RBCC Red Blood Cell Collection

GLUD1 (GLUD) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Glutamate dehydrogenase 1, mitochondrial; GDH 1; 1.4.1.3; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P00367
ID DHE3_HUMAN Reviewed; 558 AA.
AC P00367; Q5TBU3;
DT 21-JUL-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-JAN-1990, sequence version 2.
DT 22-JAN-2014, entry version 163.
DE RecName: Full=Glutamate dehydrogenase 1, mitochondrial;
DE Short=GDH 1;
DE EC=1.4.1.3;
DE Flags: Precursor;
GN Name=GLUD1; Synonyms=GLUD;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Brain, and Liver;
RX PubMed=3426581; DOI=10.1016/0006-291X(87)90381-0;
RA Nakatani Y., Banner C., von Herrat M., Schneider M.E., Smith H.H.,
RA Freese E.;
RT "Comparison of human brain and liver glutamate dehydrogenase cDNAs.";
RL Biochem. Biophys. Res. Commun. 149:405-410(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=3377777; DOI=10.1016/S0006-291X(88)80440-6;
RA Amuro N., Yamaura M., Goto Y., Okazaki T.;
RT "Molecular cloning and nucleotide sequence of the cDNA for human liver
RT glutamate dehydrogenase precursor.";
RL Biochem. Biophys. Res. Commun. 152:1395-1400(1988).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3399399; DOI=10.1093/nar/16.13.6237;
RA Nakatani Y., Schneider M.E., Banner C., Freese E.;
RT "Complete nucleotide sequence of human glutamate dehydrogenase cDNA.";
RL Nucleic Acids Res. 16:6237-6237(1988).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=3368458; DOI=10.1073/pnas.85.10.3494;
RA Mavrothalassitis G., Tzimagiorgis G., Mitsialis A., Zannis V.,
RA Plaitakis A., Papamatheakis J., Moschonas N.;
RT "Isolation and characterization of cDNA clones encoding human liver
RT glutamate dehydrogenase: evidence for a small gene family.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:3494-3498(1988).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Placenta;
RX PubMed=8486350; DOI=10.1006/geno.1993.1152;
RA Michaelidis T.M., Tzimagiorgis G., Moschonas N.K., Papamatheakis J.;
RT "The human glutamate dehydrogenase gene family: gene organization and
RT structural characterization.";
RL Genomics 16:150-160(1993).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Duodenum, and Eye;
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 PROTEIN SEQUENCE OF 54-558.
RC TISSUE=Liver;
RX PubMed=429360;
RA Julliard J.H., Smith E.L.;
RT "Partial amino acid sequence of the glutamate dehydrogenase of human
RT liver and a revision of the sequence of the bovine enzyme.";
RL J. Biol. Chem. 254:3427-3438(1979).
RN [9]
RP PROTEIN SEQUENCE OF 54-69.
RC TISSUE=Liver;
RX PubMed=1286669; DOI=10.1002/elps.11501301201;
RA Hochstrasser D.F., Frutiger S., Paquet N., Bairoch A., Ravier F.,
RA Pasquali C., Sanchez J.-C., Tissot J.-D., Bjellqvist B., Vargas R.,
RA Appel R.D., Hughes G.J.;
RT "Human liver protein map: a reference database established by
RT microsequencing and gel comparison.";
RL Electrophoresis 13:992-1001(1992).
RN [10]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 301-558.
RC TISSUE=Brain;
RX PubMed=3585334; DOI=10.1111/j.1471-4159.1987.tb03422.x;
RA Banner C., Silverman S., Thomas J.W., Lampel K.A., Vitkovic L.,
RA Huie D., Wenthold R.J.;
RT "Isolation of a human brain cDNA for glutamate dehydrogenase.";
RL J. Neurochem. 49:246-252(1987).
RN [11]
RP PROTEIN SEQUENCE OF 481-496, AND MASS SPECTROMETRY.
RC TISSUE=Brain, and Cajal-Retzius cell;
RA Lubec G., Vishwanath V.;
RL Submitted (MAR-2007) to UniProtKB.
RN [12]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 540-558.
RX PubMed=8314555; DOI=10.1007/BF00217767;
RA Tzimagiorgis G., Leversha M.A., Chroniary K., Goulielmos G.,
RA Sargent C.A., Ferguson-Smith M., Moschonas N.K.;
RT "Structure and expression analysis of a member of the human glutamate
RT dehydrogenase (GLUD) gene family mapped to chromosome 10p11.2.";
RL Hum. Genet. 91:433-438(1993).
RN [13]
RP ADP-RIBOSYLATION AT CYS-172.
RX PubMed=16023112; DOI=10.1016/j.febslet.2005.06.041;
RA Choi M.M., Huh J.W., Yang S.J., Cho E.H., Choi S.Y., Cho S.W.;
RT "Identification of ADP-ribosylation site in human glutamate
RT dehydrogenase isozymes.";
RL FEBS Lett. 579:4125-4130(2005).
RN [14]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-84; LYS-480 AND LYS-503, AND
RP MASS SPECTROMETRY.
RX PubMed=19608861; DOI=10.1126/science.1175371;
RA Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M.,
RA Walther T.C., Olsen J.V., Mann M.;
RT "Lysine acetylation targets protein complexes and co-regulates major
RT cellular functions.";
RL Science 325:834-840(2009).
RN [15]
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 [16]
RP CHARACTERIZATION OF VARIANT TYR-507, AND ALLOSTERIC REGULATION.
RX PubMed=11254391; DOI=10.1006/jmbi.2001.4499;
RA Smith T.J., Peterson P.E., Schmidt T., Fang J., Stanley C.A.;
RT "Structures of bovine glutamate dehydrogenase complexes elucidate the
RT mechanism of purine regulation.";
RL J. Mol. Biol. 307:707-720(2001).
RN [17]
RP MUTAGENESIS OF SER-501 AND ARG-516, CHARACTERIZATION OF VARIANT
RP TYR-507, AND ALLOSTERIC REGULATION.
RX PubMed=11903050; DOI=10.1042/0264-6021:3630081;
RA Fang J., Hsu B.Y.L., MacMullen C.M., Poncz M., Smith T.J.,
RA Stanley C.A.;
RT "Expression, purification and characterization of human glutamate
RT dehydrogenase (GDH) allosteric regulatory mutations.";
RL Biochem. J. 363:81-87(2002).
RN [18]
RP ADP-RIBOSYLATION.
RX PubMed=16959573; DOI=10.1016/j.cell.2006.06.057;
RA Haigis M.C., Mostoslavsky R., Haigis K.M., Fahie K.,
RA Christodoulou D.C., Murphy A.J., Valenzuela D.M., Yancopoulos G.D.,
RA Karow M., Blander G., Wolberger C., Prolla T.A., Weindruch R.,
RA Alt F.W., Guarente L.;
RT "SIRT4 inhibits glutamate dehydrogenase and opposes the effects of
RT calorie restriction in pancreatic beta cells.";
RL Cell 126:941-954(2006).
RN [19]
RP X-RAY CRYSTALLOGRAPHY (2.7 ANGSTROMS) OF 54-558.
RX PubMed=12054821; DOI=10.1016/S0022-2836(02)00161-4;
RA Smith T.J., Schmidt T., Fang J., Wu J., Siuzdak G., Stanley C.A.;
RT "The structure of apo human glutamate dehydrogenase details subunit
RT communication and allostery.";
RL J. Mol. Biol. 318:765-777(2002).
RN [20]
RP X-RAY CRYSTALLOGRAPHY (3.3 ANGSTROMS) OF 63-558 OF MUTANT ALA-516, AND
RP ALLOSTERIC REGULATION.
RX PubMed=12653548; DOI=10.1021/bi0206917;
RA Banerjee S., Schmidt T., Fang J., Stanley C.A., Smith T.J.;
RT "Structural studies on ADP activation of mammalian glutamate
RT dehydrogenase and the evolution of regulation.";
RL Biochemistry 42:3446-3456(2003).
RN [21]
RP REVIEW ON VARIANTS.
RX PubMed=10338089;
RX DOI=10.1002/(SICI)1098-1004(1999)13:5<351::AID-HUMU3>3.3.CO;2-I;
RA Meissner T., Beinbrech B., Mayatepek E.;
RT "Congenital hyperinsulinism: molecular basis of a heterogeneous
RT disease.";
RL Hum. Mutat. 13:351-361(1999).
RN [22]
RP VARIANTS HHF6 LEU-498; SER-499; ASP-499; PRO-501 AND TYR-507.
RX PubMed=9571255; DOI=10.1056/NEJM199805073381904;
RA Stanley C.A., Lieu Y.K., Hsu B.Y.L., Burlina A.B., Greenberg C.R.,
RA Hopwood N.J., Perlman K., Rich B.H., Zammarchi E., Poncz M.;
RT "Hyperinsulinism and hyperammonemia in infants with regulatory
RT mutations of the glutamate dehydrogenase gene.";
RL N. Engl. J. Med. 338:1352-1357(1998).
RN [23]
RP VARIANTS HHF6 LYS-318 AND ALA-349.
RX PubMed=10636977; DOI=10.1016/S0022-3476(00)90052-0;
RA Miki Y., Taki T., Ohura T., Kato H., Yanagisawa M., Hayashi Y.;
RT "Novel missense mutations in the glutamate dehydrogenase gene in the
RT congenital hyperinsulinism-hyperammonemia syndrome.";
RL J. Pediatr. 136:69-72(2000).
RN [24]
RP VARIANTS HHF6 CYS-274 AND HIS-322.
RX PubMed=11214910; DOI=10.1007/s004390000432;
RA Santer R., Kinner M., Passarge M., Superti-Furga A., Mayatepek E.,
RA Meissner T., Schneppenheim R., Schaub J.;
RT "Novel missense mutations outside the allosteric domain of glutamate
RT dehydrogenase are prevalent in European patients with the congenital
RT hyperinsulinism-hyperammonemia syndrome.";
RL Hum. Genet. 108:66-71(2001).
RN [25]
RP VARIANTS HHF6 CYS-270; CYS-274; THR-318; CYS-319; CYS-322 AND HIS-322.
RX PubMed=11297618; DOI=10.1210/jc.86.4.1782;
RA MacMullen C., Fang J., Hsu B.Y.L., Kelly A., de Lonlay-Debeney P.,
RA Saudubray J.-M., Ganguly A., Smith T.J., Stanley C.A., Brown R.,
RA Buist N., Dasouki M., Fefferman R., Grange D., Karaviti L., Luedke C.,
RA Marriage B., McLaughlin J., Perlman K., Seashore M., van Vliet G.;
RT "Hyperinsulinism/hyperammonemia syndrome in children with regulatory
RT mutations in the inhibitory guanosine triphosphate-binding domain of
RT glutamate dehydrogenase.";
RL J. Clin. Endocrinol. Metab. 86:1782-1787(2001).
CC -!- FUNCTION: Mitochondrial glutamate dehydrogenase that converts L-
CC glutamate into alpha-ketoglutarate. Plays a key role in glutamine
CC anaplerosis by producing alpha-ketoglutarate, an important
CC intermediate in the tricarboxylic acid cycle. May be involved in
CC learning and memory reactions by increasing the turnover of the
CC excitatory neurotransmitter glutamate (By similarity).
CC -!- CATALYTIC ACTIVITY: L-glutamate + H(2)O + NAD(P)(+) = 2-
CC oxoglutarate + NH(3) + NAD(P)H.
CC -!- ENZYME REGULATION: Subject to allosteric regulation. Activated by
CC ADP. Inhibited by GTP and ATP. ADP can occupy the NADH binding
CC site and activate the enzyme.
CC -!- SUBUNIT: Homohexamer.
CC -!- SUBCELLULAR LOCATION: Mitochondrion matrix.
CC -!- PTM: ADP-ribosylated by SIRT4, leading to inactivate glutamate
CC dehydrogenase activity (By similarity). Stoichiometry shows that
CC ADP-ribosylation occurs in one subunit per catalytically active
CC homohexamer.
CC -!- DISEASE: Familial hyperinsulinemic hypoglycemia 6 (HHF6)
CC [MIM:606762]: Familial hyperinsulinemic hypoglycemia [MIM:256450],
CC also referred to as congenital hyperinsulinism, nesidioblastosis,
CC or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is
CC the most common cause of persistent hypoglycemia in infancy and is
CC due to defective negative feedback regulation of insulin secretion
CC by low glucose levels. In HHF6 elevated oxidation rate of
CC glutamate to alpha-ketoglutarate stimulates insulin secretion in
CC the pancreatic beta cells, while they impair detoxification of
CC ammonium in the liver. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the Glu/Leu/Phe/Val dehydrogenases family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/GLUD1";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Glutamate dehydrogenase 1
CC entry;
CC URL="http://en.wikipedia.org/wiki/Glutamate_dehydrogenase_1";
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DR EMBL; X07674; CAA30521.1; -; mRNA.
DR EMBL; M20867; AAA52526.1; -; mRNA.
DR EMBL; M37154; AAA52525.1; -; mRNA.
DR EMBL; X07769; CAA30598.1; -; mRNA.
DR EMBL; J03248; AAA52523.1; -; mRNA.
DR EMBL; X66300; CAA46994.2; -; Genomic_DNA.
DR EMBL; X66301; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66302; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66303; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66304; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66305; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66306; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66307; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66308; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66309; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66311; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; X66312; CAA46994.2; JOINED; Genomic_DNA.
DR EMBL; AL136982; CAI17120.1; -; Genomic_DNA.
DR EMBL; BC040132; AAH40132.1; -; mRNA.
DR EMBL; BC112946; AAI12947.1; -; mRNA.
DR EMBL; X67491; CAA47830.1; -; Genomic_DNA.
DR PIR; A28208; DEHUE.
DR PIR; I37424; I37424.
DR PIR; S29331; S29331.
DR PIR; S60192; S60192.
DR RefSeq; NP_005262.1; NM_005271.3.
DR UniGene; Hs.500409; -.
DR PDB; 1L1F; X-ray; 2.70 A; A/B/C/D/E/F=54-558.
DR PDB; 1NR1; X-ray; 3.30 A; A/B/C/D/E/F=63-558.
DR PDBsum; 1L1F; -.
DR PDBsum; 1NR1; -.
DR ProteinModelPortal; P00367; -.
DR SMR; P00367; 63-558.
DR IntAct; P00367; 18.
DR MINT; MINT-5005913; -.
DR STRING; 9606.ENSP00000277865; -.
DR DrugBank; DB00142; L-Glutamic Acid.
DR DrugBank; DB00157; NADH.
DR PhosphoSite; P00367; -.
DR DMDM; 118541; -.
DR REPRODUCTION-2DPAGE; IPI00016801; -.
DR SWISS-2DPAGE; P00367; -.
DR UCD-2DPAGE; P00367; -.
DR PaxDb; P00367; -.
DR PeptideAtlas; P00367; -.
DR PRIDE; P00367; -.
DR Ensembl; ENST00000277865; ENSP00000277865; ENSG00000148672.
DR GeneID; 2746; -.
DR KEGG; hsa:2746; -.
DR UCSC; uc001keg.3; human.
DR CTD; 2746; -.
DR GeneCards; GC10M088809; -.
DR HGNC; HGNC:4335; GLUD1.
DR HPA; HPA042492; -.
DR HPA; HPA044839; -.
DR MIM; 138130; gene.
DR MIM; 606762; phenotype.
DR neXtProt; NX_P00367; -.
DR Orphanet; 35878; Hyperinsulinism-hyperammonemia syndrome.
DR PharmGKB; PA28737; -.
DR eggNOG; COG0334; -.
DR HOGENOM; HOG000243801; -.
DR HOVERGEN; HBG005479; -.
DR InParanoid; P00367; -.
DR KO; K00261; -.
DR OMA; SGLEYTM; -.
DR OrthoDB; EOG73NG50; -.
DR PhylomeDB; P00367; -.
DR BioCyc; MetaCyc:HS07548-MONOMER; -.
DR BRENDA; 1.4.1.3; 2681.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P00367; -.
DR EvolutionaryTrace; P00367; -.
DR GeneWiki; Glutamate_dehydrogenase_1; -.
DR GenomeRNAi; 2746; -.
DR NextBio; 10824; -.
DR PRO; PR:P00367; -.
DR ArrayExpress; P00367; -.
DR Bgee; P00367; -.
DR CleanEx; HS_GLUD1; -.
DR Genevestigator; P00367; -.
DR GO; GO:0005759; C:mitochondrial matrix; TAS:Reactome.
DR GO; GO:0043531; F:ADP binding; IDA:BHF-UCL.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0004352; F:glutamate dehydrogenase (NAD+) activity; IDA:UniProtKB.
DR GO; GO:0004353; F:glutamate dehydrogenase [NAD(P)+] activity; IDA:BHF-UCL.
DR GO; GO:0005525; F:GTP binding; IDA:BHF-UCL.
DR GO; GO:0042802; F:identical protein binding; TAS:BHF-UCL.
DR GO; GO:0070728; F:leucine binding; IDA:BHF-UCL.
DR GO; GO:0070403; F:NAD+ binding; IDA:BHF-UCL.
DR GO; GO:0034641; P:cellular nitrogen compound metabolic process; TAS:Reactome.
DR GO; GO:0006537; P:glutamate biosynthetic process; IDA:BHF-UCL.
DR GO; GO:0006538; P:glutamate catabolic process; IDA:UniProtKB.
DR GO; GO:0006541; P:glutamine metabolic process; ISS:UniProtKB.
DR GO; GO:0032024; P:positive regulation of insulin secretion; IMP:BHF-UCL.
DR GO; GO:0072350; P:tricarboxylic acid metabolic process; ISS:UniProtKB.
DR Gene3D; 3.40.50.720; -; 1.
DR InterPro; IPR006095; Glu/Leu/Phe/Val_DH.
DR InterPro; IPR006096; Glu/Leu/Phe/Val_DH_C.
DR InterPro; IPR006097; Glu/Leu/Phe/Val_DH_dimer_dom.
DR InterPro; IPR016040; NAD(P)-bd_dom.
DR Pfam; PF00208; ELFV_dehydrog; 1.
DR Pfam; PF02812; ELFV_dehydrog_N; 1.
DR PRINTS; PR00082; GLFDHDRGNASE.
DR SMART; SM00839; ELFV_dehydrog; 1.
DR PROSITE; PS00074; GLFV_DEHYDROGENASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ADP-ribosylation; ATP-binding;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW GTP-binding; Mitochondrion; NADP; Nucleotide-binding; Oxidoreductase;
KW Phosphoprotein; Reference proteome; Transit peptide.
FT TRANSIT 1 53 Mitochondrion.
FT CHAIN 54 558 Glutamate dehydrogenase 1, mitochondrial.
FT /FTId=PRO_0000007206.
FT NP_BIND 141 143 NAD (By similarity).
FT ACT_SITE 183 183
FT BINDING 147 147 Substrate (By similarity).
FT BINDING 171 171 Substrate (By similarity).
FT BINDING 176 176 NAD (By similarity).
FT BINDING 252 252 NAD (By similarity).
FT BINDING 266 266 GTP (By similarity).
FT BINDING 270 270 GTP (By similarity).
FT BINDING 319 319 GTP (By similarity).
FT BINDING 322 322 GTP (By similarity).
FT BINDING 438 438 Substrate (By similarity).
FT BINDING 444 444 NAD (By similarity).
FT BINDING 450 450 ADP (By similarity).
FT BINDING 516 516 ADP (By similarity).
FT MOD_RES 79 79 Phosphoserine (By similarity).
FT MOD_RES 84 84 N6-acetyllysine; alternate.
FT MOD_RES 84 84 N6-succinyllysine; alternate (By
FT similarity).
FT MOD_RES 110 110 N6-acetyllysine; alternate (By
FT similarity).
FT MOD_RES 110 110 N6-succinyllysine; alternate (By
FT similarity).
FT MOD_RES 128 128 Phosphoserine (By similarity).
FT MOD_RES 135 135 Phosphotyrosine (By similarity).
FT MOD_RES 162 162 N6-acetyllysine; alternate (By
FT similarity).
FT MOD_RES 162 162 N6-succinyllysine; alternate (By
FT similarity).
FT MOD_RES 171 171 N6-acetyllysine (By similarity).
FT MOD_RES 172 172 ADP-ribosylcysteine.
FT MOD_RES 183 183 N6-acetyllysine (By similarity).
FT MOD_RES 187 187 N6-acetyllysine (By similarity).
FT MOD_RES 191 191 N6-acetyllysine (By similarity).
FT MOD_RES 211 211 N6-acetyllysine (By similarity).
FT MOD_RES 326 326 N6-acetyllysine (By similarity).
FT MOD_RES 346 346 N6-acetyllysine (By similarity).
FT MOD_RES 352 352 N6-acetyllysine (By similarity).
FT MOD_RES 363 363 N6-acetyllysine; alternate (By
FT similarity).
FT MOD_RES 363 363 N6-succinyllysine; alternate (By
FT similarity).
FT MOD_RES 365 365 N6-acetyllysine (By similarity).
FT MOD_RES 386 386 N6-acetyllysine (By similarity).
FT MOD_RES 390 390 N6-acetyllysine (By similarity).
FT MOD_RES 399 399 N6-acetyllysine (By similarity).
FT MOD_RES 415 415 N6-acetyllysine; alternate (By
FT similarity).
FT MOD_RES 415 415 N6-succinyllysine; alternate (By
FT similarity).
FT MOD_RES 457 457 N6-acetyllysine; alternate (By
FT similarity).
FT MOD_RES 457 457 N6-malonyllysine; alternate (By
FT similarity).
FT MOD_RES 457 457 N6-succinyllysine; alternate (By
FT similarity).
FT MOD_RES 477 477 N6-acetyllysine (By similarity).
FT MOD_RES 480 480 N6-acetyllysine.
FT MOD_RES 503 503 N6-acetyllysine; alternate.
FT MOD_RES 503 503 N6-malonyllysine; alternate (By
FT similarity).
FT MOD_RES 503 503 N6-succinyllysine; alternate (By
FT similarity).
FT MOD_RES 527 527 N6-acetyllysine; alternate (By
FT similarity).
FT MOD_RES 527 527 N6-malonyllysine; alternate (By
FT similarity).
FT MOD_RES 527 527 N6-succinyllysine; alternate (By
FT similarity).
FT MOD_RES 545 545 N6-acetyllysine; alternate (By
FT similarity).
FT MOD_RES 545 545 N6-succinyllysine; alternate (By
FT similarity).
FT MOD_RES 548 548 N6-acetyllysine (By similarity).
FT VARIANT 270 270 S -> C (in HHF6; diminished sensitivity
FT to GTP).
FT /FTId=VAR_016760.
FT VARIANT 274 274 R -> C (in HHF6; diminished sensitivity
FT to GTP; dbSNP:rs56275071).
FT /FTId=VAR_016761.
FT VARIANT 318 318 R -> K (in HHF6).
FT /FTId=VAR_009270.
FT VARIANT 318 318 R -> T (in HHF6; diminished sensitivity
FT to GTP).
FT /FTId=VAR_016762.
FT VARIANT 319 319 Y -> C (in HHF6).
FT /FTId=VAR_016763.
FT VARIANT 322 322 R -> C (in HHF6; diminished sensitivity
FT to GTP).
FT /FTId=VAR_016764.
FT VARIANT 322 322 R -> H (in HHF6; diminished sensitivity
FT to GTP).
FT /FTId=VAR_016765.
FT VARIANT 349 349 E -> A (in HHF6).
FT /FTId=VAR_009271.
FT VARIANT 498 498 S -> L (in HHF6).
FT /FTId=VAR_008666.
FT VARIANT 499 499 G -> D (in HHF6).
FT /FTId=VAR_008667.
FT VARIANT 499 499 G -> S (in HHF6).
FT /FTId=VAR_008668.
FT VARIANT 501 501 S -> P (in HHF6).
FT /FTId=VAR_008669.
FT VARIANT 507 507 H -> Y (in HHF6; abolishes inhibition by
FT ATP; no effect on activation by ADP).
FT /FTId=VAR_008670.
FT MUTAGEN 501 501 S->A: Reduces activity and inhibition by
FT GTP.
FT MUTAGEN 507 507 H->A: Strongly reduces inhibition by GTP.
FT MUTAGEN 516 516 R->A: Abolishes activation by ADP.
FT HELIX 66 90
FT HELIX 91 93
FT HELIX 95 97
FT HELIX 99 102
FT HELIX 104 109
FT STRAND 113 123
FT STRAND 125 127
FT STRAND 129 138
FT STRAND 142 152
FT HELIX 158 174
FT STRAND 180 186
FT HELIX 190 192
FT HELIX 195 211
FT TURN 217 219
FT STRAND 220 223
FT HELIX 230 242
FT TURN 243 247
FT HELIX 251 253
FT HELIX 260 262
FT HELIX 271 284
FT HELIX 287 293
FT STRAND 298 300
FT STRAND 303 307
FT HELIX 311 322
FT STRAND 326 331
FT HELIX 345 354
FT STRAND 355 358
FT TURN 371 373
FT STRAND 377 381
FT STRAND 383 386
FT TURN 390 392
FT HELIX 393 395
FT STRAND 399 402
FT STRAND 405 407
FT HELIX 411 419
FT STRAND 423 425
FT HELIX 427 430
FT HELIX 433 447
FT TURN 451 455
FT HELIX 456 475
FT TURN 476 479
FT STRAND 481 484
FT HELIX 491 498
FT HELIX 502 527
FT HELIX 534 551
SQ SEQUENCE 558 AA; 61398 MW; A7319A840F57FBB2 CRC64;
MYRYLGEALL LSRAGPAALG SASADSAALL GWARGQPAAA PQPGLALAAR RHYSEAVADR
EDDPNFFKMV EGFFDRGASI VEDKLVEDLR TRESEEQKRN RVRGILRIIK PCNHVLSLSF
PIRRDDGSWE VIEGYRAQHS QHRTPCKGGI RYSTDVSVDE VKALASLMTY KCAVVDVPFG
GAKAGVKINP KNYTDNELEK ITRRFTMELA KKGFIGPGID VPAPDMSTGE REMSWIADTY
ASTIGHYDIN AHACVTGKPI SQGGIHGRIS ATGRGVFHGI ENFINEASYM SILGMTPGFG
DKTFVVQGFG NVGLHSMRYL HRFGAKCIAV GESDGSIWNP DGIDPKELED FKLQHGSILG
FPKAKPYEGS ILEADCDILI PAASEKQLTK SNAPRVKAKI IAEGANGPTT PEADKIFLER
NIMVIPDLYL NAGGVTVSYF EWLKNLNHVS YGRLTFKYER DSNYHLLMSV QESLERKFGK
HGGTIPIVPT AEFQDRISGA SEKDIVHSGL AYTMERSARQ IMRTAMKYNL GLDLRTAAYV
NAIEKVFKVY NEAGVTFT
//

MIM 138130
*RECORD*
*FIELD* NO
138130
*FIELD* TI
*138130 GLUTAMATE DEHYDROGENASE 1; GLUD1
;;GLUD;;
GDH
*FIELD* TX

DESCRIPTION

L-glutamate dehydrogenase (EC 1.4.1.3) has a central role in nitrogen
read moremetabolism in plants and animals. Glutamate dehydrogenase is found in
all organisms and catalyzes the oxidative deamination of 1-glutamate to
2-oxoglutarate (Smith et al., 2001). Glutamate, the main substrate of
GLUD, is present in brain in concentrations higher than in other organs.
In nervous tissue, GLUD appears to function in both the synthesis and
the catabolism of glutamate and perhaps in ammonia detoxification
(Mavrothalassitis et al., 1988).

CLONING

Hanauer et al. (1985) detected a cDNA clone expressed in skeletal muscle
that they concluded is homologous with GLUD because of close
similarities of its deduced amino acid sequence to that of the bovine
protein. Mavrothalassitis et al. (1988) reported the characterization of
4 human liver cDNA clones encoding the entire sequence of GLUD.
Blot-hybridization analysis of genomic DNA suggested that the human
enzyme is encoded by a small multigene family. Multiple GLUD-related
transcripts were identified in human, monkey, and rabbit tissues.
Nakatani et al. (1988) reported the complete sequence of GLUD cDNA.

Son et al. (2013) reported that whereas most cells use GLUD1 to convert
glutamine-derived glutamate into alpha-ketoglutarate in the mitochondria
to fuel the tricarboxylic acid cycle, pancreatic ductal adenocarcinoma
(see 260350) cells rely on a distinct pathway in which glutamine-derived
aspartate is transported into the cytoplasm, where it can be converted
into oxaloacetate by aspartate transaminase (GOT1; 138180). Son et al.
(2013) found that knockdown of KRAS (190070) in PDAC cells resulted in a
marked increase in GLUD1 and a decrease in GOT1 expression at both the
transcriptional and the protein levels. Additionally, they showed that
expression on GOT1 increased and GLUD1 decreased in an oncogenic
KRAS-dependent manner in vivo. Son et al. (2013) concluded that their
findings demonstrated that the reprogramming of glutamine metabolism is
mediated by oncogenic KRAS, the signature genetic alteration in PDAC,
through the transcriptional upregulation and repression of key metabolic
enzymes in this pathway.

MAPPING

By in situ hybridization, Hanauer et al. (1985) mapped the GLUD1 gene to
10q23-q24.

By analysis of somatic cell hybrids and by in situ hybridization,
Anagnou et al. (1989) confirmed the assignment of GLUD1 to chromosome
10, but concluded that the precise localization is 10q21.1-q21.2. By in
situ hybridization, Jung et al. (1989) mapped the gene to 10q23, and
Deloukas et al. (1993) refined the localization to 10q23.3.

Using a RFLP in the study of recombinant inbred strains, Shaughnessy et
al. (1989) found that the murine Glud locus cosegregates with Rib1
(180440) and Tcra (see 186880), which are known to be on mouse
chromosome 14. By genomic Southern analysis of a panel of Chinese
hamster/mouse somatic cell hybrids, Tzimagiorgis et al. (1991) concluded
that there are 2 independent mouse GLUD loci, termed Glud and Glud2,
which map to chromosome 14 and 7, respectively. By homology, the Glud
locus on chromosome 14 is likely to be the functional one. On the other
hand, their evidence appeared to indicate that the Glud2 gene on mouse
chromosome 7 is not a processed pseudogene. Both chromosome 7 and 14 of
the mouse have regions of linkage homology to human 10q.

- Pseudogenes

Several GLUD pseudogenes have been identified. Hanauer et al. (1985) and
Anagnou et al. (1989) confirmed the presence of a pseudogene, GLUDP1, on
Xq26-28. Jung et al. (1989) mapped the GLUDP1 pseudogene to Xq24.
Michaelidis et al. (1993) identified 4 presumed truncated pseudogenes,
at least 2 of which may have been generated by retrotransposition.
Deloukas et al. (1993) concluded that there are 2 GLUD pseudogenes on
10q which are not linked to the functional gene: GLUDP2 at 10q11.2 and
GLUDP3 at 10q22.1. Tzimagiorgis et al. (1993) mapped another locus,
termed GLUDP5, to 10p11.2. They pointed out that the work of their group
(Michaelidis et al., 1993) raised the number of human GLUD loci to 6.

GENE STRUCTURE

Michaelidis et al. (1993) determined that the GLUD1 gene is about 45 kb
long and contains 13 exons.

BIOCHEMICAL FEATURES

Hanauer et al. (1985) suggested that the GLUD clones they detected may
be useful in study of the postulated relationship of partial glutamate
dehydrogenase deficiency and a form of olivopontocerebellar atrophy
(OPCA). Plaitakis et al. (1980, 1982, 1984) and Duvoisin et al. (1983)
found partial deficiency of GLUD in fibroblasts and leukocytes of some
patients with OPCA. Yamaguchi et al. (1982) and Sorbi et al. (1986)
found a similar deficiency in platelets of OPCA patients. Barbeau et al.
(1980) could find no abnormality of GLUD in 8 patients with a dominant
form of OPCA.

MOLECULAR GENETICS

In 2 infants with hyperinsulinemic hypoglycemia and hyperammonemia
(606762), Stanley et al. (1997) identified heterozygosity for activating
mutations in the GLUD1 gene (138130.0001 and 138130.0002).

In a study of 4 sporadic and 2 familial cases, Stanley et al. (1998)
identified 5 missense mutations that alter 1 of 4 amino acids between
residues 446 and 454 in exons 11 and 12 of the GLUD1 gene (see, e.g.,
138130.0003-138130.0005), a region that encodes the allosteric domain.
All of these mutations were associated with a diminished inhibitory
effect of guanosine triphosphate (GTP) on glutamate dehydrogenase
activity.

*FIELD* AV
.0001
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
GLUD1, HIS454TYR

In an infant with the syndrome of hypoglycemia due to congenital
hyperinsulinism combined with persistent unexplained hyperammonemia
(606762), Stanley et al. (1997) identified heterozygosity for a C-to-T
transition at nucleotide 1519 in the GLUD1 gene, predicted to cause a
his454-to-tyr (H454Y) substitution in the mature protein. The patient
was a sporadic case. Also see 138130.0002.

.0002
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
GLUD1, SER445LEU

In an infant with the syndrome of hypoglycemia due to congenital
hyperinsulinism combined with persistent unexplained hyperammonemia
(606762), Stanley et al. (1997) identified heterozygosity for a C-to-T
transition at nucleotide 1493 in the GLUD1 gene, predicted to cause a
ser445-to-leu (S448L) substitution in the mature GDH peptide. Both of
the mutations reported by Stanley et al. (1997) (see 138130.0001)
affected only 1 of the 2 GDH alleles and were not present in the
parents, indicating that the disorder is autosomal dominant.

In 3 unrelated Japanese infants with congenital
hyperinsulinism-hyperammonemia, Miki et al. (2000) identified
heterozygosity for the S445L mutation in the allosteric domain of the
GLUD1 gene.

.0003
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
GLUD1, SER448PRO

In affected members of 2 separate families with hyperinsulinemic
hypoglycemia and hyperammonemia (606762), one from Canada and the other
from Italy, Stanley et al. (1998) identified heterozygosity for a C-to-T
transition at nucleotide 1514, resulting in a ser448-to-pro (S448P)
substitution. In each family, a mother and child were affected. This
mutation results in less severe hypoglycemia than that seen in patients
with a sporadic mutation. Basal enzyme activity was 38% of normal.

In family 2 studied by Thornton et al. (1998), Glaser et al. (1998)
identified the S448P mutation in the GLUD1 gene.

.0004
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
GLUD1, GLY446SER

In 2 unrelated individuals with hyperinsulinism-hyperammonemia syndrome
(606762), Stanley et al. (1998) identified heterozygosity for a G-to-A
transition at nucleotide 1508 of the GLUD1 gene, resulting in a
gly446-to-ser (G446S) substitution at codon 446. This dominant mutation
causes severe hypoglycemia and a 2- to 5-fold increase in plasma
ammonium concentration due to decreased sensitivity to GTP-induced
inhibition, which was demonstrated in the patients' lymphoblasts.

.0005
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
GLUD1, GLY446ASP

In 2 unrelated individuals with the hyperinsulinism/hyperammonemia
syndrome (606762), Stanley et al. (1998) identified heterozygosity for a
G-to-A transition at nucleotide 1509 of the GLUD1 gene, resulting in a
gly446-to-asp (G446D) substitution. This dominant mutation results in
severe hypoglycemia and a 2- to 5-fold increase in plasma ammonium
concentration due to decreased sensitivity to GTP-induced inhibition,
which was demonstrated in the patients' lymphoblasts.

.0006
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
GLUD1, GLU296ALA

In a 6-month-old Japanese girl with hyperinsulinemic hypoglycemia and
hyperammonemia (606762), Miki et al. (2000) identified heterozygosity
for a 1059A-C transversion in exon 7 of the GLUD1 gene, resulting in a
glu296-to-ala (E296A) substitution within the catalytic domain.

.0007
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
GLUD1, ARG265LYS

In a 6-day-old Japanese boy with hyperinsulinemic hypoglycemia and
hyperammonemia (606762), Miki et al. (2000) identified heterozygosity
for a 966G-A transition in exon 7 of the GLUD1 gene, resulting in an
arg265-to-lys (R265K) substitution within the catalytic domain.

.0008
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
GLUD1, ARG221CYS

In 5 affected members of a 3-generation family with hyperinsulinemic
hypoglycemia and hyperammonemia (606762), Santer et al. (2001)
identified heterozygosity for an 833C-T transition in exon 6 of the
GLUD1 gene, resulting in an arg221-to-cys (R221C) substitution within
the catalytic domain.

.0009
HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6
GLUD1, ARG269HIS

In 9 affected members of 6 unrelated families with hyperinsulinemic
hypoglycemia and hyperammonemia (606762), Santer et al. (2001)
identified heterozygosity for a 978G-A transition in exon 7 of the GLUD1
gene, resulting in an arg269-to-his (R269H) substitution within the
catalytic domain.

*FIELD* SA
Colon et al. (1986); Hanauer et al. (1987); Nelson et al. (1977)
*FIELD* RF
1. Anagnou, N. P.; Seuanez, H.; Modi, W.; O'Brien, S. J.; Papmatheakis,
J.; Moschonas, N.: Chromosomal mapping of the human glutamate dehydrogenase
(GLUD) genes to chromosomes 10q21.1-21.2 and Xq26-28. (Abstract) Am.
J. Hum. Genet. 45 (suppl.): A170 only, 1989.

2. Barbeau, A.; Charbonneau, M.; Cloutier, T.: Leucocyte glutamate
dehydrogenase in various hereditary ataxias. Canad. J. Neurol. Sci. 7:
421-424, 1980.

3. Colon, A. D.; Plaitakis, A.; Perakis, A.; Berl, S.; Clarke, D.
D.: Purification and characterization of a soluble and a particulate
glutamate dehydrogenase from rat brain. J. Neurochem. 46: 1811-1819,
1986.

4. Deloukas, P.; Dauwerse, J. G.; Moschonas, N. K.; van Ommen, G.
J. B.; van Loon, A. P. G. M.: Three human glutamate dehydrogenase
genes (GLUD1, GLUDP2, and GLUDP3) are located on chromosome 10q, but
are not closely physically linked. Genomics 17: 676-681, 1993.

5. Duvoisin, R. C.; Chokroverty, S.; Lepore, F.; Nicklas, W. J.:
Glutamate dehydrogenase deficiency in patients with olivopontocerebellar
atrophy. Neurology 33: 1322-1326, 1983.

6. Glaser, B.; Thornton, P. S.; Herold, K.; Stanley, C. A.: Clinical
and molecular heterogeneity of familial hyperinsulinism. (Letter) J.
Pediat. 133: 801-802, 1998.

7. Hanauer, A.; Mandel, J. L.; Mattei, M. G.: X-linked and autosomal
sequences corresponding to glutamate dehydrogenase (GLUD) and to an
anonymous cDNA. (Abstract) Cytogenet. Cell Genet. 40: 647-648, 1985.

8. Hanauer, A.; Mattei, M. G.; Mandel, J. L.: Presence of a TaqI
polymorphism in the human glutamate dehydrogenase (GLUD) gene on chromosome
10. Nucleic Acids Res. 15: 6308 only, 1987.

9. Jung, K. Y.; Warter, S.; Rumpler, Y.: Assignment of the GDH loci
to human chromosomes 10q23 and Xq24 by in situ hybridization. Ann.
Genet. 32: 109-110, 1989.

10. Mavrothalassitis, G.; Tzimagiorgis, G.; Mitsialis, A.; Zannis,
V.; Plaitakis, A.; Papamatheakis, J.; Moschonas, N.: Isolation and
characterization of cDNA clones encoding human liver glutamate dehydrogenase:
evidence for a small gene family. Proc. Nat. Acad. Sci. 85: 3494-3498,
1988.

11. Michaelidis, T. M.; Tzimagiorgis, G.; Moschonas, N. K.; Papamatheakis,
J.: The human glutamate dehydrogenase gene family: gene organization
and structural characterization. Genomics 16: 150-160, 1993.

12. Miki, Y.; Taki, T.; Ohura, T.; Kato, H.; Yanagisawa, M.; Hayashi,
Y.: Novel missense mutations in the glutamate dehydrogenase gene
in the congenital hyperinsulinism-hyperammonemia syndrome. J. Pediat. 136:
69-72, 2000.

13. Nakatani, Y.; Schneider, M.; Banner, C.; Freese, E.: Complete
nucleotide sequence of human glutamate dehydrogenase cDNA. Nucleic
Acids Res. 16: 6237 only, 1988.

14. Nelson, R. L.; Povey, M. S.; Hopkinson, D. A.; Harris, H.: Electrophoresis
of human L-glutamate dehydrogenase: tissue distribution and preliminary
population survey. Biochem. Genet. 15: 87-91, 1977.

15. Plaitakis, A.; Berl, S.; Yahr, M. D.: Abnormal glutamate metabolism
in an adult-onset degenerative neurological disorder. Science 216:
193-196, 1982.

16. Plaitakis, A.; Berl, S.; Yahr, M. D.: Neurological disorders
associated with deficiency of glutamate dehydrogenase. Ann. Neurol. 15:
144-153, 1984.

17. Plaitakis, A.; Nicklas, W. J.; Desnick, R. J.: Glutamate dehydrogenase
deficiency in three patients with spinocerebellar syndrome. Ann.
Neurol. 7: 297-303, 1980.

18. Santer, R.; Kinner, M.; Passarge, M.; Superti-Furga, A.; Mayatepek,
E.; Meissner, T.; Schneppenheim, R.; Schaub, J.: Novel missense mutations
outside the allosteric domain of glutamate dehydrogenase are prevalent
in European patients with the congenital hyperinsulinism-hyperammonemia
syndrome. Hum. Genet. 108: 66-71, 2001.

19. Shaughnessy, J., Jr.; Mock, B.; Duncan, R.; Potter, M.; Banner,
C.: A restriction fragment length polymorphism at murine Glud locus
cosegregates with Rib-1, Es-10, and Tcra on chromosome 14. Nucleic
Acids Res. 17: 2881 only, 1989.

20. Smith, T. J.; Peterson, P. E.; Schmidt, T.; Fang, J.; Stanley,
C. A.: Structures of bovine glutamate dehydrogenase complexes elucidate
the mechanism of purine regulation. J. Molec. Biol. 307: 707-720,
2001.

21. Son, J.; Lyssiotis, C. A.; Ying, H.; Wang, X.; Hua, S.; Ligorio,
M.; Perera, R. M.; Ferrone, C. R.; Mullarky, E.; Shyh-Chang, N.; Kang,
Y.; Fleming, J. B.; Bardeesy, N.; Asara, J. M.; Haigis, M. C.; DePinho,
R. A.; Cantley, L. C.; Kimmelman, A. C.: Glutamine supports pancreatic
cancer growth through a KRAS-regulated metabolic pathway. Nature 496:
101-105, 2013. Note: Erratum: Nature 499: 504 only, 2013.

22. Sorbi, S.; Tonini, S.; Giannini, E.; Piacentini, S.; Marini, P.;
Amaducci, L.: Abnormal platelet glutamate dehydrogenase activity
and activation in dominant and nondominant olivopontocerebellar atrophy. Ann.
Neurol. 19: 239-245, 1986.

23. Stanley, C. A.; Lieu, Y.; Hsu, B.; Poncz, M.: Hypoglycemia in
infants with hyperinsulinism and hyperammonemia: gain of function
mutations in the pathway of leucine-mediated insulin secretion. (Abstract) Diabetes 46
(suppl. 1): 217A only, 1997.

24. Stanley, C. A.; Lieu, Y. K.; Hsu, B. Y. L.; Burlina, A. B.; Greenberg,
C. R.; Hopwood, N. J.; Perlman, K.; Rich, B. H.; Zammarchi, E.; Poncz,
M.: Hyperinsulinism and hyperammonemia in infants with regulatory
mutations of the glutamate dehydrogenase gene. New Eng. J. Med. 338:
1352-1357, 1998.

25. Thornton, P. S.; Satin-Smith, M. S.; Herold, K.; Glaser, B.; Chiu,
K. C.; Nestorowicz, A.; Permutt, M. A.; Baker, L.; Stanley, C. A.
: Familial hyperinsulinism with apparent autosomal dominant inheritance:
clinical and genetic differences from the autosomal recessive variant. J.
Pediat. 132: 9-14, 1998.

26. Tzimagiorgis, G.; Adamson, M. C.; Kozak, C. A.; Moschonas, N.
K.: Chromosomal mapping of glutamate dehydrogenase gene sequences
to mouse chromosomes 7 and 14. Genomics 10: 83-88, 1991.

27. Tzimagiorgis, G.; Leversha, M. A.; Chroniary, K.; Goulielmos,
G.; Sargent, C. A.; Ferguson-Smith, M.; Moschonas, N. K.: Structure
and expression analysis of a member of the human glutamate dehydrogenase
(GLUD) gene family mapped to chromosome 10p11.2. Hum. Genet. 91:
433-438, 1993.

28. Yamaguchi, T.; Hayashi, K.; Murakami, H.; Ota, K.; Maruyama, S.
: Glutamate dehydrogenase deficiency in spinocerebellar degeneration. Neurochem.
Res. 7: 627-636, 1982.

*FIELD* CN
Ada Hamosh - updated: 5/30/2013
Marla J. F. O'Neill - updated: 3/20/2006
Cassandra L. Kniffin - reorganized: 3/21/2002
John A. Phillips, III - updated: 2/20/2002
John A. Phillips, III - updated: 10/4/2001
Ada Hamosh - updated: 4/26/2001
Victor A. McKusick - updated: 1/31/2001
Victor A. McKusick - updated: 4/11/2000
Ada Hamosh - updated: 6/17/1998
Victor A. McKusick - updated: 6/10/1998
Victor A. McKusick - updated: 4/15/1998
Victor A. McKusick - edited: 2/21/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
mgross: 10/04/2013
alopez: 10/1/2013
alopez: 5/30/2013
terry: 9/8/2010
wwang: 4/20/2009
carol: 3/30/2006
carol: 3/28/2006
terry: 3/27/2006
carol: 3/20/2006
carol: 3/25/2002
carol: 3/21/2002
ckniffin: 3/20/2002
alopez: 2/20/2002
cwells: 10/9/2001
cwells: 10/4/2001
alopez: 5/8/2001
terry: 4/26/2001
mcapotos: 2/6/2001
mcapotos: 2/2/2001
terry: 1/31/2001
mcapotos: 5/2/2000
mcapotos: 4/27/2000
terry: 4/11/2000
carol: 6/4/1999
dholmes: 7/9/1998
carol: 6/18/1998
terry: 6/17/1998
carol: 6/10/1998
carol: 4/20/1998
terry: 4/15/1998
mark: 2/21/1997
terry: 7/18/1994
davew: 6/28/1994
mimadm: 4/14/1994
carol: 11/12/1993
carol: 9/21/1993
carol: 8/18/1993

MIM 606762
*RECORD*
*FIELD* NO
606762
*FIELD* TI
#606762 HYPERINSULINEMIC HYPOGLYCEMIA, FAMILIAL, 6; HHF6
;;HYPERINSULINISM-HYPERAMMONEMIA SYNDROME
read more*FIELD* TX
A number sign (#) is used with this entry because familial
hyperinsulinemic hypoglycemia-6 is caused by heterozygous mutation in
the glutamate dehydrogenase (GDH) gene (GLUD1; 138130) on chromosome
10q23.3.

For a phenotypic description and a discussion of genetic heterogeneity
of familial hyperinsulinemic hypoglycemia, see HHF1 (256450).

CLINICAL FEATURES

A distinct syndrome of hyperinsulinism and hyperammonemia in 3 unrelated
children was described by Zammarchi et al. (1996) and Weinzimer et al.
(1997). In addition, Zammarchi et al. (1996) suggested that the defect
involved leucine hypersensitivity. Hsu et al. (2001) studied 8 children
and 6 adults with hypoglycemia due to congenital hyperinsulinism
combined with persistent unexplained hyperammonemia. In each of these
cases, known metabolic disorders were ruled out. All had dominantly
expressed mutations of glutamine dehydrogenase and plasma concentrations
of ammonium that were 2 to 5 times normal. The median age at onset of
hypoglycemia in the 14 patients was 9 months; diagnosis was delayed
beyond age 2 years in 6 patients, and 4 were not given a diagnosis until
adulthood. Fasting tests revealed unequivocal evidence of
hyperinsulinism in only 1 of 7 patients. Three did not develop
hypoglycemia until 12 to 24 hours of fasting; however, all 7
demonstrated inappropriate glycemic responses to glucagon that were
characteristic of hyperinsulinism. In response to oral protein, all 12
patients with hyperinsulinism/hyperammonemia showed a fall in blood
glucose compared with none of 5 control subjects. Insulin responses to
protein loading were similar in the patients with
hyperinsulinism/hyperammonemia and control subjects. Hsu et al. (2001)
concluded that the postprandial blood glucose response to a protein meal
is more sensitive than prolonged fasting for detecting hypoglycemia in
the hyperinsulinism/hyperammonemia syndrome.

Kelly et al. (2001) postulated that children with
hyperinsulinism/hyperammonemia syndrome would have exaggerated acute
insulin responses to leucine in the postabsorptive state. As
hyperglycemia increases beta-cell guanosine triphosphate (GTP), they
also postulated that high glucose concentrations would extinguish
abnormal responsiveness to leucine in hyperinsulinism/hyperammonemia
syndrome patients. After an overnight fast, 7 patients had acute insulin
response to leucine administered intravenously. Four patients then had
acute insulin responses to leucine repeated at hyperglycemia. High blood
glucose suppressed their abnormal baseline acute insulin responses to
leucine. The authors concluded that protein-induced hypoglycemia in
hyperinsulinism/hyperammonemia syndrome patients may be prevented by
carbohydrate loading before protein consumption.

De Lonlay et al. (2001) studied 12 unrelated patients with
hyperinsulinism and hyperammonemia and observed clinically heterogeneous
phenotypes, with neonatal- and infancy-onset hypoglycemia and variable
responsiveness to medical (diazoxide) and dietary (leucine-restricted
diet) treatment. Hyperammonemia was constant and not influenced by oral
protein, by protein- and leucine-restricted diet, or by sodium benzoate
or N-carbamylglutamate administration. Mean basal GDH activity in
cultured lymphocytes did not differ between patients and controls, but
the sensitivity of GDH activity to inhibition by GTP was reduced in all
patient lymphoblast cultures. The activating effect of leucine on GDH
activity varied among the patients; 4 patients had a significant
decrease of sensitivity that correlated with a negative clinical
response to dietary leucine.

Ihara et al. (2005) reported a Japanese girl who presented in infancy
with delayed growth and hyperammonemia. Liver biopsy showed decreased
activity of carbamoyl phosphate synthetase-1 (CPS1; 608307), and she was
given a diagnosis of CPS1 deficiency (237300) based on enzymatic
studies. Her blood glucose was relatively low on retrospective analysis.
Treatment with protein restriction, sodium benzoate, and arginine failed
to reduce the ammonia throughout childhood. At age 15 years, she showed
borderline intelligence, and biochemical studies showed low serum
glucose and inappropriately high insulin. The correct diagnosis of
hyperinsulinism-hyperammonemia syndrome due to a de novo heterozygous
GLUD1 mutation was confirmed by genetic analysis (S445L; 138130.0002).
Ihara et al. (2005) could not explain the secondary CPS1 enzymatic
deficiency in this patient, but suggested that the urea cycle may not
have been functioning sufficiently in this patient.

PATHOGENESIS

Stanley et al. (1997) postulated that the hyperinsulinism-hyperammonemia
syndrome is due to excessive oxidation of glutamate by glutamate
dehydrogenase, since depletion of hepatic glutamate would reduce
synthesis of N-acetylglutamate needed to stimulate ureagenesis.
Moreover, leucine-mediated insulin release involves allosteric
activation of GLUD. Mutations of GLUD1 cause the
hyperinsulinism/hyperammonemia syndrome by desensitizing glutamate
dehydrogenase to allosteric inhibition by GTP. Normal allosteric
activation of GLUD1 by leucine is thus uninhibited.

Based on enzymatic studies on lymphoblasts, MacMullen et al. (2001)
concluded that allosteric regulation of GDH as a control site for amino
acid-stimulated insulin secretion is important and that the GTP-binding
site is essential for regulation of GDH activity by both GTP and ATP.

MOLECULAR GENETICS

Stanley et al. (1997) studied GLUD activity and cDNA using cultured
lymphoblasts from 2 infants with hyperinsulinism and hyperammonemia and
their parents. In these patients, heterozygous mutations were found in
the GLUD1 gene (138130.0001, 138130.0002). The C-terminal region
affected by the mutations was known to confer responsiveness to
allosteric regulators of GLUD activity. These unusual mutations resulted
in a gain rather than a loss of enzyme function. In their report of 4
sporadic and 2 familial cases, Stanley et al. (1998) found 5 missense
mutations clustered within a range of 10 codons in exons 11 and 12 of
the GLUD1 gene, which predicted an effect on the presumed allosteric
domain of the enzyme (see, e.g., 138130.0003-138130.0005). All of these
mutations were associated with a diminished inhibitory effect of GTP on
glutamate dehydrogenase activity.

In family 2 with hyperinsulinemic hypoglycemia studied by Thornton et
al. (1998), Glaser et al. (1998) identified the S448P mutation in the
GLUD1 gene.

Miki et al. (2000) performed mutation analysis of 5 unrelated Japanese
patients (3 girls and 2 boys) with hyperinsulinism-hyperammonemia
syndrome. All had convulsions or loss of consciousness resulting from
hypoglycemia before the age of 1 year and asymptomatic, minimally
elevated plasma ammonia levels. Heterozygous missense mutations were
found in all. Three patients had a previously identified mutation,
ser445 to leu (138130.0002), located in the allosteric domain. Two
others were heterozygous for missense mutations within the catalytic
domain of the gene (138130.0006 and 138130.0007). The site of the
mutations was not correlated with the severity of hypoglycemia.

Santer et al. (2001) investigated 14 patients from 7 European families
with mild hyperinsulinism. In 1 of the families, a novel heterozygous
missense mutation in exon 6 (R221C; 138130.0008) was detected, and in
all other cases from 6 unrelated families, the novel heterozygous
missense mutation R269H (138130.0009) was found in exon 7. When
glutamate dehydrogenase activity was measured in lymphocytes isolated
from affected patients, both mutations were shown to result in a normal
basal activity but a diminished sensitivity to GTP. The observation of
the high prevalence of the exon 7 mutation both in familial and in
sporadic cases of hyperinsulinism-hyperammonemia syndrome suggested a
mutation hotspot and justified mutation screening for this mutation by
mismatch PCR-based restriction enzyme digestion in patients with
hyperinsulinism. In the 7 families with hyperinsulinism-hyperammonemia
syndrome studied by Santer et al. (2001), 4 had more than 1 affected
member. In 8 of 14 cases, hyperammonemia was documented, and 8 cases had
signs of significant leucine sensitivity.

In 65 hyperinsulinism/hyperammonemia probands screened for GDH
mutations, MacMullen et al. (2001) identified 19 (29%) who had mutations
in a domain encoded by exons 6 and 7. Six new mutations were found. In
all 5 mutations tested, lymphoblast GDH showed reduced sensitivity to
allosteric inhibition by GTP, consistent with a gain of enzyme function.
Studies of ATP allosteric effects on GDH showed a triphasic response
with a decrease in high affinity inhibition of enzyme activity in
hyperinsulinism/hyperammonemia lymphoblasts. All of the residues altered
by exons 6 and 7 hyperinsulinism/hyperammonemia mutations lie in the
GTP-binding domain of the enzyme.

De Lonlay et al. (2001) analyzed the GLUD1 gene in 11 unrelated patients
with hyperinsulinism/hyperammonemia and identified 6 different
heterozygous missense mutations in 10 patients. Three mutations were
located within and 3 outside the GTP-binding site, without any
correlation between phenotype and genotype.

*FIELD* RF
1. de Lonlay, P.; Benelli, C.; Fouque, F.; Ganguly, A.; Aral, B.;
Dionisi-Vici, C.; Touati, G.; Heinrichs, C.; Rabier, D.; Kamoun, P.;
Robert, J.-J.; Stanley, C.; Saudubray, J.-M.: Hyperinsulinism and
hyperammonemia syndrome: report of twelve unrelated patients. Pediat.
Res. 50: 353-357, 2001.

2. Glaser, B.; Thornton, P. S.; Herold, K.; Stanley, C. A.: Clinical
and molecular heterogeneity of familial hyperinsulinism. (Letter) J.
Pediat. 133: 801-802, 1998.

3. Hsu, B. Y. L.; Kelly, A.; Thornton, P. S.; Greenberg, C. R.; Dilling,
L. A.; Stanley, C. A.: Protein-sensitive and fasting hypoglycemia
in children with the hyperinsulinism/hyperammonemia syndrome. J.
Pediat. 138: 383-389, 2001.

4. Ihara, K.; Miyako, K.; Ishimura, M.; Kuromaru, R.; Wang, H.-Y.;
Yasuda, K.; Hara, T.: A case of hyperinsulinism/hyperammonaemia syndrome
with reduced carbamoyl-phosphate synthetase-1 activity in liver: a
pitfall in enzymatic diagnosis for hyperammonaemia. J. Inherit. Metab.
Dis. 28: 681-687, 2005.

5. Kelly, A.; Ng, D.; Ferry, R. J., Jr.; Grimberg, A.; Koo-McCoy,
S.; Thornton, P. S.; Stanley, C. A.: Acute insulin responses to leucine
in children with the hyperinsulinism/hyperammonemia syndrome. J.
Clin. Endocr. Metab. 86: 3724-3728, 2001.

6. MacMullen, C.; Fang, J.; Hsu, B. Y. L.; Kelly, A.; de Lonlay-Debeney,
P.; Saudubray, J.-M.; Ganguly, A.; Smith, T. J.; Stanley, C. A.; The
Hyperinsulinism/Hyperammonemia Contributing Investigators: Hyperinsulinism/hyperammonemia
syndrome in children with regulatory mutations in the inhibitory guanosine
triphosphate-binding domain of glutamate dehydrogenase. J. Clin.
Endocr. Metab. 86: 1782-1787, 2001.

7. Miki, Y.; Taki, T.; Ohura, T.; Kato, H.; Yanagisawa, M.; Hayashi,
Y.: Novel missense mutations in the glutamate dehydrogenase gene
in the congenital hyperinsulinism-hyperammonemia syndrome. J. Pediat. 136:
69-72, 2000.

8. Santer, R.; Kinner, M.; Passarge, M.; Superti-Furga, A.; Mayatepek,
E.; Meissner, T.; Schneppenheim, R.; Schaub, J.: Novel missense mutations
outside the allosteric domain of glutamate dehydrogenase are prevalent
in European patients with the congenital hyperinsulinism-hyperammonemia
syndrome. Hum. Genet. 108: 66-71, 2001.

9. Stanley, C. A.; Lieu, Y.; Hsu, B.; Poncz, M.: Hypoglycemia in
infants with hyperinsulinism & hyperammonemia: gain of function mutations
in the pathway of leucine-mediated insulin secretion. (Abstract) Diabetes 46
(suppl. 1): 217A only, 1997.

10. Stanley, C. A.; Lieu, Y. K.; Hsu, B. Y. L.; Burlina, A. B.; Greenberg,
C. R.; Hopwood, N. J.; Perlman, K.; Rich, B. H.; Zammarchi, E.; Poncz,
M.: Hyperinsulinism and hyperammonemia in infants with regulatory
mutations of the glutamate dehydrogenase gene. New Eng. J. Med. 338:
1352-1357, 1998.

11. Thornton, P. S.; Satin-Smith, M. S.; Herold, K.; Glaser, B.; Chiu,
K. C.; Nestorowicz, A.; Permutt, M. A.; Baker, L.; Stanley, C. A.
: Familial hyperinsulinism with apparent autosomal dominant inheritance:
clinical and genetic differences from the autosomal recessive variant. J.
Pediat. 132: 9-14, 1998.

12. Weinzimer, S. A.; Stanley, C. A.; Berry, G. T.; Yudkoff, M.; Tuchman,
M.; Thornton, P. S.: A syndrome of congenital hyperinsulinism and
hyperammonemia. J. Pediat. 130: 661-664, 1997.

13. Zammarchi, E.; Filippi, L.; Novembre, E.; Donati, M. A.: Biochemical
evaluation of a patient with a familial form of leucine-sensitive
hypoglycemia and concomitant hyperammonemia. Metabolism 45: 957-960,
1996.

*FIELD* CS
INHERITANCE:
Autosomal dominant

NEUROLOGIC:
[Central nervous system];
Seizures, hypoglycemic;
Loss of consciousness due to hypoglycemia;
Mental retardation due to repeated episodes of hypoglycemia

ENDOCRINE FEATURES:
Hyperinsulinemic hypoglycemia

LABORATORY ABNORMALITIES:
Hypoglycemia;
Hyperinsulinemia;
Hyperammonemia, asymptomatic (2-5 times normal)

MISCELLANEOUS:
Genetic heterogeneity (see HHF1 256450);
Mean age at onset of hypoglycemia may be delayed (median, 9 months,
diagnosis sometimes made in adulthood)

MOLECULAR BASIS:
Caused by mutations in the glutamate dehydrogenase gene (GLUD1, 138130.0001)

*FIELD* CN
Marla J. F. O'Neill - updated: 04/24/2006

*FIELD* CD
Cassandra L. Kniffin: 5/7/2002

*FIELD* ED
joanna: 04/24/2006
ckniffin: 5/7/2002

*FIELD* CN
Marla J. F. O'Neill - updated: 5/6/2008
Marla J. F. O'Neill - updated: 3/20/2006

*FIELD* CD
Cassandra L. Kniffin: 3/15/2002

*FIELD* ED
wwang: 05/06/2010
ckniffin: 5/4/2010
carol: 5/8/2008
terry: 5/6/2008
carol: 3/30/2006
carol: 3/28/2006
terry: 3/27/2006
carol: 3/20/2006
carol: 3/21/2002
ckniffin: 3/20/2002