Glutaminase deficiency

Summary

Glutaminase deficiency (MONDO:0600001) is a disease caused by GLS (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: GLS (GenCC Definitive)
• Cohort genes: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	glutaminase deficiency
Mondo ID	MONDO:0600001
GARD	0026291
Is cancer (heuristic)	no

Also known as: glutaminase deficiency

Data availability: 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › disorder of glutamine metabolism › glutaminase deficiency

Related subtypes (1): congenital brain dysgenesis due to glutamine synthetase deficiency

Subtypes (2): developmental and epileptic encephalopathy, 71, spastic ataxia-dysarthria due to glutaminase deficiency

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GLS	Definitive	Autosomal recessive	glutaminase deficiency	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLS	Orphanet:557056	Spastic ataxia-dysarthria due to glutaminase deficiency
GLS	Orphanet:557064	Neonatal epileptic encephalopathy due to glutaminase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLS	HGNC:4331	ENSG00000115419	O94925	Glutaminase kidney isoform, mitochondrial	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLS	Glutaminase kidney isoform, mitochondrial	Catalyzes the first reaction in the primary pathway for the renal catabolism of glutamine.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLS	Scaffold/PPI	no	3.5.1.2	Ankyrin_rpt, Beta-lactam/transpept-like, Glutaminase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
middle temporal gyrus	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLS	287	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, pons

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLS	1,902

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLS	O94925	50

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glutamate and glutamine metabolism	1	815.7×	0.003	GLS
Glutamate Neurotransmitter Release Cycle	1	456.8×	0.003	GLS
TP53 Regulates Metabolic Genes	1	129.8×	0.008	GLS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
L-glutamine catabolic process	1	5617.3×	8e-04	GLS
obsolete glutamate biosynthetic process	1	3370.4×	8e-04	GLS
intracellular glutamate homeostasis	1	2808.7×	8e-04	GLS
suckling behavior	1	1685.2×	0.001	GLS
regulation of respiratory gaseous exchange by nervous system process	1	1296.3×	0.001	GLS
protein homotetramerization	1	237.3×	0.005	GLS
chemical synaptic transmission	1	77.3×	0.013	GLS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 0

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLS	2	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TELAGLENASTAT	2	GLS
IPN-60090	1	GLS

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GLS	187	Binding:185, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GLS	3.5.1.2	glutaminase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
GLS	187

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
TELAGLENASTAT	2	GLS
IPN-60090	1	GLS

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	GLS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

0 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Clinical trials & evidence

Clinical trials

Clinical trials: 0.