Hemolytic anemia due to glutathione reductase deficiency

Summary

Hemolytic anemia due to glutathione reductase deficiency (MONDO:0019531) is a disease caused by GSR (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GSR (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 90

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hemolytic anemia due to glutathione reductase deficiency
Mondo ID	MONDO:0019531
OMIM	618660
Orphanet	90030
DOID	DOID:0051009
UMLS	C5231513
MedGen	1684855
GARD	0016784
Is cancer (heuristic)	no

Also known as: hemolytic anemia due to glutathione reductase deficiency

Data availability: 90 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › anemia › congenital anemia › congenital nonspherocytic hemolytic anemia › hemolytic anemia due to glutathione reductase deficiency

Related subtypes (9): anemia, nonspherocytic hemolytic, gamma-glutamylcysteine synthetase deficiency, glutathione synthetase deficiency without 5-oxoprolinuria, non-spherocytic hemolytic anemia due to hexokinase deficiency, hemolytic anemia due to pyrimidine 5’ nucleotidase deficiency, pyruvate kinase deficiency of red cells, hemolytic anemia due to adenylate kinase deficiency, hemolytic anemia due to glucophosphate isomerase deficiency, hemolytic anemia due to erythrocyte adenosine deaminase overproduction

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

90 retrieved; paginated sample, class counts are floors:

57 uncertain significance, 9 likely benign, 6 benign, 6 conflicting classifications of pathogenicity, 5 benign/likely benign, 4 pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
694660	NM_000637.5(GSR):c.1286-229_*499del	GSR	Pathogenic	no assertion criteria provided
694661	NM_000637.5(GSR):c.993G>A (p.Trp331Ter)	GSR	Pathogenic	no assertion criteria provided
694662	NM_000637.5(GSR):c.1121G>C (p.Gly374Ala)	GSR	Pathogenic	no assertion criteria provided
548962	NM_020338.4(ZMIZ1):c.2758dup (p.Gln920fs)	ZMIZ1	Pathogenic	criteria provided, multiple submitters, no conflicts
3065567	NM_000637.5(GSR):c.342del (p.Met113_Trp114insTer)	GSR	Likely pathogenic	criteria provided, single submitter
3065853	NM_000637.5(GSR):c.640G>A (p.Gly214Ser)	GSR	Likely pathogenic	criteria provided, single submitter
4849357	NM_000637.5(GSR):c.70C>T (p.Arg24Ter)	GSR	Likely pathogenic	criteria provided, single submitter
1693976	NM_000637.5(GSR):c.493-18T>G	GSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2658517	NM_000637.5(GSR):c.94G>T (p.Glu32Ter)	GSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4078864	NM_000637.5(GSR):c.421C>T (p.Arg141Cys)	GSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4683329	NM_000637.5(GSR):c.306C>T (p.Cys102=)	GSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
618149	NM_000637.5(GSR):c.866T>C (p.Val289Ala)	GSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
810272	NM_000637.5(GSR):c.694G>A (p.Gly232Ser)	GSR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1163476	NM_000637.5(GSR):c.679C>G (p.Leu227Val)	GSR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1163477	NM_000637.5(GSR):c.439C>G (p.Arg147Gly)	GSR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1330556	NM_000637.5(GSR):c.859G>A (p.Val287Met)	GSR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679476	NM_000637.5(GSR):c.307G>A (p.Val103Met)	GSR	Uncertain significance	criteria provided, single submitter
2213161	NM_000637.5(GSR):c.439C>T (p.Arg147Trp)	GSR	Uncertain significance	criteria provided, multiple submitters, no conflicts
2275409	NM_000637.5(GSR):c.331A>C (p.Lys111Gln)	GSR	Uncertain significance	criteria provided, multiple submitters, no conflicts
2304629	NM_000637.5(GSR):c.488C>T (p.Thr163Ile)	GSR	Uncertain significance	criteria provided, multiple submitters, no conflicts
2345425	NM_000637.5(GSR):c.428T>C (p.Ile143Thr)	GSR	Uncertain significance	criteria provided, multiple submitters, no conflicts
2383177	NM_000637.5(GSR):c.836C>T (p.Thr279Met)	GSR	Uncertain significance	criteria provided, multiple submitters, no conflicts
2432312	NM_000637.5(GSR):c.1196A>C (p.Glu399Ala)	GSR	Uncertain significance	criteria provided, single submitter
2432313	NM_000637.5(GSR):c.1023C>G (p.Asp341Glu)	GSR	Uncertain significance	criteria provided, single submitter
2432314	NM_000637.5(GSR):c.395C>T (p.Pro132Leu)	GSR	Uncertain significance	criteria provided, single submitter
2432316	NM_000637.5(GSR):c.1525G>A (p.Ala509Thr)	GSR	Uncertain significance	criteria provided, single submitter
2432317	NM_000637.5(GSR):c.1256C>T (p.Pro419Leu)	GSR	Uncertain significance	criteria provided, single submitter
2432319	NM_000637.5(GSR):c.781A>G (p.Ile261Val)	GSR	Uncertain significance	criteria provided, single submitter
2432320	NM_000637.5(GSR):c.1171C>T (p.Arg391Ter)	GSR	Uncertain significance	criteria provided, single submitter
2432321	NM_000637.5(GSR):c.372T>C (p.His124=)	GSR	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
GSR	Strong	Autosomal recessive	hemolytic anemia due to glutathione reductase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GSR	Orphanet:90030	Hemolytic anemia due to glutathione reductase deficiency
ZMIZ1	Orphanet:528084	Non-specific syndromic intellectual disability

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GSR	HGNC:4623	ENSG00000104687	P00390	Glutathione reductase, mitochondrial	gencc,clinvar
ZMIZ1	HGNC:16493	ENSG00000108175	Q9ULJ6	Zinc finger MIZ domain-containing protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GSR	Glutathione reductase, mitochondrial	Catalyzes the reduction of glutathione disulfide (GSSG) to reduced glutathione (GSH).
ZMIZ1	Zinc finger MIZ domain-containing protein 1	Acts as a transcriptional coactivator.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GSR	Enzyme (other)	yes	1.8.1.7	Pyr_nuc-diS_OxRdtase, Pyr_nucl-diS_OxRdtase_dimer, Glutathione_Rdtase_euk/bac
ZMIZ1	Transcription factor	no		Znf_MIZ, Znf_RING/FYVE/PHD, ZMIZ1_N

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
epithelium of nasopharynx	1
islet of Langerhans	1
pylorus	1
dorsal motor nucleus of vagus nerve	1
seminal vesicle	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GSR	277	ubiquitous	marker	pylorus, islet of Langerhans, epithelium of nasopharynx
ZMIZ1	295	ubiquitous	marker	dorsal motor nucleus of vagus nerve, tibia, seminal vesicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GSR	4,564
ZMIZ1	1,773

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GSR	P00390	27
ZMIZ1	Q9ULJ6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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
Metabolism of ingested H2SeO4 and H2SeO3 into H2Se	1	2855.0×	0.002	GSR
NFE2L2 regulating anti-oxidant/detoxification enzymes	1	543.8×	0.004	GSR
Interconversion of nucleotide di- and triphosphates	1	356.9×	0.004	GSR
Detoxification of Reactive Oxygen Species	1	300.5×	0.004	GSR
TP53 Regulates Metabolic Genes	1	129.8×	0.008	GSR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyramidal neuron migration to cerebral cortex	1	2808.7×	0.006	ZMIZ1
vitellogenesis	1	1685.2×	0.006	ZMIZ1
developmental growth	1	366.4×	0.010	ZMIZ1
SMAD protein signal transduction	1	366.4×	0.010	ZMIZ1
androgen receptor signaling pathway	1	351.1×	0.010	ZMIZ1
artery morphogenesis	1	337.0×	0.010	ZMIZ1
positive regulation of T cell differentiation	1	227.7×	0.010	ZMIZ1
heart morphogenesis	1	187.2×	0.010	ZMIZ1
glutathione metabolic process	1	175.5×	0.010	GSR
positive regulation of Notch signaling pathway	1	175.5×	0.010	ZMIZ1
cell redox homeostasis	1	172.0×	0.010	GSR
protein sumoylation	1	162.0×	0.010	ZMIZ1
positive regulation of fibroblast proliferation	1	147.8×	0.010	ZMIZ1
cellular senescence	1	147.8×	0.010	ZMIZ1
vasculogenesis	1	127.7×	0.010	ZMIZ1
transforming growth factor beta receptor signaling pathway	1	79.5×	0.015	ZMIZ1
cellular response to oxidative stress	1	77.3×	0.015	GSR
in utero embryonic development	1	36.0×	0.031	ZMIZ1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.137	ZMIZ1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ZMIZ1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
GSR	NIFEDIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GSR	8	4
ZMIZ1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIFEDIPINE	4	GSR
METHYLENE BLUE ANHYDROUS	4	GSR
CARMUSTINE	4	GSR
MENADIONE	4	GSR
GLUTAMIC ACID	3	GSR
MOLIBRESIB	2	GSR
ELLAGIC ACID	2	GSR
LYSINE	2	GSR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GSR	114	Binding:108, Functional:5, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GSR	1.8.1.7	glutathione-disulfide reductase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GSR	114

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

8 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)
NIFEDIPINE	4	GSR
METHYLENE BLUE ANHYDROUS	4	GSR
CARMUSTINE	4	GSR
MENADIONE	4	GSR
GLUTAMIC ACID	3	GSR
MOLIBRESIB	2	GSR
ELLAGIC ACID	2	GSR
LYSINE	2	GSR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GSR
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	1	ZMIZ1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ZMIZ1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.