GLUD1

Summary

GLUD1 (glutamate dehydrogenase 1, HGNC:4335) is a protein-coding gene on chromosome 10q23.2, encoding Glutamate dehydrogenase 1, mitochondrial (P00367). Mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate into alpha-ketoglutarate.

This gene encodes glutamate dehydrogenase, which is a mitochondrial matrix enzyme that catalyzes the oxidative deamination of glutamate to alpha-ketoglutarate and ammonia. This enzyme has an important role in regulating amino acid-induced insulin secretion. It is allosterically activated by ADP and inhibited by GTP and ATP. Activating mutations in this gene are a common cause of congenital hyperinsulinism. Alternative splicing of this gene results in multiple transcript variants. The related glutamate dehydrogenase 2 gene on the human X-chromosome originated from this gene via retrotransposition and encodes a soluble form of glutamate dehydrogenase. Related pseudogenes have been identified on chromosomes 10, 18 and X.

Source: NCBI Gene 2746 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyperinsulinism-hyperammonemia syndrome (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 298 total — 9 pathogenic, 3 likely-pathogenic
• MANE Select transcript: NM_005271

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4335
Approved symbol	GLUD1
Name	glutamate dehydrogenase 1
Location	10q23.2
Locus type	gene with protein product
Status	Approved
Aliases	GDH, GDH1, hGDH1
Ensembl gene	ENSG00000148672
Ensembl biotype	protein_coding
OMIM	138130
Entrez	2746

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 26 protein_coding, 9 retained_intron, 6 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000277865, ENST00000465164, ENST00000474574, ENST00000487058, ENST00000681987, ENST00000681988, ENST00000682396, ENST00000682507, ENST00000682622, ENST00000682833, ENST00000683022, ENST00000683256, ENST00000683269, ENST00000683647, ENST00000683649, ENST00000683783, ENST00000683813, ENST00000684032, ENST00000684201, ENST00000684338, ENST00000684372, ENST00000684392, ENST00000684434, ENST00000684546, ENST00000684665, ENST00000684690, ENST00000684699, ENST00000898382, ENST00000898383, ENST00000898384, ENST00000898385, ENST00000898386, ENST00000898387, ENST00000898388, ENST00000898389, ENST00000898390, ENST00000898391, ENST00000898392, ENST00000915199, ENST00000915200, ENST00000915201, ENST00000944406, ENST00000944407

RefSeq mRNA: 7 — MANE Select: NM_005271 NM_001318900, NM_001318901, NM_001318902, NM_001318904, NM_001318905, NM_001318906, NM_005271

CCDS: CCDS7382, CCDS91291

Canonical transcript exons

ENST00000277865 — 13 exons

Exon	Start	End
ENSE00000986495	87094325	87094843
ENSE00000986499	87068063	87068157
ENSE00001700347	87060161	87060241
ENSE00001717914	87053342	87053404
ENSE00001777902	87050202	87051870
ENSE00001791971	87057691	87057782
ENSE00002201813	87060688	87060825
ENSE00002470150	87075968	87076023
ENSE00002498877	87074551	87074614
ENSE00003508787	87062656	87062835
ENSE00003598982	87059150	87059273
ENSE00003628334	87076576	87076656
ENSE00003654192	87060915	87061052

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.2935 / max 1411.1280, expressed in 1811 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110427	18.0235	1804
110426	2.6187	978
110429	2.5000	1501
110428	2.1513	1347

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.09	gold quality
nucleus accumbens	UBERON:0001882	99.09	gold quality
superior vestibular nucleus	UBERON:0007227	99.09	gold quality
amygdala	UBERON:0001876	99.07	gold quality
caudate nucleus	UBERON:0001873	99.06	gold quality
liver	UBERON:0002107	98.99	gold quality
corpus callosum	UBERON:0002336	98.95	gold quality
medulla oblongata	UBERON:0001896	98.92	gold quality
lateral globus pallidus	UBERON:0002476	98.92	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	98.91	gold quality
substantia nigra pars compacta	UBERON:0001965	98.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.84	gold quality
subthalamic nucleus	UBERON:0001906	98.78	gold quality
putamen	UBERON:0001874	98.77	gold quality
pons	UBERON:0000988	98.69	gold quality
hypothalamus	UBERON:0001898	98.69	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.59	gold quality
CA1 field of hippocampus	UBERON:0003881	98.52	gold quality
inferior olivary complex	UBERON:0002127	98.47	gold quality
globus pallidus	UBERON:0001875	98.45	gold quality
midbrain	UBERON:0001891	98.43	gold quality
substantia nigra	UBERON:0002038	98.42	gold quality
medial globus pallidus	UBERON:0002477	98.36	gold quality
cingulate cortex	UBERON:0003027	98.35	gold quality
anterior cingulate cortex	UBERON:0009835	98.35	gold quality
right frontal lobe	UBERON:0002810	98.32	gold quality
renal medulla	UBERON:0000362	98.28	gold quality
ventral tegmental area	UBERON:0002691	98.27	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.19	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	98.19	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	13.24
E-ANND-3	yes	11.80
E-MTAB-3929	no	370.02

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RARB, TBP

miRNA regulators (miRDB)

110 targeting GLUD1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4715-3P	99.98	66.03	670
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-8062	99.88	68.43	995
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-4495	99.82	72.08	3080

Literature-anchored findings (GeneRIF, showing 40)

• Two missense mutations give rise to two different forms of congenital hyperinsulinism/hyperammonemia. (PMID:11840195)
• increased glutamate dehydrogenase activity confers on beta-cells the ability to secrete insulin in response to glutamine (PMID:11872671)
• Expression, purification and characterization of human glutamate dehydrogenase (GDH) allosteric regulatory mutations (PMID:11903050)
• identify the structural basis for allosteric differences of GlUD1 and GLUD2 (PMID:11950837)
• Tyr187 is responsible for the efficient base binding of ADP to human GDH. (PMID:12022886)
• site-directed mutagenesis showing involvement of Glu(279)in NAD+ binding (PMID:12193607)
• substitution of Ser for Arg-443 (but not substitution of Thr for Ser-331, Leu for Met-370, or Leu for Met-415) virtually abolished basal activity and totally abrogated the activation of the enzyme by l-leucine (1-10 mm) in the absence of other effectors (PMID:12324473)
• These results suggest that the Ser443 residue plays an important role in the different thermal stability of human glutamate dehydrogenase isozymes (hGDH1 and hGDH2). (PMID:15044002)
• inhibition of glutamate dehydrogenase results in sulfite neurotoxicity (PMID:15273247)
• GLUD2 originated by retroposition from GLUD1 in the hominoid ancestor less than 23 million years ago. (PMID:15378063)
• results suggest that cysteine 323 plays an important role in catalysis by human GDH isozymes; C323 is not directly involved in allosteric regulation. (PMID:15750346)
• GLUD1 may have a role in hyperinsulinism/hyperammonaemia syndrome (PMID:16151898)
• Results describe the electrophysiological mechanisms underlying the dysregulated insulin secretion in pancreatic beta cells with glutamate dehydrogenase mutations. (PMID:16492972)
• we describe a family with a dominantly inherited mutation in GDH in Myoclonic absence epilepsy with photosensitivity. (PMID:18321734)
• GLUD1 parental protein localizes to mitochondria and the cytoplasm, GLUD2 is specifically targeted to mitochondria. (PMID:18688271)
• Although GDH activity is also highly expressed in the brain, central nervous system (CNS) manifestations of GLUD1 activating mutations have remained relatively unexplored. (PMID:19046183)
• Neurological disorders in HHS are more frequent than previously thought and might suggest that mutations in the GTP binding site of GDH could be associated with more frequent epilepsy. (PMID:19046187)
• Hence, while most of the hGDHs translocate into the mitochondria (a process associated with cleavage of the signal sequence), part of the protein localizes to the endoplasmic reticulum, probably serving additional functions (PMID:19448744)
• down-regulation of GDH in response to decreased fetal liver output and reduced umbilical artery glutamate concentrations may occur in human fetal growth restriction pregnancies (PMID:19500843)
• Heterozygous missense mutations were detected in 15 patients with HI/HA, 2 of which are novel (N410D and D451V). (PMID:19690084)
• High glutamate dehydrogenase is associated with glioblastoma. (PMID:19826036)
• Transgenic mice overexpressing glutamate dehydrogenase 1 exhibited decreases in long-term potentiation of synaptic activity and spine density in hippocampal neurons. (PMID:19890003)
• Gradual decrease in leukocyte GLDH activity may be a key factor for neurodegenerative aging processes. (PMID:20197649)
• This protein has been found differentially expressed in the anterior cingulate cortex in women patients with schizophrenia. (PMID:20381070)
• In Chinese, R269H, S445L mutation of the GLUD1 leads to congenital hyperinsulinism. (PMID:20931523)
• [review] Hyperinsulinemic hypoglycemia and hyperammonemia demonstrate the important role of GDH in insulin regulation and illustrate unexpectedly important reasons for the unusually complex allosteric regulation of GDH. (PMID:21130127)
• Transgenic mice are useful in defining the molecular pathways affected by the over-activation of GLUD transgene in glutamatergic neurons of the brain and spinal cord. (PMID:21397652)
• Human GDH1 appears to act like bovine GDH1, but human GDH2 does not show the same enhancement of branched chain alpha-keto acid dehydrogenase complex enzyme activities. (PMID:21621574)
• Green tea polyphenols control dysregulated glutamate dehydrogenase in transgenic mice by hijacking the ADP activation site. (PMID:21813650)
• GDH interactions with aristolochic acid induce apoptosis of renal tubular epithelial cells. (PMID:21901531)
• Report glutamate dehydrogenase mutations in Japanese patients with congenital hyperinsulinism and hyperammonemia syndrome. (PMID:22106762)
• A protein encoded by this locus was found to be differentially expressed in postmortem brains from patients with atypical frontotemporal lobar degeneration. (PMID:22360420)
• first N-terminal alpha helical structure is crucial for the mitochondrial import of hGDH2 and these findings may have implications in understanding the evolutionary mechanisms that led to the large mitochondrial targeting signals of human GDHs (PMID:22658952)
• Lack of Glud1 in transgenic mouse brain inhibits GDH activity regardless of enzymatic direction, modified glutamate handling, decreased glutamate catabolism and increased glutamine levels without affecting synaptic transmission. (PMID:22924626)
• HER2- type breast cancer had the highest expression of stromal GLS1, tumoral GDH, stromal GDH, and tumoral ASCT, while TNBC had the lowest tumoral GDH expression. (PMID:23507704)
• The data suggest a dual mechanism by which glutamate dehydrogenase activity modulates autophagy, i.e., by activating MTORC1 and by limiting the formation of reactive oxygen species. (PMID:23575388)
• stromal expression of the glutamine-metabolism-related proteins GLS1, GDH, ASCT2 increases with worsening histological phyllodes tumor grade. (PMID:23636801)
• The GDH1 is a key metabolic enzyme with emerging roles in insulin regulation. MitoNEET forms a covalent complex with GDH1 through disulfide bond formation and acts as an activator. (PMID:24295216)
• SIRT3 and glutamate dehydrogenase are altered in follicular cells of women with reduced ovarian reserve or advanced maternal age (PMID:24771001)
• side-chain interactions between 409 and 443 positions in the ‘antenna’ region of GDH are crucial for basal catalytic activity, allosteric regulation, and relative resistance to thermal inactivation (PMID:25620628)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	glud1a	ENSDARG00000008816
mus_musculus	Glud1	ENSMUSG00000021794
rattus_norvegicus	Glud1	ENSRNOG00000057367
drosophila_melanogaster	Gdh	FBGN0001098
drosophila_melanogaster	bb8	FBGN0039071
caenorhabditis_elegans		WBGENE00014095

Paralogs (1): GLUD2 (ENSG00000182890)

Protein

Protein identifiers

Glutamate dehydrogenase 1, mitochondrial — P00367 (reviewed: P00367)

All UniProt accessions (10): P00367, A0A804HHS2, A0A804HHU3, A0A804HIA0, A0A804HJD7, A0A804HJH3, A0A804HJZ0, A0A804HKE0, A0A804HLC0, E9KL48

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial glutamate dehydrogenase that catalyzes the conversion of L-glutamate into alpha-ketoglutarate. Plays a key role in glutamine anaplerosis by producing alpha-ketoglutarate, an important intermediate in the tricarboxylic acid cycle. Plays a role in insulin homeostasis. May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate.

Subunit / interactions. Homohexamer. Interacts with HADH; this interaction inhibits the activation of GLUD1.

Subcellular location. Mitochondrion. Endoplasmic reticulum.

Post-translational modifications. ADP-ribosylated by SIRT4, leading to inactivate glutamate dehydrogenase activity. Stoichiometry shows that ADP-ribosylation occurs in one subunit per catalytically active homohexamer.

Disease relevance. Hyperinsulinemic hypoglycemia, familial, 6 (HHF6) [MIM:606762] A form of hyperinsulinemic hypoglycemia, a clinically and genetically heterogeneous disorder characterized by inappropriate insulin secretion from the pancreatic beta-cells in the presence of low blood glucose levels. HHF6 is an autosomal dominant form characterized by hypoglycemia due to congenital hyperinsulinism combined with persistent hyperammonemia. Clinical features include loss of consciousness due to hypoglycemia, hypoglycemic seizures, and mental retardation. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Subject to allosteric regulation. Activated by ADP. Inhibited by GTP and ATP. ADP can occupy the NADH binding site and activate the enzyme. Inhibited by SIRT4. Inhibited by HADH.

Similarity. Belongs to the Glu/Leu/Phe/Val dehydrogenases family.

Isoforms (3)

UniProt ID	Names	Canonical?
P00367-1	1	yes
P00367-2	2
P00367-3	3

RefSeq proteins (7): NP_001305829, NP_001305830, NP_001305831, NP_001305833, NP_001305834, NP_001305835, NP_005262* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006095	Glu/Leu/Phe/Val/Trp_DH	Family
IPR006096	Glu/Leu/Phe/Val/Trp_DH_C	Domain
IPR006097	Glu/Leu/Phe/Val/Trp_DH_dimer	Domain
IPR033524	Glu/Leu/Phe/Val_DH_AS	Active_site
IPR033922	NAD_bind_Glu_DH	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR046346	Aminoacid_DH-like_N_sf	Homologous_superfamily

Pfam: PF00208, PF02812

Enzyme classification (BRENDA):

• EC 1.4.1.3 — glutamate dehydrogenase [NAD(P)+] (BRENDA: 48 organisms, 64 substrates, 129 inhibitors, 445 Km, 127 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.0051–14	116
NADH	0.0002–0.98	88
L-GLUTAMATE	0.24–52	53
NAD+	0.014–10.01	43
NH3	0.38–100	36
NH4+	0.0424–160	35
NADPH	0.006–0.78	31
NADP+	0.004–0.637	15
GLUTAMATE	0.25–23.8	14
ALPHA-KETOGLUTARATE	0.0029	1
N6-(2-AMINOETHYL)-NAD+	0.291	1
N6-(2-AMINOETHYL)-NADP+	0.273	1
N6-(2-HYDROXY-3-TRIMETHYLAMMONIUMPROPYL)-NAD+	0.148	1
N6-(3-SULFONATOPROPYL)-NAD+	0.052	1
NORVALINE	49	1

Catalyzed reactions (Rhea), 2 shown:

• L-glutamate + NADP(+) + H2O = 2-oxoglutarate + NH4(+) + NADPH + H(+) (RHEA:11612)
• L-glutamate + NAD(+) + H2O = 2-oxoglutarate + NH4(+) + NADH + H(+) (RHEA:15133)

UniProt features (135 total): modified residue 55, helix 22, strand 17, binding site 13, sequence variant 13, turn 7, splice variant 3, mutagenesis site 2, transit peptide 1, chain 1, active site 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
8SK8	ELECTRON MICROSCOPY	2.31
8KGY	ELECTRON MICROSCOPY	2.59
1L1F	X-RAY DIFFRACTION	2.7
6DQG	X-RAY DIFFRACTION	2.7
8W4J	ELECTRON MICROSCOPY	3.06
7UZM	ELECTRON MICROSCOPY	3.24
1NR1	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00367-F1	90.75	0.87

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 183

Ligand- & substrate-binding residues (13): 319; 322; 438; 444; 450; 516; 141–143; 147; 171; 176; 252; 266 …

Post-translational modifications (55): 68, 79, 84, 84, 110, 110, 128, 135, 147, 162, 162, 171, 172, 183, 183, 187, 191, 191, 200, 211 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
501	reduces activity and inhibition by gtp.
516	abolishes activation by adp.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-2151201	Transcriptional activation of mitochondrial biogenesis
R-HSA-8964539	Glutamate and glutamine metabolism
R-HSA-9837999	Mitochondrial protein degradation

MSigDB gene sets: 377 (showing top): MODULE_93, ELVIDGE_HYPOXIA_DN, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_BIOSYNTHETIC_PROCESS, KAAB_FAILED_HEART_ATRIUM_DN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_INSULIN_SECRETION, GOBP_GLUTAMATE_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_REGULATION_OF_HORMONE_LEVELS

GO Biological Process (7): obsolete glutamate biosynthetic process (GO:0006537), L-glutamate catabolic process (GO:0006538), L-glutamine metabolic process (GO:0006541), substantia nigra development (GO:0021762), positive regulation of insulin secretion (GO:0032024), tricarboxylic acid metabolic process (GO:0072350), amino acid metabolic process (GO:0006520)

GO Molecular Function (13): L-glutamate dehydrogenase (NAD+) activity (GO:0004352), L-glutamate dehydrogenase [NAD(P)+] activity (GO:0004353), L-glutamate dehydrogenase (NADP+) activity (GO:0004354), ATP binding (GO:0005524), GTP binding (GO:0005525), protein homodimerization activity (GO:0042803), ADP binding (GO:0043531), NAD+ binding (GO:0070403), L-leucine binding (GO:0070728), nucleotide binding (GO:0000166), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-NH2 group of donors, NAD or NADP as acceptor (GO:0016639)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mitochondrial biogenesis	1
Metabolism of amino acids and derivatives	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
L-glutamate dehydrogenase [NAD(P)+] activity	2
adenyl ribonucleotide binding	2
purine ribonucleoside triphosphate binding	2
anion binding	2
cytoplasm	2
intracellular membrane-bounded organelle	2
glutamate metabolic process	1
dicarboxylic acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
midbrain development	1
neural nucleus development	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
carboxylic acid metabolic process	1
primary metabolic process	1
amino-acid dehydrogenase [NAD(P)+] activity	1
guanyl ribonucleotide binding	1
identical protein binding	1
protein dimerization activity	1
NAD binding	1
amino acid binding	1
carboxylic acid binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on the CH-NH2 group of donors	1
intracellular anatomical structure	1
cellular anatomical structure	1
mitochondrion	1
intracellular organelle lumen	1
endomembrane system	1

Protein interactions and networks

STRING

2806 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLUD1	NRXN2	Q9P2S2	863
GLUD1	NRXN1	Q9ULB1	853
GLUD1	CBLN1	P02682	836
GLUD1	GLUL	P15104	797
GLUD1	PC	P11498	780
GLUD1	PDHA2	P29803	769
GLUD1	SIRT4	Q9Y6E7	763
GLUD1	RIPK3	Q9Y572	748
GLUD1	GLS	O94925	736
GLUD1	GOT1	P17174	717
GLUD1	GOT2	P00505	708
GLUD1	PDHA1	P08559	706
GLUD1	PGK2	P07205	682
GLUD1	GLS2	Q9UI32	666
GLUD1	FH	P07954	665

IntAct

182 interactions, top by confidence:

A	B	Type	Score
KLHL22	GLUD1	psi-mi:“MI:0914”(association)	0.840
KLHL22	GLUD1	psi-mi:“MI:0915”(physical association)	0.840
KLHL22	GLUD1	psi-mi:“MI:0407”(direct interaction)	0.840
CDK5	FIBP	psi-mi:“MI:0914”(association)	0.840
NDUFS3	NDUFS8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
KLHL22	METTL15	psi-mi:“MI:0914”(association)	0.640
CUL3	GLUD1	psi-mi:“MI:0915”(physical association)	0.620
CUL3	GLUD1	psi-mi:“MI:0914”(association)	0.620
GLUD2	GLUD1	psi-mi:“MI:0915”(physical association)	0.590
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
	GLUD1	psi-mi:“MI:0407”(direct interaction)	0.560
ILK	ILVBL	psi-mi:“MI:0914”(association)	0.530
STAT3	BANF1	psi-mi:“MI:0914”(association)	0.530
EBNA-LP	HAX1	psi-mi:“MI:0914”(association)	0.530
NEK10	GLUD1	psi-mi:“MI:2364”(proximity)	0.480

BioGRID (321): GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-RNA), GLUD1 (Affinity Capture-MS), GLUD1 (Proximity Label-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS), GLUD1 (Affinity Capture-MS)

ESM2 similar proteins: A2WYF4, A2XSL4, A9RBS1, B8A7A3, B8AIC3, B9F058, E3PZR9, E3PZS0, E3PZS1, E3PZS2, E3PZS3, O22832, O24428, P00366, P00367, P10860, P22243, P22337, P26443, P28645, P29108, P32061, P32062, P32063, P42174, P46253, P49448, Q01753, Q01771, Q04499, Q10S55, Q40073, Q40731, Q41319, Q41510, Q42770, Q42807, Q43593, Q56X52, Q64HZ8

Diamond homologs: A2XMV1, A2XW22, A3MUY9, A3MWK6, F2Z610, O04937, O59650, O74024, P00366, P00367, P00368, P00369, P00370, P0CL72, P0CL73, P0DMG3, P0DMG4, P10860, P13154, P15111, P24295, P26443, P27346, P28997, P28998, P29051, P29507, P31026, P39475, P39633, P39708, P42174, P43793, P49448, P50735, P52596, P54385, P54386, P54531, P80053

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
RIPK3	up-regulates	GLUD1	binding
SIRT4	“down-regulates activity”	GLUD1	glycosylation
EGFR	“up-regulates activity”	GLUD1	phosphorylation
GLUD1	“up-regulates quantity”	2-oxoglutarate(2-)	“chemical modification”
GLUD1	“down-regulates quantity”	“glutamic acid”	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 187 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
MyD88 cascade initiated on plasma membrane	6	9.7×	8e-03
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	6	9.1×	8e-03
MyD88 dependent cascade initiated on endosome	6	9.1×	8e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	6.1×	8e-03
PIP3 activates AKT signaling	10	5.3×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein autophosphorylation	9	8.4×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

298 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	3
Uncertain significance	152
Likely benign	84
Benign	9

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1072420	NM_005271.5(GLUD1):c.1507A>G (p.Lys503Glu)	Pathogenic
16122	NM_005271.5(GLUD1):c.1493C>T (p.Ser498Leu)	Pathogenic
16125	NM_005271.5(GLUD1):c.1496G>A (p.Gly499Asp)	Pathogenic
16126	NM_005271.5(GLUD1):c.1046A>C (p.Glu349Ala)	Pathogenic
16128	NM_005271.5(GLUD1):c.820C>T (p.Arg274Cys)	Pathogenic
226111	NM_005271.5(GLUD1):c.1496G>T (p.Gly499Val)	Pathogenic
3251213	NM_005271.5(GLUD1):c.944A>G (p.His315Arg)	Pathogenic
4086000	NM_005271.5(GLUD1):c.1479_1492delinsGAGTACAA (p.Phe493_Ser498delinsLeuSerThrThr)	Pathogenic
447454	NM_005271.5(GLUD1):c.956A>G (p.Tyr319Cys)	Pathogenic
1338646	NM_005271.5(GLUD1):c.954A>T (p.Arg318Ser)	Likely pathogenic
1685333	NM_005271.5(GLUD1):c.1496G>C (p.Gly499Ala)	Likely pathogenic
2632672	NM_005271.5(GLUD1):c.791G>A (p.Gly264Glu)	Likely pathogenic

SpliceAI

2238 predictions. Top by Δscore:

Variant	Effect	Δscore
10:87051867:TTTG:T	acceptor_gain	1.0000
10:87051868:TTG:T	acceptor_gain	1.0000
10:87051869:TG:T	acceptor_gain	1.0000
10:87053263:CAGT:C	donor_gain	1.0000
10:87053340:AC:A	donor_gain	1.0000
10:87053341:CC:C	donor_gain	1.0000
10:87053402:ACCCT:A	acceptor_loss	1.0000
10:87053403:CC:C	acceptor_gain	1.0000
10:87053404:CCTAT:C	acceptor_gain	1.0000
10:87053405:C:A	acceptor_loss	1.0000
10:87053406:T:A	acceptor_loss	1.0000
10:87057689:A:AC	donor_gain	1.0000
10:87057690:C:CC	donor_gain	1.0000
10:87057779:GACA:G	acceptor_gain	1.0000
10:87057781:CA:C	acceptor_gain	1.0000
10:87057782:AC:A	acceptor_loss	1.0000
10:87057783:C:CC	acceptor_gain	1.0000
10:87059145:CTCA:C	donor_gain	1.0000
10:87059146:TCA:T	donor_loss	1.0000
10:87059148:A:AC	donor_gain	1.0000
10:87059148:AC:A	donor_loss	1.0000
10:87059149:C:CA	donor_gain	1.0000
10:87059149:CT:C	donor_gain	1.0000
10:87059149:CTG:C	donor_gain	1.0000
10:87059149:CTGA:C	donor_gain	1.0000
10:87059149:CTGAG:C	donor_gain	1.0000
10:87059269:AGATC:A	acceptor_gain	1.0000
10:87059270:GATC:G	acceptor_gain	1.0000
10:87059271:ATC:A	acceptor_gain	1.0000
10:87059272:TC:T	acceptor_gain	1.0000

AlphaMissense

3678 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:87051804:C:G	A542P	1.000
10:87051815:G:T	A538D	1.000
10:87051818:G:T	A537D	1.000
10:87051823:T:A	R535S	1.000
10:87051823:T:G	R535S	1.000
10:87051824:C:A	R535I	1.000
10:87051824:C:G	R535T	1.000
10:87053346:G:T	A518D	1.000
10:87053370:A:C	L510W	1.000
10:87053370:A:G	L510S	1.000
10:87053373:C:T	G509D	1.000
10:87053374:C:G	G509R	1.000
10:87053377:A:G	S508P	1.000
10:87053382:A:T	V506E	1.000
10:87053383:C:T	V506M	1.000
10:87053393:C:A	E502D	1.000
10:87053393:C:G	E502D	1.000
10:87053394:T:A	E502V	1.000
10:87057776:A:T	V470D	1.000
10:87057780:A:G	S469P	1.000
10:87059168:A:G	S462P	1.000
10:87059184:G:C	F456L	1.000
10:87059184:G:T	F456L	1.000
10:87059186:A:G	F456L	1.000
10:87059191:A:G	L454S	1.000
10:87059197:C:T	G452D	1.000
10:87059198:C:G	G452R	1.000
10:87059206:A:T	V449D	1.000
10:87059215:A:G	L446P	1.000
10:87059217:A:C	N445K	1.000

dbSNP variants (sampled 300 via entrez): RS1000064540 (10:87069158 T>C), RS1000181652 (10:87055726 A>C), RS1000299706 (10:87064204 C>T), RS1000315964 (10:87093370 A>G), RS1000341714 (10:87075003 G>A,T), RS1000358499 (10:87057234 G>A), RS1000404995 (10:87058757 G>A), RS1000604880 (10:87089261 A>G), RS1000796347 (10:87056029 T>C,G), RS1000857570 (10:87057637 A>C), RS1000971571 (10:87087442 G>T), RS1000991854 (10:87095417 C>T), RS1001001458 (10:87080865 C>T), RS1001017067 (10:87063905 G>A), RS1001135038 (10:87080590 G>A,C)

Disease associations

OMIM: gene MIM:138130 | disease phenotypes: MIM:606762

GenCC curated gene-disease

Disease	Classification	Inheritance
hyperinsulinism-hyperammonemia syndrome	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hyperinsulinism-hyperammonemia syndrome	Definitive	AD

Mondo (4): hyperinsulinism-hyperammonemia syndrome (MONDO:0011717), familial hyperinsulinism (MONDO:0017182), monogenic diabetes (MONDO:0015967), intellectual disability (MONDO:0001071)

Orphanet (4): Hyperinsulinism-hyperammonemia syndrome (Orphanet:35878), Familial hyperinsulinism (Orphanet:276525), Rare genetic diabetes mellitus (Orphanet:183625), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010276_13	Renal underexcretion gout	9.000000e-11

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C538375	Hyperinsulinemic hypoglycemia, familial, 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

68 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression	7
bisphenol A	affects cotreatment, increases methylation, decreases expression, increases expression, affects expression	4
Cyclosporine	decreases expression	4
sodium arsenite	decreases expression, increases expression	2
cupric chloride	decreases expression	2
Arsenic Trioxide	decreases expression, increases expression	2
Acetaminophen	decreases expression	2
Tretinoin	affects cotreatment, decreases expression	2
Valproic Acid	affects expression, decreases expression, decreases methylation	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
bisphenol F	increases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
lead acetate	decreases expression	1
titanium dioxide	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cypermethrin	increases expression	1
alpha-hydroxyglutarate	decreases abundance, decreases expression	1
periodate-oxidized adenosine	affects expression	1
epigallocatechin gallate	decreases expression, decreases reaction, decreases abundance	1
arsenic disulfide	increases methylation	1
K 7174	decreases expression	1
candoxin	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SQ10	HAP1 GLUD1 (-) 1	Cancer cell line	Male
CVCL_XP19	HAP1 GLUD1 (-) 2	Cancer cell line	Male
CVCL_XP20	HAP1 GLUD1 (-) 3	Cancer cell line	Male
CVCL_XP21	HAP1 GLUD1 (-) 4	Cancer cell line	Male
CVCL_XP22	HAP1 GLUD1 (-) 5	Cancer cell line	Male

Clinical trials (associated diseases)

244 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT01070758	PHASE4	COMPLETED	Lanreotide Autogel Treatment of Patients With Congenital Hyperinsulinism of Infancy
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT03042416	PHASE3	COMPLETED	18F-DOPA PET Imaging: an Evaluation of Biodistribution and Safety
NCT03777176	PHASE3	COMPLETED	A Two-Period Open-label Trial Evaluating Efficacy and Safety of Dasiglucagon in Children With Congenital Hyperinsulinism
NCT03941236	PHASE3	ACTIVE_NOT_RECRUITING	Extension Trial Evaluating the Long-term Safety and Efficacy of Dasiglucagon in Children With Congenital Hyperinsulinism
NCT04706910	PHASE3	RECRUITING	18F-DOPA II - PET Imaging Optimization
NCT06208215	PHASE3	ACTIVE_NOT_RECRUITING	RZ358 Treatment for Congenital Hyperinsulinism
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT04984798	PHASE2	WITHDRAWN	Vitamin E Efficacy in HI/HA
NCT00674440	PHASE2	COMPLETED	Utility of [F-18] fluoroDOPA for Neonatal Hyperinsulinism
NCT00987168	PHASE2	COMPLETED	Sandostatine® LP and Hyperinsulinism
NCT01468454	PHASE2	COMPLETED	Phase II Safety and Efficacy Study of 18FDOPA PET-CT in Children With Hyperinsulinemic Hypoglycemia
NCT02604485	PHASE2	COMPLETED	A Single-Dose Open-Label Study of XOMA 358 in Subjects With Congenital Hyperinsulinism
NCT02937558	PHASE2	COMPLETED	CSI-Glucagon for Prevention of Hypoglycemia in Children With Congenital Hyperinsulinism
NCT03053284	PHASE2	WITHDRAWN	Pasireotide in Hyperinsulinemic Hypoglycemia
NCT03770637	PHASE2	COMPLETED	Glucagon Ready to Use (RTU) in Subjects With Hyperinsulinemic Hypoglycemia After Bariatric Surgery
NCT03984370	PHASE2	COMPLETED	Dasiglucagon in the Treatment of Postprandial Hypoglycaemia After Roux-en-Y Gastric Bypass
NCT04205604	PHASE2	RECRUITING	18FluoroLDOPA PET Imaging for the Detection and Localization of Focal Congenital Hyperinsulinism
NCT04538989	PHASE2	COMPLETED	An Open-Label Multiple Dose Study of RZ358 in Patients With Congenital Hyperinsulinism
NCT04652479	PHASE2	COMPLETED	Avexitide Safety and Efficacy to Treat Acquired Hyperinsulinemic Hypoglycemia
NCT04732416	PHASE2	ACTIVE_NOT_RECRUITING	HM15136 (Efpegerglucagon) Treatment for 8 Weeks in Subjects Aged ≥2 Years With Congenital Hyperinsulinism (CHI)
NCT04836273	PHASE2	COMPLETED	Treatment of Post-bariatric Hypoglycaemia
NCT06976658	PHASE2	RECRUITING	Glucokinase Activator in Monogenic Diabetes
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02021604	PHASE1	RECRUITING	Fluorodopa F 18 in Congenital Hyperinsulinism and Insulinoma
NCT02685852	PHASE1	COMPLETED	Evaluating Exenatide for the Treatment of Postprandial Hyperinsulinemic Hypoglycemia
NCT03103009	PHASE1	COMPLETED	Treatment Plan for an Individual Patient With Pasireotide for Hyperinsulinemic Hypoglycemia
NCT01795144	PHASE1	COMPLETED	Incretin Regulation of Insulin Secretion in Monogenic Diabetes
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns