GRXCR2

Summary

GRXCR2 (glutaredoxin and cysteine rich domain containing 2, HGNC:33862) is a protein-coding gene on chromosome 5q32, encoding Glutaredoxin domain-containing cysteine-rich protein 2 (A6NFK2). Required for hearing.

This gene encodes a protein containing a glutaredoxin domain, which functions in protein S-glutathionylation. A mutation in this gene was found in a family with autoosomal recessive nonsyndromic sensorineural deafness-101.

Source: NCBI Gene 643226 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive nonsyndromic hearing loss 101 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 109 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 5
• MANE Select transcript: NM_001080516

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33862
Approved symbol	GRXCR2
Name	glutaredoxin and cysteine rich domain containing 2
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	DFNB101
Ensembl gene	ENSG00000204928
Ensembl biotype	protein_coding
OMIM	615762
Entrez	643226

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000377976, ENST00000639411

RefSeq mRNA: 1 — MANE Select: NM_001080516 NM_001080516

CCDS: CCDS34263

Canonical transcript exons

ENST00000377976 — 3 exons

Exon	Start	End
ENSE00001416400	145866501	145866728
ENSE00001475731	145872633	145873014
ENSE00003805370	145858521	145859915

Expression profiles

Bgee: expression breadth broad, 24 present calls, max score 86.22.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.22	gold quality
apex of heart	UBERON:0002098	69.21	gold quality
right atrium auricular region	UBERON:0006631	60.83	gold quality
heart left ventricle	UBERON:0002084	53.76	gold quality
heart	UBERON:0000948	52.21	gold quality
left testis	UBERON:0004533	45.74	gold quality
testis	UBERON:0000473	45.48	gold quality
right testis	UBERON:0004534	44.70	gold quality
skin of abdomen	UBERON:0001416	44.15	gold quality
zone of skin	UBERON:0000014	43.96	gold quality
skin of leg	UBERON:0001511	43.57	gold quality
right lobe of thyroid gland	UBERON:0001119	40.33	gold quality
tonsil	UBERON:0002372	39.57	gold quality
calcaneal tendon	UBERON:0003701	39.40	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
sural nerve	UBERON:0015488	36.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	36.36	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	36.31	silver quality
mucosa of transverse colon	UBERON:0004991	36.17	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
thyroid gland	UBERON:0002046	36.13	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
left lobe of thyroid gland	UBERON:0001120	35.45	silver quality
saliva-secreting gland	UBERON:0001044	34.82	gold quality
bone marrow	UBERON:0002371	34.30	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
right uterine tube	UBERON:0001302	33.04	gold quality
gall bladder	UBERON:0002110	32.35	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.12

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 3)

• ur results indicate that GRXCR2 should be considered in differential genetic diagnosis for individuals with early onset, moderate-to-severe and progressive hearing loss. (PMID:24619944)
• GRXCR2 plays an intrinsic role in bundle orientation, organization, and sensory function in the inner ear during development and at maturity (PMID:30157177)
• Whole exome sequencing reveals a biallelic frameshift mutation in GRXCR2 in hearing impairment in Cameroon. (PMID:33528103)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Grxcr2	ENSMUSG00000073574
rattus_norvegicus	Grxcr2	ENSRNOG00000039325
drosophila_melanogaster	CG12206	FBGN0029662
drosophila_melanogaster	CG31559	FBGN0051559
caenorhabditis_elegans		WBGENE00021593

Paralogs (2): GLRX2 (ENSG00000023572), GRXCR1 (ENSG00000215203)

Protein

Protein identifiers

Glutaredoxin domain-containing cysteine-rich protein 2 — A6NFK2 (reviewed: A6NFK2)

Alternative names: GRXCR1-like protein, Glutaredoxin domain-containing cysteine-rich protein 1-like protein

All UniProt accessions (2): A6NFK2, A0A1W2PQQ7

UniProt curated annotations — full annotation on UniProt →

Function. Required for hearing. Plays a role in maintaining cochlear stereocilia bundles that are involved in sound detection. Ensures the restriction of TPRN to the basal region of stereocilia in hair cells.

Subunit / interactions. Interacts with TPRN; the interaction restricts TPRN to the stereocilum basal region.

Subcellular location. Cell projection. Stereocilium.

Disease relevance. Deafness, autosomal recessive, 101 (DFNB101) [MIM:615837] A form of non-syndromic deafness characterized by bilateral, moderate to severe hearing loss. Vestibular function is unaffected. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the GRXCR2 family.

RefSeq proteins (1): NP_001073985* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR033023	GRXCR2	Family
IPR036410	HSP_DnaJ_Cys-rich_dom_sf	Homologous_superfamily

Pfam: PF23733

UniProt features (6 total): region of interest 2, compositionally biased region 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NFK2-F1	59.23	0.02

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 47 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_NEUROGENESIS, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_EAR_DEVELOPMENT, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS, GOBP_EAR_MORPHOGENESIS, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_AUDITORY_RECEPTOR_CELL_DEVELOPMENT, GOBP_MECHANORECEPTOR_DIFFERENTIATION, GOBP_HAIR_CELL_DIFFERENTIATION, GOBP_SENSORY_PERCEPTION, GOCC_NEURON_PROJECTION, GOBP_EMBRYO_DEVELOPMENT

GO Biological Process (3): sensory perception of sound (GO:0007605), auditory receptor cell stereocilium organization (GO:0060088), inner ear receptor cell stereocilium organization (GO:0060122)

GO Molecular Function (0):

GO Cellular Component (5): microvillus (GO:0005902), stereocilium shaft (GO:0120043), stereocilium base (GO:0120044), stereocilium (GO:0032420), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
actin-based cell projection	2
stereocilium	2
sensory perception of mechanical stimulus	1
auditory receptor cell morphogenesis	1
inner ear receptor cell stereocilium organization	1
neuron projection development	1
inner ear receptor cell development	1
actin filament bundle	1
stereocilium bundle	1
neuron projection	1

Protein interactions and networks

STRING

378 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRXCR2	STRC	Q7RTU9	687
GRXCR2	CLIC5	Q9NZA1	671
GRXCR2	CLIC6	Q96NY7	651
GRXCR2	TPRN	Q4KMQ1	632
GRXCR2	CLRN2	A0PK11	565
GRXCR2	ESPN	B1AK53	530
GRXCR2	PPP1R17	O96001	505
GRXCR2	E9PNW1	E9PNW1	498
GRXCR2	RIPOR2	Q9Y4F9	495
GRXCR2	GIPC3	Q8TF64	494
GRXCR2	NSG2	Q9Y328	493
GRXCR2	CHRNA10	Q9GZZ6	490
GRXCR2	USH1G	Q495M9	490
GRXCR2	CABP2	Q9NPB3	478
GRXCR2	PRELID2	Q8N945	478

IntAct

2 interactions, top by confidence:

A	B	Type	Score
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (1): GRXCR2 (Affinity Capture-MS)

ESM2 similar proteins: A2XTW9, A6NFK2, A8MW92, D3Z1Q2, D3Z6S9, F1N8V3, F8W4H9, M0R2J8, P0DM64, P0DO92, P58270, P62932, Q01954, Q0P5X5, Q3TYR5, Q40359, Q49A92, Q4R989, Q503Y8, Q5XEM9, Q5XIV2, Q66HF0, Q6ZN30, Q6ZVD7, Q7L4S7, Q7PCK7, Q7TP54, Q80T69, Q8BMQ3, Q8BZJ8, Q8C5V0, Q8IZS5, Q8K4P8, Q8K4S1, Q8LA16, Q8NA82, Q8S8M9, Q8WWI1, Q8WWY6, Q96G30

Diamond homologs: A6NFK2, A8MXD5, Q3TYR5, Q50H32, O23419, Q02784, Q0JM76, Q6NLU2, Q8LBK6, Q9FLE8, Q9HDW8, Q9LH89, Q9VNL4, Q9W4S1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	57
Likely benign	27
Benign	14

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1192284	NM_001080516.2(GRXCR2):c.323C>T (p.Ala108Val)	Pathogenic
133347	NM_001080516.2(GRXCR2):c.714dup (p.Gly239fs)	Pathogenic
1943443	NM_001080516.2(GRXCR2):c.463G>T (p.Glu155Ter)	Pathogenic
2124823	NM_001080516.2(GRXCR2):c.100C>T (p.Gln34Ter)	Pathogenic
3246459	NC_000005.9:g.(?145239296)(145252531_?)del	Pathogenic
4682638	GRCh37/hg19 5q32(chr5:144614507-145878493)x1	Pathogenic
3601167	NM_001080516.2(GRXCR2):c.247C>T (p.Gln83Ter)	Likely pathogenic
4277768	NM_001080516.2(GRXCR2):c.397C>T (p.Arg133Ter)	Likely pathogenic

SpliceAI

471 predictions. Top by Δscore:

Variant	Effect	Δscore
5:145872629:CAA:C	donor_loss	0.9900
5:145872630:AACCT:A	donor_loss	0.9900
5:145872632:C:CA	donor_loss	0.9900
5:145936692:AAGG:A	donor_loss	0.9900
5:145936693:AGG:A	donor_loss	0.9900
5:145936694:GGTT:G	donor_loss	0.9900
5:145936695:G:T	donor_loss	0.9900
5:145872829:T:TA	donor_gain	0.9800
5:145859917:T:A	acceptor_loss	0.9700
5:145861720:T:TA	donor_gain	0.9700
5:145872880:CG:C	donor_gain	0.9700
5:145870955:TAGC:T	donor_gain	0.9600
5:145872629:CAACC:C	donor_gain	0.9600
5:145936695:G:GG	donor_gain	0.9600
5:145859911:CCTTC:C	acceptor_gain	0.9500
5:145859912:CTTC:C	acceptor_gain	0.9500
5:145859912:CTTCC:C	acceptor_gain	0.9500
5:145859913:TTCCT:T	acceptor_gain	0.9500
5:145866659:T:TC	acceptor_gain	0.9500
5:145866657:C:CT	acceptor_gain	0.9400
5:145866724:AGGGG:A	acceptor_gain	0.9400
5:145872917:T:A	donor_gain	0.9400
5:145859916:C:CC	acceptor_gain	0.9300
5:145866576:G:C	donor_gain	0.9300
5:145866729:C:CC	acceptor_gain	0.9200
5:145936693:AG:A	donor_gain	0.9200
5:145936694:GG:G	donor_gain	0.9200
5:145859913:TTC:T	acceptor_gain	0.9100
5:145936613:G:GT	donor_gain	0.9100
5:145866725:GGGG:G	acceptor_gain	0.9000

AlphaMissense

1649 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:145859786:A:G	C232R	1.000
5:145859848:C:G	C211S	1.000
5:145859849:A:G	C211R	1.000
5:145859849:A:T	C211S	1.000
5:145872907:A:G	F21S	1.000
5:145859775:G:C	C235W	0.999
5:145859776:C:G	C235S	0.999
5:145859776:C:T	C235Y	0.999
5:145859777:A:G	C235R	0.999
5:145859777:A:T	C235S	0.999
5:145859785:C:G	C232S	0.999
5:145859786:A:T	C232S	0.999
5:145859811:A:C	F223L	0.999
5:145859811:A:T	F223L	0.999
5:145859813:A:G	F223L	0.999
5:145859847:G:C	C211W	0.999
5:145859848:C:T	C211Y	0.999
5:145859856:G:C	C208W	0.999
5:145859857:C:G	C208S	0.999
5:145859858:A:G	C208R	0.999
5:145859858:A:T	C208S	0.999
5:145866679:A:G	L129P	0.999
5:145872906:A:C	F21L	0.999
5:145872906:A:T	F21L	0.999
5:145872908:A:G	F21L	0.999
5:145859753:A:G	C243R	0.998
5:145859776:C:A	C235F	0.998
5:145859784:G:C	C232W	0.998
5:145859785:C:T	C232Y	0.998
5:145859812:A:G	F223S	0.998

dbSNP variants (sampled 300 via entrez): RS1000021931 (5:145929341 T>C), RS1000023388 (5:145883036 G>A,C,T), RS1000072265 (5:145922381 C>T), RS1000089936 (5:145929909 T>A), RS1000143645 (5:145920970 C>A,T), RS1000211750 (5:145905495 A>G), RS1000237753 (5:145888491 A>G), RS1000411616 (5:145883447 A>G), RS1000425129 (5:145922682 A>G,T), RS1000452143 (5:145871400 C>T), RS1000459895 (5:145893331 G>A,C), RS1000531111 (5:145929593 GTTTTACCAATTACTTGGA>G,GTTTTACCAATTACTTGGATTTTACCAATTACTTGGA), RS1000588057 (5:145878275 T>C), RS1000604770 (5:145906744 G>A), RS1000636021 (5:145924908 G>A)

Disease associations

OMIM: gene MIM:615762 | disease phenotypes: MIM:220290, MIM:607197, MIM:615837

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive nonsyndromic hearing loss 101	Strong	Autosomal recessive
nonsyndromic genetic hearing loss	Moderate	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Moderate	AR

Mondo (3): hearing loss, autosomal recessive (MONDO:0019588), autosomal recessive nonsyndromic hearing loss 101 (MONDO:0014363), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (2): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000505	Visual impairment
HP:0001751	Abnormal vestibular function
HP:0008619	Bilateral sensorineural hearing impairment
HP:0011463	Childhood onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009173_1	Response to (pegylated) interferon in HBeAG-positive hepatitis B	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007859	response to interferon

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

1 total (human), top 1 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations