17/1992
carol: 9/13/1991
MIM
601002
*RECORD*
*FIELD* NO
601002
*FIELD* TI
*601002 GLUTATHIONE SYNTHETASE; GSS
;;GSHS
*FIELD* TX
DESCRIPTION
Glutathione (GSH), a ubiquitous low molecular mass thiol, is important
read morefor a variety of biologic functions, including protection of cells from
oxidative damage by free radicals, detoxification of xenobiotics, and
membrane transport (Meister and Anderson, 1983; Uhlig and Wendel, 1992).
The consecutive actions of gamma-glutamylcysteine synthetase (606857)
and glutathione synthetase produce GSH from the amino acids cysteine,
glutamate, and glycine.
CLONING
Shi et al. (1996) cloned and characterized the human GSS gene.
MAPPING
Webb et al. (1995) found by Southern blots hybridized with a glutathione
synthetase cDNA that there appears to be a single glutathione synthetase
gene (GSS) in the human genome. Analysis of somatic cell hybrids showed
that GSS is located on chromosome 20, and this assignment was refined to
20q11.2 by fluorescence in situ hybridization.
MOLECULAR GENETICS
Shi et al. (1996) performed a mutation search of the GSS gene in 3
families with glutathione synthetase deficiency (GSSD; 266130), or
5-oxoprolinuria, an autosomal recessive disorder characterized, in its
severe form, by massive urinary excretion of 5-oxoproline, metabolic
acidosis, hemolytic anemia, and central nervous system damage. They
identified 7 mutations at the GSS locus on 6 alleles: 1 splice site
mutation, 2 deletions, and 4 missense mutations
(601002.0001-601002.0006). Bacterial expression and yeast
complementation assays of the cDNAs encoded by these alleles
demonstrated their functional defects. They also identified a homozygous
missense mutation in the GSS gene (601002.0007) in an individual
affected by the milder form of GSS deficiency, which is apparently
restricted to erythrocytes and only associated with hemolytic anemia
(GSSDE; 231900).
Dahl et al. (1997) identified a total of 13 different mutations in the
GSS gene in 9 patients with severe glutathione synthetase deficiency.
The patients were all unrelated and came from different geographic
areas. All patients had presented with metabolic acidosis, hemolytic
anemia, and 5-oxoprolinuria; however, neurologic symptoms were variable.
Among the 13 different missense mutations involved, 2 were found in
patients presenting with functional impairment of the central nervous
system. One of these, aged 22 years at last examination, had a low
normal IQ and abnormal retinogram. Four patients were found to be
compound heterozygotes and 2 were apparently homozygous. Reduced enzyme
activities were demonstrated in recombinant protein expressed from cDNAs
in 4 cases with different missense mutations. The results from
biochemical analysis of patient specimens, supported by the properties
of the expressed mutant proteins, indicated that residual activity was
present in affected individuals. Dahl et al. (1997) suggested that
complete loss of function of both glutathione synthetase alleles is
probably lethal. They postulated that missense mutations will account
for the phenotype in most patients with severe GS deficiency.
In 41 patients (33 previously reported) with glutathione synthetase
deficiency from 33 families, Njalsson et al. (2005) evaluated genotype,
enzyme activity, metabolite levels, and clinical phenotype. They
identified 27 different mutations; 23 patients were homozygotes and 18
were compound heterozygotes. The moderate and severe clinical phenotypes
could not be distinguished based on enzyme activity or glutathione or
gamma-glutamylcysteine levels in cultured fibroblasts. All mutations
causing frameshifts, premature stop codons, or aberrant splicing were
associated with moderate or severe clinical phenotypes. Njalsson et al.
(2005) concluded that additional genetic or environmental factors modify
at least the moderate and severe phenotypes and that the clinical
classification given to patients may be influenced by variation in
follow-up.
*FIELD* AV
.0001
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, ARG164GLN
In a family in which 2 brothers exhibited 5-oxoprolinuria (GSSD;
266130), metabolic acidosis, hemolytic anemia, and mental retardation,
Shi et al. (1996) found compound heterozygosity for mutations in the GSS
gene: a G-to-A transition at the end of exon 4 (position 491) of the
cDNA, which may cause an RNA splicing error or a missense mutation
(arg164-to-gln); and, in exon 1, a deletion of G corresponding to
nucleotide 3 or 4 in the cDNA sequence (+1ATGGCC...), predicting a
frameshift and/or abolition of the translation initiation site. These 2
changes were designated as 491G-A and 3(4)delG, respectively.
.0002
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, 1-BP DEL, NT3/4G
See 601002.0001 and Shi et al. (1996).
.0003
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, ARG267TRP
In a patient with 5-oxoprolinuria (266130), Shi et al. (1996) found
compound heterozygosity for 2 C-to-T transitions at nucleotides 799 and
847, implying 2 missense mutations: arg267 to trp and arg283 to cys
(601002.0004) in exons 8 and 9, respectively.
.0004
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, ARG283CYS
See 601002.0003 and Shi et al. (1996).
.0005
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, ARG125CYS
In a patient with 5-oxoprolinuria (266130), Shi et al. (1996) found 3
sequence alterations: 2 missense mutations (373C-T, leading to arg125 to
cys, and 941C-T, leading to pro314 to leu) plus a 6-bp in-frame deletion
(1137del6, resulting in the deletion of val380 and gln381) in exons 4,
9, and 11, respectively. The arg125-to-cys mutation was transmitted from
the father; the other 2 mutations came from the mother, indicating that
they are on the same allele (601002.0006). In an in vitro expression
system, the mutant cDNAs corresponding to the 2 alleles from this family
failed to complement and produced proteins with undetectable activity
(373C-T) or altered solubility (doubly mutant allele).
.0006
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, PRO314LEU AND 6-BP DEL, NT1137
See 601002.0005 and Shi et al. (1996).
.0007
GLUTATHIONE SYNTHETASE DEFICIENCY OF ERYTHROCYTES, HEMOLYTIC ANEMIA
DUE TO
GSS, ASP219GLY
In a patient with GSS deficiency restricted to erythrocytes and
associated only with hemolytic anemia (GSSDE; 231900) (Mohler et al.,
1970), Shi et al. (1996) found homozygosity for the nucleotide
substitution 656A-G that resulted in the missense mutation asp219 to gly
(D219G). Although the patient's parents were not related, they were both
of Scottish descent, and the families had lived in the same county for
several generations. The allele was responsible for reduced activity and
instability of the expressed protein, but was more active than the other
6 alleles which were found by Shi et al. (1996) to result in
5-oxoprolinuria.
Vives Corrons et al. (2001) found the D219G mutation in 2 unrelated
Spanish adults with a well-compensated hemolytic syndrome without anemia
or splenomegaly at steady state. One of these patients was diagnosed
after an episode of acute hemolytic anemia following fava bean
ingestion.
*FIELD* RF
1. Dahl, N.; Pigg, M.; Ristoff, E.; Gali, R.; Carlsson, B.; Mannervik,
B.; Larsson, A.; Board, P.: Missense mutations in the human glutathione
synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria,
hemolytic anemia and neurological dysfunction. Hum. Molec. Genet. 6:
1147-1152, 1997.
2. Meister, A.; Anderson, M. E.: Glutathione. Annu. Rev. Biochem. 52:
711-760, 1983.
3. Mohler, D. N.; Majerus, P. W.; Minnich, V.; Hess, C. E.; Garrick,
M. D.: Glutathione synthetase deficiency as a cause of hereditary
hemolytic disease. New Eng. J. Med. 283: 1253-1257, 1970.
4. Njalsson, R.; Ristoff, E.; Carlsson, K.; Winkler, A.; Larsson,
A.; Norgren, S.: Genotype, enzyme activity, glutathione level, and
clinical phenotype in patients with glutathione synthetase deficiency. Hum.
Genet. 116: 384-389, 2005.
5. Shi, Z.-Z.; Habib, G. M.; Rhead, W. J.; Gahl, W. A.; He, X.; Sazer,
S.; Lieberman, M. W.: Mutations in the glutathione synthetase gene
cause 5-oxoprolinuria. Nature Genet. 14: 361-365, 1996.
6. Uhlig, S.; Wendel, A.: The physiological consequences of glutathione
variations. Life Sci. 51: 1083-1094, 1992.
7. Vives Corrons, J.-L.; Alvarez, R.; Pujades, A.; Zarza, R.; Oliva,
E.; Lasheras, G.; Callis, M.; Ribes, A.; Gelbart, T.; Beutler, E.
: Hereditary non-spherocytic haemolytic anaemia due to red blood cell
glutathione synthetase deficiency in four unrelated patients from
Spain: clinical and molecular studies. Brit. J. Haemat. 112: 475-482,
2001.
8. Webb, G. C.; Vaska, V. L.; Gali, R. R.; Ford, J. H.; Board, P.
G.: The gene encoding human glutathione synthetase (GSS) maps to
the long arm of chromosome 20 at band 11.2. Genomics 30: 617-619,
1995.
*FIELD* CN
Marla J. F. O'Neill - updated: 6/21/2005
Carol A. Bocchini - reorganized: 10/4/2001
Victor A. McKusick - updated: 5/18/2001
Victor A. McKusick - updated: 8/15/1997
*FIELD* CD
Victor A. McKusick: 1/21/1996
*FIELD* ED
carol: 01/24/2013
wwang: 7/1/2005
wwang: 6/29/2005
terry: 6/21/2005
terry: 4/21/2005
carol: 4/17/2002
carol: 10/4/2001
mcapotos: 6/1/2001
mcapotos: 5/29/2001
terry: 5/18/2001
kayiaros: 7/13/1999
terry: 5/10/1999
terry: 6/4/1998
jenny: 8/20/1997
terry: 8/15/1997
terry: 7/29/1997
terry: 10/31/1996
terry: 10/28/1996
terry: 2/6/1996
mark: 1/21/1996
*RECORD*
*FIELD* NO
601002
*FIELD* TI
*601002 GLUTATHIONE SYNTHETASE; GSS
;;GSHS
*FIELD* TX
DESCRIPTION
Glutathione (GSH), a ubiquitous low molecular mass thiol, is important
read morefor a variety of biologic functions, including protection of cells from
oxidative damage by free radicals, detoxification of xenobiotics, and
membrane transport (Meister and Anderson, 1983; Uhlig and Wendel, 1992).
The consecutive actions of gamma-glutamylcysteine synthetase (606857)
and glutathione synthetase produce GSH from the amino acids cysteine,
glutamate, and glycine.
CLONING
Shi et al. (1996) cloned and characterized the human GSS gene.
MAPPING
Webb et al. (1995) found by Southern blots hybridized with a glutathione
synthetase cDNA that there appears to be a single glutathione synthetase
gene (GSS) in the human genome. Analysis of somatic cell hybrids showed
that GSS is located on chromosome 20, and this assignment was refined to
20q11.2 by fluorescence in situ hybridization.
MOLECULAR GENETICS
Shi et al. (1996) performed a mutation search of the GSS gene in 3
families with glutathione synthetase deficiency (GSSD; 266130), or
5-oxoprolinuria, an autosomal recessive disorder characterized, in its
severe form, by massive urinary excretion of 5-oxoproline, metabolic
acidosis, hemolytic anemia, and central nervous system damage. They
identified 7 mutations at the GSS locus on 6 alleles: 1 splice site
mutation, 2 deletions, and 4 missense mutations
(601002.0001-601002.0006). Bacterial expression and yeast
complementation assays of the cDNAs encoded by these alleles
demonstrated their functional defects. They also identified a homozygous
missense mutation in the GSS gene (601002.0007) in an individual
affected by the milder form of GSS deficiency, which is apparently
restricted to erythrocytes and only associated with hemolytic anemia
(GSSDE; 231900).
Dahl et al. (1997) identified a total of 13 different mutations in the
GSS gene in 9 patients with severe glutathione synthetase deficiency.
The patients were all unrelated and came from different geographic
areas. All patients had presented with metabolic acidosis, hemolytic
anemia, and 5-oxoprolinuria; however, neurologic symptoms were variable.
Among the 13 different missense mutations involved, 2 were found in
patients presenting with functional impairment of the central nervous
system. One of these, aged 22 years at last examination, had a low
normal IQ and abnormal retinogram. Four patients were found to be
compound heterozygotes and 2 were apparently homozygous. Reduced enzyme
activities were demonstrated in recombinant protein expressed from cDNAs
in 4 cases with different missense mutations. The results from
biochemical analysis of patient specimens, supported by the properties
of the expressed mutant proteins, indicated that residual activity was
present in affected individuals. Dahl et al. (1997) suggested that
complete loss of function of both glutathione synthetase alleles is
probably lethal. They postulated that missense mutations will account
for the phenotype in most patients with severe GS deficiency.
In 41 patients (33 previously reported) with glutathione synthetase
deficiency from 33 families, Njalsson et al. (2005) evaluated genotype,
enzyme activity, metabolite levels, and clinical phenotype. They
identified 27 different mutations; 23 patients were homozygotes and 18
were compound heterozygotes. The moderate and severe clinical phenotypes
could not be distinguished based on enzyme activity or glutathione or
gamma-glutamylcysteine levels in cultured fibroblasts. All mutations
causing frameshifts, premature stop codons, or aberrant splicing were
associated with moderate or severe clinical phenotypes. Njalsson et al.
(2005) concluded that additional genetic or environmental factors modify
at least the moderate and severe phenotypes and that the clinical
classification given to patients may be influenced by variation in
follow-up.
*FIELD* AV
.0001
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, ARG164GLN
In a family in which 2 brothers exhibited 5-oxoprolinuria (GSSD;
266130), metabolic acidosis, hemolytic anemia, and mental retardation,
Shi et al. (1996) found compound heterozygosity for mutations in the GSS
gene: a G-to-A transition at the end of exon 4 (position 491) of the
cDNA, which may cause an RNA splicing error or a missense mutation
(arg164-to-gln); and, in exon 1, a deletion of G corresponding to
nucleotide 3 or 4 in the cDNA sequence (+1ATGGCC...), predicting a
frameshift and/or abolition of the translation initiation site. These 2
changes were designated as 491G-A and 3(4)delG, respectively.
.0002
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, 1-BP DEL, NT3/4G
See 601002.0001 and Shi et al. (1996).
.0003
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, ARG267TRP
In a patient with 5-oxoprolinuria (266130), Shi et al. (1996) found
compound heterozygosity for 2 C-to-T transitions at nucleotides 799 and
847, implying 2 missense mutations: arg267 to trp and arg283 to cys
(601002.0004) in exons 8 and 9, respectively.
.0004
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, ARG283CYS
See 601002.0003 and Shi et al. (1996).
.0005
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, ARG125CYS
In a patient with 5-oxoprolinuria (266130), Shi et al. (1996) found 3
sequence alterations: 2 missense mutations (373C-T, leading to arg125 to
cys, and 941C-T, leading to pro314 to leu) plus a 6-bp in-frame deletion
(1137del6, resulting in the deletion of val380 and gln381) in exons 4,
9, and 11, respectively. The arg125-to-cys mutation was transmitted from
the father; the other 2 mutations came from the mother, indicating that
they are on the same allele (601002.0006). In an in vitro expression
system, the mutant cDNAs corresponding to the 2 alleles from this family
failed to complement and produced proteins with undetectable activity
(373C-T) or altered solubility (doubly mutant allele).
.0006
GLUTATHIONE SYNTHETASE DEFICIENCY
GSS, PRO314LEU AND 6-BP DEL, NT1137
See 601002.0005 and Shi et al. (1996).
.0007
GLUTATHIONE SYNTHETASE DEFICIENCY OF ERYTHROCYTES, HEMOLYTIC ANEMIA
DUE TO
GSS, ASP219GLY
In a patient with GSS deficiency restricted to erythrocytes and
associated only with hemolytic anemia (GSSDE; 231900) (Mohler et al.,
1970), Shi et al. (1996) found homozygosity for the nucleotide
substitution 656A-G that resulted in the missense mutation asp219 to gly
(D219G). Although the patient's parents were not related, they were both
of Scottish descent, and the families had lived in the same county for
several generations. The allele was responsible for reduced activity and
instability of the expressed protein, but was more active than the other
6 alleles which were found by Shi et al. (1996) to result in
5-oxoprolinuria.
Vives Corrons et al. (2001) found the D219G mutation in 2 unrelated
Spanish adults with a well-compensated hemolytic syndrome without anemia
or splenomegaly at steady state. One of these patients was diagnosed
after an episode of acute hemolytic anemia following fava bean
ingestion.
*FIELD* RF
1. Dahl, N.; Pigg, M.; Ristoff, E.; Gali, R.; Carlsson, B.; Mannervik,
B.; Larsson, A.; Board, P.: Missense mutations in the human glutathione
synthetase gene result in severe metabolic acidosis, 5-oxoprolinuria,
hemolytic anemia and neurological dysfunction. Hum. Molec. Genet. 6:
1147-1152, 1997.
2. Meister, A.; Anderson, M. E.: Glutathione. Annu. Rev. Biochem. 52:
711-760, 1983.
3. Mohler, D. N.; Majerus, P. W.; Minnich, V.; Hess, C. E.; Garrick,
M. D.: Glutathione synthetase deficiency as a cause of hereditary
hemolytic disease. New Eng. J. Med. 283: 1253-1257, 1970.
4. Njalsson, R.; Ristoff, E.; Carlsson, K.; Winkler, A.; Larsson,
A.; Norgren, S.: Genotype, enzyme activity, glutathione level, and
clinical phenotype in patients with glutathione synthetase deficiency. Hum.
Genet. 116: 384-389, 2005.
5. Shi, Z.-Z.; Habib, G. M.; Rhead, W. J.; Gahl, W. A.; He, X.; Sazer,
S.; Lieberman, M. W.: Mutations in the glutathione synthetase gene
cause 5-oxoprolinuria. Nature Genet. 14: 361-365, 1996.
6. Uhlig, S.; Wendel, A.: The physiological consequences of glutathione
variations. Life Sci. 51: 1083-1094, 1992.
7. Vives Corrons, J.-L.; Alvarez, R.; Pujades, A.; Zarza, R.; Oliva,
E.; Lasheras, G.; Callis, M.; Ribes, A.; Gelbart, T.; Beutler, E.
: Hereditary non-spherocytic haemolytic anaemia due to red blood cell
glutathione synthetase deficiency in four unrelated patients from
Spain: clinical and molecular studies. Brit. J. Haemat. 112: 475-482,
2001.
8. Webb, G. C.; Vaska, V. L.; Gali, R. R.; Ford, J. H.; Board, P.
G.: The gene encoding human glutathione synthetase (GSS) maps to
the long arm of chromosome 20 at band 11.2. Genomics 30: 617-619,
1995.
*FIELD* CN
Marla J. F. O'Neill - updated: 6/21/2005
Carol A. Bocchini - reorganized: 10/4/2001
Victor A. McKusick - updated: 5/18/2001
Victor A. McKusick - updated: 8/15/1997
*FIELD* CD
Victor A. McKusick: 1/21/1996
*FIELD* ED
carol: 01/24/2013
wwang: 7/1/2005
wwang: 6/29/2005
terry: 6/21/2005
terry: 4/21/2005
carol: 4/17/2002
carol: 10/4/2001
mcapotos: 6/1/2001
mcapotos: 5/29/2001
terry: 5/18/2001
kayiaros: 7/13/1999
terry: 5/10/1999
terry: 6/4/1998
jenny: 8/20/1997
terry: 8/15/1997
terry: 7/29/1997
terry: 10/31/1996
terry: 10/28/1996
terry: 2/6/1996
mark: 1/21/1996