RBCC Red Blood Cell Collection

GLUL (GLNS) [Confidence: low (only semi-automatic identification from reviews)]
Glutamine synthetase; GS; 6.3.1.2 (Glutamate decarboxylase; 4.1.1.15; Glutamate--ammonia ligase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P15104
ID GLNA_HUMAN Reviewed; 373 AA.
AC P15104; Q499Y9; Q5T9Z1; Q7Z3W4; Q8IZ17;
DT 01-APR-1990, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 4.
DT 22-JAN-2014, entry version 154.
DE RecName: Full=Glutamine synthetase;
DE Short=GS;
DE EC=6.3.1.2;
DE AltName: Full=Glutamate decarboxylase;
DE EC=4.1.1.15;
DE AltName: Full=Glutamate--ammonia ligase;
GN Name=GLUL; Synonyms=GLNS;
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=Liver;
RX PubMed=2888076; DOI=10.1093/nar/15.15.6293;
RA Gibbs C.S., Campbell K.E., Wilson R.H.;
RT "Sequence of a human glutamine synthetase cDNA.";
RL Nucleic Acids Res. 15:6293-6293(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=1681907; DOI=10.1016/0167-4781(91)90111-X;
RA van den Hoff M.J.B., Geerts W.J.C., Das A.T., Moorman A.F.M.,
RA Lamers W.H.;
RT "cDNA sequence of the long mRNA for human glutamine synthase.";
RL Biochim. Biophys. Acta 1090:249-251(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Liver;
RX PubMed=7909780;
RA Christa L., Simon M.T., Flinois J.P., Gebhardt R., Brechot C.,
RA Lasserre C.;
RT "Overexpression of glutamine synthetase in human primary liver
RT cancer.";
RL Gastroenterology 106:1312-1320(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RA Haberle J., Koch H.G.;
RL Submitted (NOV-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Retina;
RX PubMed=17974005; DOI=10.1186/1471-2164-8-399;
RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U.,
RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H.,
RA Heubner D., Hoerlein A., Michel G., Wedler H., Koehrer K.,
RA Ottenwaelder B., Poustka A., Wiemann S., Schupp I.;
RT "The full-ORF clone resource of the German cDNA consortium.";
RL BMC Genomics 8:399-399(2007).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D.,
RA Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A.,
RA Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F.,
RA McDonald L., Evans R., Phillips K., Atkinson A., Cooper R., Jones C.,
RA Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P.,
RA Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K.,
RA Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G.,
RA Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D.,
RA Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G.,
RA Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J.,
RA Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R.,
RA Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D.,
RA Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G.,
RA Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M.,
RA Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J.,
RA Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M.,
RA Loveland J., Lovell J., Lush M.J., Lyne R., Martin S.,
RA Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S.,
RA Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C.,
RA Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z.,
RA Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E.,
RA Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A.,
RA Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R.,
RA Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V.,
RA Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain, Colon, Eye, Muscle, and Testis;
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 MASS SPECTROMETRY, AND SUBUNIT.
RC TISSUE=Brain;
RX PubMed=12387715; DOI=10.1023/A:1020574003027;
RA Boksha I.S., Schonfeld H.J., Langen H., Muller F., Tereshkina E.B.,
RA Burbaeva G.S.H.;
RT "Glutamine synthetase isolated from human brain: octameric structure
RT and homology of partial primary structure with human liver glutamine
RT synthetase.";
RL Biochemistry (Mosc.) 67:1012-1020(2002).
RN [9]
RP FUNCTION, AND DEVELOPMENTAL STAGE.
RX PubMed=18662667; DOI=10.1016/j.abb.2008.07.009;
RA Vermeulen T., Goerg B., Vogl T., Wolf M., Varga G., Toutain A.,
RA Paul R., Schliess F., Haeussinger D., Haeberle J.;
RT "Glutamine synthetase is essential for proliferation of fetal skin
RT fibroblasts.";
RL Arch. Biochem. Biophys. 478:96-102(2008).
RN [10]
RP INDUCTION.
RX PubMed=18555765; DOI=10.1016/j.bone.2008.04.016;
RA Olkku A., Mahonen A.;
RT "Wnt and steroid pathways control glutamate signalling by regulating
RT glutamine synthetase activity in osteoblastic cells.";
RL Bone 43:483-493(2008).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT THR-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 [12]
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 [13]
RP VARIANTS CSGD CYS-324 AND CYS-341, AND CHARACTERIZATION OF VARIANTS
RP CSGD CYS-324 AND CYS-341.
RX PubMed=16267323; DOI=10.1056/NEJMoa050456;
RA Haeberle J., Goerg B., Rutsch F., Schmidt E., Toutain A.,
RA Benoist J.-F., Gelot A., Suc A.-L., Hoehne W., Schliess F.,
RA Haeussinger D., Koch H.G.;
RT "Congenital glutamine deficiency with glutamine synthetase
RT mutations.";
RL N. Engl. J. Med. 353:1926-1933(2005).
CC -!- FUNCTION: This enzyme has 2 functions: it catalyzes the production
CC of glutamine and 4-aminobutanoate (gamma-aminobutyric acid, GABA),
CC the latter in a pyridoxal phosphate-independent manner (By
CC similarity). Essential for proliferation of fetal skin
CC fibroblasts.
CC -!- CATALYTIC ACTIVITY: ATP + L-glutamate + NH(3) = ADP + phosphate +
CC L-glutamine.
CC -!- CATALYTIC ACTIVITY: L-glutamate = 4-aminobutanoate + CO(2).
CC -!- COFACTOR: Biotin (By similarity).
CC -!- COFACTOR: Magnesium or manganese (By similarity).
CC -!- SUBUNIT: Homooctamer and homotetramer. Interacts with PALMD (By
CC similarity).
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-746653, EBI-746653;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Mitochondrion (By similarity).
CC -!- DEVELOPMENTAL STAGE: Expressed during early fetal stages.
CC -!- INDUCTION: By glucocorticoids. Vitamin D and the Wnt signaling
CC pathway inhibit its expression and activity.
CC -!- PTM: Ubiquitinated by ZNRF1 (By similarity).
CC -!- DISEASE: Congenital systemic glutamine deficiency (CSGD)
CC [MIM:610015]: Rare developmental disorder with severe brain
CC malformation resulting in multi-organ failure and neonatal death.
CC Glutamine is largely absent from affected patients serum, urine
CC and cerebrospinal fluid. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the glutamine synthetase family.
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Glutamine synthetase entry;
CC URL="http://en.wikipedia.org/wiki/Glutamine_synthetase";
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DR EMBL; Y00387; CAA68457.1; -; mRNA.
DR EMBL; X59834; CAA42495.1; -; mRNA.
DR EMBL; S70290; AAB30693.1; -; mRNA.
DR EMBL; AY486122; AAS57904.1; -; mRNA.
DR EMBL; AY486123; AAS57905.1; -; Genomic_DNA.
DR EMBL; BX537384; CAD97626.1; -; mRNA.
DR EMBL; AL139344; CAI19842.1; -; Genomic_DNA.
DR EMBL; BC010037; AAH10037.1; -; mRNA.
DR EMBL; BC011700; AAH11700.1; -; mRNA.
DR EMBL; BC011852; AAH11852.1; -; mRNA.
DR EMBL; BC018992; AAH18992.1; -; mRNA.
DR EMBL; BC031964; AAH31964.1; -; mRNA.
DR EMBL; BC051726; AAH51726.1; -; mRNA.
DR PIR; S18455; AJHUQ.
DR RefSeq; NP_001028216.1; NM_001033044.2.
DR RefSeq; NP_001028228.1; NM_001033056.2.
DR RefSeq; NP_002056.2; NM_002065.5.
DR UniGene; Hs.518525; -.
DR PDB; 2OJW; X-ray; 2.05 A; A/B/C/D/E=5-364.
DR PDB; 2QC8; X-ray; 2.60 A; A/B/C/D/E/F/G/H/I/J=5-365.
DR PDBsum; 2OJW; -.
DR PDBsum; 2QC8; -.
DR ProteinModelPortal; P15104; -.
DR SMR; P15104; 10-365.
DR DIP; DIP-308N; -.
DR IntAct; P15104; 18.
DR MINT; MINT-1183856; -.
DR STRING; 9606.ENSP00000307900; -.
DR BindingDB; P15104; -.
DR ChEMBL; CHEMBL4612; -.
DR DrugBank; DB00023; Asparaginase.
DR DrugBank; DB00142; L-Glutamic Acid.
DR DrugBank; DB00130; L-Glutamine.
DR DrugBank; DB00134; L-Methionine.
DR PhosphoSite; P15104; -.
DR DMDM; 1169929; -.
DR REPRODUCTION-2DPAGE; IPI00010130; -.
DR UCD-2DPAGE; P15104; -.
DR PaxDb; P15104; -.
DR PeptideAtlas; P15104; -.
DR PRIDE; P15104; -.
DR DNASU; 2752; -.
DR Ensembl; ENST00000311223; ENSP00000307900; ENSG00000135821.
DR Ensembl; ENST00000331872; ENSP00000356537; ENSG00000135821.
DR Ensembl; ENST00000339526; ENSP00000344958; ENSG00000135821.
DR Ensembl; ENST00000417584; ENSP00000398320; ENSG00000135821.
DR GeneID; 2752; -.
DR KEGG; hsa:2752; -.
DR UCSC; uc001gpa.2; human.
DR CTD; 2752; -.
DR GeneCards; GC01M182350; -.
DR HGNC; HGNC:4341; GLUL.
DR HPA; CAB008636; -.
DR HPA; HPA007316; -.
DR HPA; HPA007571; -.
DR MIM; 138290; gene.
DR MIM; 610015; phenotype.
DR neXtProt; NX_P15104; -.
DR Orphanet; 71278; Congenital brain dysgenesis due to glutamine synthetase deficiency.
DR PharmGKB; PA28743; -.
DR eggNOG; COG0174; -.
DR HOGENOM; HOG000061500; -.
DR HOVERGEN; HBG005847; -.
DR InParanoid; P15104; -.
DR KO; K01915; -.
DR OMA; YGIDIEF; -.
DR OrthoDB; EOG7CZK5G; -.
DR BioCyc; MetaCyc:HS06066-MONOMER; -.
DR Reactome; REACT_111217; Metabolism.
DR Reactome; REACT_13685; Neuronal System.
DR SABIO-RK; P15104; -.
DR ChiTaRS; GLUL; human.
DR EvolutionaryTrace; P15104; -.
DR GenomeRNAi; 2752; -.
DR NextBio; 10840; -.
DR PRO; PR:P15104; -.
DR ArrayExpress; P15104; -.
DR Bgee; P15104; -.
DR CleanEx; HS_GLUL; -.
DR Genevestigator; P15104; -.
DR GO; GO:0043679; C:axon terminus; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0043204; C:perikaryon; IEA:Ensembl.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0005791; C:rough endoplasmic reticulum; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0016595; F:glutamate binding; IEA:Ensembl.
DR GO; GO:0004351; F:glutamate decarboxylase activity; IEA:UniProtKB-EC.
DR GO; GO:0004356; F:glutamate-ammonia ligase activity; EXP:Reactome.
DR GO; GO:0000287; F:magnesium ion binding; IEA:Ensembl.
DR GO; GO:0030145; F:manganese ion binding; IEA:Ensembl.
DR GO; GO:0008283; P:cell proliferation; IDA:UniProtKB.
DR GO; GO:0034641; P:cellular nitrogen compound metabolic process; TAS:Reactome.
DR GO; GO:0006538; P:glutamate catabolic process; TAS:BHF-UCL.
DR GO; GO:0006542; P:glutamine biosynthetic process; TAS:BHF-UCL.
DR GO; GO:0001504; P:neurotransmitter uptake; TAS:Reactome.
DR GO; GO:0050679; P:positive regulation of epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0032024; P:positive regulation of insulin secretion; IEA:Ensembl.
DR GO; GO:0051968; P:positive regulation of synaptic transmission, glutamatergic; IEA:Ensembl.
DR GO; GO:0051260; P:protein homooligomerization; IEA:Ensembl.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Ensembl.
DR Gene3D; 3.30.590.10; -; 1.
DR InterPro; IPR008147; Gln_synt_beta.
DR InterPro; IPR014746; Gln_synth/guanido_kin_cat_dom.
DR InterPro; IPR008146; Gln_synth_cat_dom.
DR InterPro; IPR027303; Gln_synth_gly_rich_site.
DR InterPro; IPR027302; Gln_synth_N_conserv_site.
DR Pfam; PF00120; Gln-synt_C; 1.
DR Pfam; PF03951; Gln-synt_N; 1.
DR SUPFAM; SSF54368; SSF54368; 1.
DR PROSITE; PS00180; GLNA_1; 1.
DR PROSITE; PS00181; GLNA_ATP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; ATP-binding; Complete proteome; Cytoplasm;
KW Disease mutation; Ligase; Lyase; Mitochondrion; Nucleotide-binding;
KW Phosphoprotein; Reference proteome; Ubl conjugation.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 373 Glutamine synthetase.
FT /FTId=PRO_0000153139.
FT MOD_RES 2 2 N-acetylthreonine.
FT MOD_RES 104 104 Phosphotyrosine (By similarity).
FT VARIANT 324 324 R -> C (in CSGD; reduced glutamine
FT synthetase activity).
FT /FTId=VAR_026560.
FT VARIANT 341 341 R -> C (in CSGD; suggests reduced
FT glutamine synthetase activity).
FT /FTId=VAR_026561.
FT CONFLICT 7 7 S -> Y (in Ref. 7; AAH31964).
FT CONFLICT 154 154 F -> L (in Ref. 5; CAD97626).
FT CONFLICT 155 155 P -> T (in Ref. 7; AAH31964).
FT CONFLICT 314 314 A -> G (in Ref. 1; CAA68457).
FT CONFLICT 322 323 SI -> RL (in Ref. 2; CAA42495).
FT CONFLICT 347 347 D -> E (in Ref. 2; CAA42495).
FT HELIX 5 8
FT HELIX 11 18
FT STRAND 26 33
FT STRAND 40 49
FT HELIX 54 56
FT STRAND 60 63
FT TURN 64 68
FT STRAND 69 71
FT HELIX 72 74
FT STRAND 76 86
FT TURN 88 90
FT STRAND 95 102
FT STRAND 106 108
FT HELIX 114 123
FT HELIX 124 127
FT STRAND 130 140
FT STRAND 144 146
FT STRAND 158 160
FT TURN 167 169
FT HELIX 173 186
FT STRAND 190 195
FT STRAND 201 210
FT HELIX 213 232
FT STRAND 235 237
FT STRAND 245 247
FT STRAND 251 257
FT HELIX 259 262
FT TURN 264 266
FT HELIX 267 278
FT HELIX 281 287
FT TURN 290 295
FT HELIX 296 298
FT STRAND 314 316
FT STRAND 321 325
FT HELIX 327 332
FT STRAND 337 339
FT HELIX 348 359
SQ SEQUENCE 373 AA; 42064 MW; 45390C100924FAF3 CRC64;
MTTSASSHLN KGIKQVYMSL PQGEKVQAMY IWIDGTGEGL RCKTRTLDSE PKCVEELPEW
NFDGSSTLQS EGSNSDMYLV PAAMFRDPFR KDPNKLVLCE VFKYNRRPAE TNLRHTCKRI
MDMVSNQHPW FGMEQEYTLM GTDGHPFGWP SNGFPGPQGP YYCGVGADRA YGRDIVEAHY
RACLYAGVKI AGTNAEVMPA QWEFQIGPCE GISMGDHLWV ARFILHRVCE DFGVIATFDP
KPIPGNWNGA GCHTNFSTKA MREENGLKYI EEAIEKLSKR HQYHIRAYDP KGGLDNARRL
TGFHETSNIN DFSAGVANRS ASIRIPRTVG QEKKGYFEDR RPSANCDPFS VTEALIRTCL
LNETGDEPFQ YKN
//

MIM 138290
*RECORD*
*FIELD* NO
138290
*FIELD* TI
*138290 GLUTAMATE-AMMONIA LIGASE; GLUL
;;GLUTAMINE SYNTHETASE; GLNS
GLUTAMATE-AMMONIA LIGASE-LIKE 1, INCLUDED; GLULL1, INCLUDED;;
read moreGLUTAMATE-AMMONIA LIGASE-LIKE 2, INCLUDED; GLULL2, INCLUDED;;
GLUTAMATE-AMMONIA LIGASE-LIKE 3, INCLUDED; GLULL3, INCLUDED
*FIELD* TX

DESCRIPTION

Glutamine is a main source of energy and is involved in cell
proliferation, inhibition of apoptosis, and cell signaling (Haberle et
al., 2005). Fetal glutamine requirements are very high and depend
largely on active glutamine synthesis and the release of glutamine into
the fetal circulation by the placenta. Glutamine synthetase (EC
6.3.1.2), also called glutamate-ammonia ligase (GLUL), is expressed
throughout the body and plays an important role in controlling body pH
and in removing ammonia from the circulation. The enzyme clears
L-glutamate, the major neurotransmitter in the central nervous system,
from neuronal synapses (see references in Clancy et al., 1996).

CLONING

Gibbs et al. (1987) reported the complete 1,119-bp coding sequence of
glutamine synthetase, which they determined from a liver-derived cDNA.

Haberle et al. (2005) found that the glutamine synthetase mRNA consists
of 1,122 basepairs encoding a 374-amino acid protein with an estimated
molecular mass of 42 kD.

GENE STRUCTURE

Haberle et al. (2005) determined that the GLUL gene consists of 6 exons.

GENE FUNCTION

Pesole et al. (1991) suggested that glutamine synthetase is a good
molecular clock for determining times of divergence even as great as
that which occurred between eukaryotes and prokaryotes. One conclusion
reached by Pesole et al. (1991) was that organelle-specific enzymes,
such as those of the mitochondria, may have originated from a
duplication of nuclear genes. The endosymbiotic hypothesis suggests that
a transfer of prokaryotic genes to nuclei occurred during the evolution
of the primitive eukaryotic cell. In some cases, it is likely that the
old prokaryotic gene could not be active in the new nuclear genome
environment and was totally lost because its function in the organelle
could be dispensed with. Subsequently, a new organelle-specific enzyme
could have originated to serve specialized metabolic functions. The
presence of glutamine synthetase in mitochondria is linked to the
nitrogen metabolism of the species, and in particular to the need for
glutamine as a source of ammonia and for particular biochemical pathways
for ammonia detoxification.

Gunnersen and Haley (1992) found that the 42-kD ATP-binding protein
present in the cerebrospinal fluid of Alzheimer disease (AD) patients is
glutamine synthetase. It was detected in 38 of 39 AD CSF samples and in
only 1 of 44 control samples. In brain, glutamine synthetase plays a key
role in elimination of free ammonia and also converts the
neurotransmitter and excitotoxic amino acid glutamate to glutamine,
which is not neurotoxic.

MAPPING

Clancy et al. (1996) localized the GLUL gene to chromosome 1 by PCR
analysis of a human/rodent somatic cell hybrid panel. They also
localized a pseudogene to chromosome 9. Further localization of the
functional gene to 1q23 was accomplished by fluorescence in situ
hybridization. The glutamine synthetase gene was mapped to 5 CEPH
mega-YACs between the polymorphic PCR markers D1S117 and D1S466 by
analysis of the Whitehead Institute chromosome 1 contig map. By
fluorescence in situ hybridization, Helou et al. (1997) placed the GLUL
gene at 1q31.

Wang et al. (1996) screened a bacterial artificial chromosome (BAC)
library with a GLUL probe and isolated 18 clones. Southern blotting of
human genomic DNA revealed that all bands could be accounted for by 5
loci, suggesting that humans have a family of 5 glutamine synthetase
genes. Wang et al. (1996) used fluorescence in situ hybridization to map
the GLUL gene to chromosome 1q25 and mapped a GLUL processed pseudogene
(GLULP) to chromosome 9p13. Three related genes were also named and
mapped: GLULL1 to 5q33, GLULL2 to 11p15, and GLULL3 to 11q24. Because of
the small size of the 3 related genes, Wang et al. (1996) thought they
may be intronless pseudogenes.

MOLECULAR GENETICS

Haberle et al. (2005) described 2 unrelated newborns with congenital
glutamine synthetase deficiency (610015) with severe brain malformations
resulting in multiorgan failure and neonatal death. Glutamine was
largely absent from their serum, urine, and cerebrospinal fluid. Each
infant had a homozygous mutation in the glutamine synthetase gene, R324C
(138290.0001) and R341C (138290.0002). Studies that used immortalized
lymphocytes expressing R324C glutamine synthetase and COS-7 cells
expressing R341C glutamine synthetase suggested that these mutations are
associated with reduced glutamine synthetase activity.

Kolker et al. (2006) suggested that the chronic depletion of neuronal
glutamate stores described by Haberle et al. (2005) is a result of the
defective glutamine-glutamate cycle. Haberle et al. (2006) responded
that because the low glutamate concentrations in cerebrospinal fluid
were established with the use of chromatography, which is not
sufficiently sensitive to define glutamate concentrations accurately in
the very low range, it was not possible to include a deficiency of
glutamate in cerebrospinal fluid as one of the features of glutamine
synthetase deficiency.

Rose and Jalan (2006) suggested the possibility that inhibition of
glutamine synthetase in the brain may have lead to increased levels of
ammonia and extracellular glutamate in the brain, partly explaining the
clinical observations of Haberle et al. (2005). Haberle et al. (2006)
noted that during the course of the disease, plasma ammonia levels were
normal, and therefore hyperammonemia could not be regarded as a sign of
glutamine synthetase deficiency. Hyperammonemia would also not explain
the severe malformation of the brain and extracerebral manifestations.

In a Sudanese boy with congenital glutamine deficiency, Haberle et al.
(2011) identified a homozygous mutation in the GLUL gene (R324S;
138290.0003). The patient was alive at age 3 years but had severe
epileptic encephalopathy and severe psychomotor retardation.

*FIELD* AV
.0001
GLUTAMINE DEFICIENCY, CONGENITAL
GLUL, ARG324CYS

In an infant with congenital glutamine deficiency (610015), the
offspring of consanguineous Turkish parents, Haberle et al. (2005) found
a homozygous C-to-T transition at nucleotide 970 of the GLUL gene that
resulted in an arg324-to-cys (R324C) substitution in glutamine
synthetase. The patient was resuscitated at birth and found to be
neurologically compromised, with marked flaccidity and cardiac
insufficiency. He died at 2 days of age. On postmortem examination the
brain weighed only 202 g (335 g expected for gestational age), but no
visceral malformations were evident. Another mutation in this codon
(R324S; 138290.0003) was found in a Sudanese patient with the disorder.

.0002
GLUTAMINE DEFICIENCY, CONGENITAL
GLUL, ARG341CYS

In an infant with congenital glutamine deficiency (610015), the daughter
of consanguineous Turkish parents, Haberle et al. (2005) found
homozygosity for a C-to-T transition at nucleotide 1021 of the GLUL gene
that caused an arg341-to-cys (R341C) mutation in glutamine synthetase.
On the first day of life, convulsions and respiratory failure required
intubation and ventilation. During the first weeks of life, the infant
had voluminous yellowish stools and progressive weight loss, despite
enteral feeding. After 2 weeks, a generalized blistering erythematous
rash developed that on histologic examination supported a diagnosis of
epidermal necrolysis. Brain MRI showed markedly attenuated gyri and
subependymal cysts. She died during the fourth week of life from
multiorgan failure. The only material available from the patient
postmortem was her DNA, since her skin fibroblasts failed to grow.

.0003
GLUTAMINE DEFICIENCY, CONGENITAL
GLUL, ARG324SER

In a Sudanese boy, born of consanguineous parents, with congenital
glutamine deficiency (610015), Haberle et al. (2011) identified a
homozygous mutation in the GLUL gene, resulting in an arg324-to-ser
(R324S) substitution in a conserved residue in the active ATP-binding
site. The mutation resulted in upregulation of GLUL protein expression
in patient fibroblasts, but increased expression could not compensate
for the functional deficits of the mutant enzyme. Another mutation in
this codon (R324C; 138290.0001) was found in a Turkish patient with the
disorder. The patient reported by Haberle et al. (2011) was alive at age
3 years but had severe epileptic encephalopathy and severe psychomotor
retardation.

*FIELD* RF
1. Clancy, K. P.; Berger, R.; Cox, M.; Bleskan, J.; Walton, K. A.;
Hart, I.; Patterson, D.: Localization of the L-glutamine synthetase
gene to chromosome 1q23. Genomics 38: 418-420, 1996.

2. Gibbs, C. S.; Campbell, K. E.; Wilson, R. H.: Sequence of a human
glutamine synthetase cDNA. Nucleic Acids Res. 15: 6293 only, 1987.

3. Gunnersen, D.; Haley, B.: Detection of glutamine synthetase in
the cerebrospinal fluid of Alzheimer diseased patients: a potential
diagnostic biochemical marker. Proc. Nat. Acad. Sci. 89: 11949-11953,
1992.

4. Haberle, J.; Gorg, B.; Rutsch, F.; Schmidt, E.; Toutain, A.; Benoist,
J.-F.; Gelot, A.; Suc, A.-L.; Hohne, W.; Schliess, F.; Haussinger,
D.; Koch, H. G.: Congenital glutamine deficiency with glutamine synthetase
mutations. New Eng. J. Med. 353: 1926-1933, 2005.

5. Haberle, J.; Schliess, F.; Haussinger, D.: Reply to Kolker et
al., Rose and Jalan. (Letter) New Eng. J. Med. 354: 1094 only, 2006.

6. Haberle, J.; Shahbeck, N.; Ibrahim, K.; Hoffmann, G. F.; Ben-Omran,
T.: Natural course of glutamine synthetase deficiency in a 3 year
old patient. Molec. Genet. Metab. 103: 89-91, 2011.

7. Helou, K.; Das, A. T.; Lamers, W. H.; Hoovers, J. M. N.; Szpirer,
C.; Szpirer, J.; Klinga-Levan, K.; Levan, G.: FISH mapping of three
ammonia metabolism genes (Glul, Cps1, Glud1) in rat, and the chromosomal
localization of GLUL in human and Cps1 in mouse. Mammalian Genome 8:
362-364, 1997.

8. Kolker, S.; Hoffmann, G. F.; Okun, J. G.: Comment on congenital
glutamine deficiency with glutamine synthetase mutations. New Eng.
J. Med. 354: 1094 only, 2006.

9. Pesole, G.; Bozzetti, M. P.; Lanave, C.; Preparata, G.; Saccone,
C.: Glutamine synthetase gene evolution: a good molecular clock. Proc.
Nat. Acad. Sci. 88: 522-526, 1991.

10. Rose, C.; Jalan, R.: Comment on congenital glutamine deficiency
with glutamine synthetase mutations. New Eng. J. Med. 354: 1093
only, 2006.

11. Wang, Y.; Kudoh, J.; Kubota, R.; Asakawa, S.; Minoshima, S.; Shimizu,
N.: Chromosomal mapping of a family of human glutamine synthetase
genes: functional gene (GLUL) on 1q25, pseudogene (GLULP) on 9p13,
and three related genes (GLULL1, GLULL2, GLULL3) on 5q33, 11p15, and
11q24. Genomics 37: 195-199, 1996.

*FIELD* CN
Cassandra L. Kniffin - updated: 5/19/2011
Anne M. Stumpf - updated: 3/29/2006
Anne M. Stumpf - updated: 3/28/2006
Victor A. McKusick - updated: 3/23/2006
Jennifer P. Macke - updated: 8/28/1997
Victor A. McKusick - updated: 6/26/1997
Victor A. McKusick - updated: 2/4/1997

*FIELD* CD
Victor A. McKusick: 4/25/1988

*FIELD* ED
carol: 12/16/2013
wwang: 6/7/2011
ckniffin: 5/19/2011
carol: 5/25/2010
alopez: 3/29/2006
alopez: 3/28/2006
terry: 3/23/2006
carol: 12/3/2003
carol: 12/1/2000
carol: 12/16/1998
dholmes: 11/19/1997
dholmes: 9/4/1997
dholmes: 8/28/1997
terry: 6/26/1997
mark: 2/5/1997
jenny: 2/4/1997
terry: 1/21/1997
carol: 1/28/1993
carol: 1/12/1993
supermim: 3/16/1992
carol: 4/1/1991
supermim: 3/28/1991
carol: 11/22/1989

MIM 610015
*RECORD*
*FIELD* NO
610015
*FIELD* TI
#610015 GLUTAMINE DEFICIENCY, CONGENITAL
;;GLUTAMINE SYNTHASE DEFICIENCY, CONGENITAL SYSTEMIC
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
disorder is caused by homozygous mutation in the gene encoding glutamine
synthetase (GLUL; 138290) on chromosome 1q31.

DESCRIPTION

Congenital glutamine deficiency is a severe autosomal recessive disorder
characterized by onset at birth of encephalopathy, lack of normal
development, seizures, and hypotonia associated with variable brain
abnormalities. Three patients have been reported (summary by Haberle et
al., 2011).

CLINICAL FEATURES

Haberle et al. (2005) described 2 presumably unrelated newborns of
consanguineous Turkish ancestry who had congenital glutamine synthetase
deficiency with severe brain malformations resulting in multiorgan
failure and neonatal death. Glutamine was largely absent from their
serum, urine, and cerebrospinal fluid. The first infant died on day 2.
He had shortness of limbs, flexion contractures of elbows and knees,
camptodactyly, ulnar deviation in hands, flat nasal root, short nose,
anteverted nares, thin lips, and low-set ears. The second patient died
in week 4. She showed generalized muscular hypotonia, enteropathy with
voluminous diarrhea, necrolytic migratory erythema of the skin, and also
had broad nasal root and low-set ears.

Haberle et al. (2011) reported a child, born of consanguineous Sudanese
parents, with congenital glutamine deficiency. At birth, he showed
generalized hypotonia, lower limb hyperreflexia, and soon developed
seizures. He had severe developmental delay, apnea, recurrent
respiratory infections, and episodes of bradycardia. He developed a
transient severe epidermolytic rash. Laboratory studies showed
hyperammonemia and decreased glutamine in serum and CSF. Brain MRI
showed hypomyelination, thinning of the corpus callosum, and mild brain
atrophy with prominent cortical sulci. He was alive, but severely
handicapped, at age 3 years.

MOLECULAR GENETICS

Haberle et al. (2005) detected homozygous mutations in the GLUL gene
(138290) in each of 2 Turkish patients with a systemic glutamine
deficiency. One patient carried an arg324-to-cys substitution (R324C;
138290.0001), and the other an arg341-to-cys substitution (R341C;
138290.0002). Neither mutation was found in 160 control alleles,
including 60 alleles from Turkish persons. Parental heterozygosity
suggested an autosomal recessive mode of inheritance and confirmed
segregation of mutations in both families. Both mutations were found in
heterozygosity in the parents.

In a Sudanese boy with congenital glutamine deficiency, Haberle et al.
(2011) identified a homozygous mutation in the GLUL gene (R324S;
138290.0003).

*FIELD* RF
1. Haberle, J.; Gorg, B.; Rutsch, F.; Schmidt, E.; Toutain, A.; Benoist,
J.-F.; Gelot, A.; Suc, A.-L.; Hohne, W.; Schliess, F.; Haussinger,
D.; Koch, H. G.: Congenital glutamine deficiency with glutamine synthetase
mutations. New Eng. J. Med. 353: 1926-1933, 2005.

2. Haberle, J.; Shahbeck, N.; Ibrahim, K.; Hoffmann, G. F.; Ben-Omran,
T.: Natural course of glutamine synthetase deficiency in a 3 year
old patient. Molec. Genet. Metab. 103: 89-91, 2011.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Ears];
Low-set ears;
[Nose];
Flat, broad nasal root

CARDIOVASCULAR:
[Heart];
Bradycardia

RESPIRATORY:
Respiratory insufficiency;
Apnea

SKELETAL:
Contractures (1 patient);
[Limbs];
Micromelia (1 patient)

SKIN, NAILS, HAIR:
[Skin];
Blistering erythematous rash;
HISTOLOGY:;
Necrotic epidermolysis

NEUROLOGIC:
[Central nervous system];
Encephalopathy;
Hypotonia;
Seizures;
Delayed development, severe;
Hyperreflexia;
Brain atrophy;
Thin corpus callosum;
Abnormal gyri;
Attenuated gyri;
Periventricular cysts;
Subependymal cysts;
Ventriculomegaly;
Small, smooth cerebellum;
Hypomyelination

LABORATORY ABNORMALITIES:
Decreased glutamine in bodily fluids;
Hyperammonemia

MISCELLANEOUS:
Three patients have been reported;
Onset as neonate;
Death in infancy in 2 patients;
Variable severity of brain malformations

MOLECULAR BASIS:
Caused by mutation in the glutamate-ammonia ligase gene (GLUL, 138290.0001)

*FIELD* CD
Cassandra L. Kniffin: 5/19/2011

*FIELD* ED
joanna: 05/19/2011
ckniffin: 5/19/2011

*FIELD* CN
Cassandra L. Kniffin - updated: 5/19/2011

*FIELD* CD
Victor A. McKusick: 3/28/2006

*FIELD* ED
wwang: 06/07/2011
ckniffin: 5/19/2011
mgross: 3/28/2006
alopez: 3/28/2006