Gamma-glutamyl transpeptidase deficiency

Summary

Gamma-glutamyl transpeptidase deficiency (MONDO:0009285) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 3
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		7	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0001249	Intellectual disability	Very frequent (80-99%)
HP:0034456	Elevated circulating glutathione concentration	Very frequent (80-99%)
HP:0034586	Glutathionuria	Very frequent (80-99%)
HP:6000578	Reduced tissue gamma-glutamyltransferase activity	Very frequent (80-99%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0011968	Feeding difficulties	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	gamma-glutamyl transpeptidase deficiency
Mondo ID	MONDO:0009285
MeSH	C536836
OMIM	231950
Orphanet	33573
DOID	DOID:0111257
ICD-11	2074850874
SNOMED CT	78586005
UMLS	C0268524
MedGen	82813
GARD	0010099
Is cancer (heuristic)	no

Also known as: GGT1 deficiency · glutathioninuria · glutathionuria · inborn error of glutathione hydrolase activity · inborn glutathione hydrolase activity disorder · rare inborn error of glutathione hydrolase activity

Data availability: 3 ClinVar variants · 4 GenCC gene-disease records.

Disease family

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 › inborn disorder of the gamma-glutamyl cycle › inherited glutathione metabolism disease › gamma-glutamyl transpeptidase deficiency

Related subtypes (5): gamma-glutamylcysteine synthetase deficiency, spondylometaphyseal dysplasia, Sedaghatian type, 5-oxoprolinase deficiency, inherited glutathione synthetase deficiency, hemolytic anemia due to glutathione reductase 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

ClinVar germline variants

3 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
545540	NC_000022.10:g.24992587_25009579delinsGCCTGTAATCCCA	GGT1	Pathogenic	no assertion criteria provided
1029303	NM_001288833.2(GGT1):c.127G>A (p.Val43Met)	GGT1	Uncertain significance	criteria provided, single submitter
1262267	NM_001288833.2(GGT1):c.815T>C (p.Val272Ala)	GGT1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
GGT1	Moderate	Autosomal dominant	gamma-glutamyl transpeptidase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GGT1	Orphanet:33573	Gamma-glutamyl transpeptidase 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
GGT1	HGNC:4250	ENSG00000100031	P19440	Glutathione hydrolase 1 proenzyme	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GGT1	Glutathione hydrolase 1 proenzyme	Cleaves the gamma-glutamyl bond of extracellular glutathione (gamma-Glu-Cys-Gly), glutathione conjugates (such as maresin conjugate (13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoate, MCTR1) and other gamma-glutamyl…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GGT1	Protease	yes		GGT_peptidase, Ntn_hydrolases_N, GGT_ssub_C

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
gall bladder	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GGT1	184	broad	marker	right lobe of liver, mucosa of transverse colon, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GGT1	1,098

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GGT1	P19440	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. 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
Defective GGT1 causes GLUTH	1	11420.0×	3e-04	GGT1
Defective GGT1 in aflatoxin detoxification causes GLUTH	1	11420.0×	3e-04	GGT1
LTC4-CYSLTR mediated IL4 production	1	1903.3×	0.001	GGT1
Glutathione synthesis and recycling	1	951.7×	0.002	GGT1
Aflatoxin activation and detoxification	1	634.4×	0.002	GGT1
Synthesis of Leukotrienes (LT) and Eoxins (EX)	1	571.0×	0.002	GGT1
Paracetamol ADME	1	423.0×	0.002	GGT1

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-cysteine biosynthetic process	1	5617.3×	0.002	GGT1
peptide modification	1	4213.0×	0.002	GGT1
leukotriene D4 biosynthetic process	1	2106.5×	0.002	GGT1
glutathione catabolic process	1	1872.4×	0.002	GGT1
glutathione biosynthetic process	1	1532.0×	0.002	GGT1
leukotriene metabolic process	1	1296.3×	0.002	GGT1
glutamate metabolic process	1	1123.5×	0.002	GGT1
amino acid metabolic process	1	802.5×	0.002	GGT1
zymogen activation	1	674.1×	0.002	GGT1
regulation of immune system process	1	468.1×	0.003	GGT1
fatty acid metabolic process	1	193.7×	0.007	GGT1
regulation of inflammatory response	1	168.5×	0.007	GGT1
spermatogenesis	1	35.2×	0.029	GGT1
proteolysis	1	34.2×	0.029	GGT1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · 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).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GGT1	ASPIRIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GGT1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ASPIRIN	4	GGT1
CROBENETINE	2	GGT1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
GGT1	17	Binding:17

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)
ASPIRIN	4	GGT1
CROBENETINE	2	GGT1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GGT1
B	Phased (≥1) drug, not yet approved	0
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.