MSH4

Summary

MSH4 (mutS homolog 4, HGNC:7327) is a protein-coding gene on chromosome 1p31.1, encoding MutS protein homolog 4 (O15457). Involved in meiotic recombination.

This gene encodes a member of the DNA mismatch repair mutS family. This member is a meiosis-specific protein that is not involved in DNA mismatch correction, but is required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis I. This protein and MSH5 form a heterodimer which binds uniquely to a Holliday Junction and its developmental progenitor, thus provoking ADP-ATP exchange, and stabilizing the interaction between parental chromosomes during meiosis double-stranded break repair.

Source: NCBI Gene 4438 — RefSeq curated summary.

At a glance

• Gene–disease (curated): premature ovarian failure 20 (Strong, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 174 total — 7 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 37
• MANE Select transcript: NM_002440

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7327
Approved symbol	MSH4
Name	mutS homolog 4
Location	1p31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000057468
Ensembl biotype	protein_coding
OMIM	602105
Entrez	4438

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000263187

RefSeq mRNA: 1 — MANE Select: NM_002440 NM_002440

CCDS: CCDS670

Canonical transcript exons

ENST00000263187 — 20 exons

Exon	Start	End
ENSE00000830675	75822409	75822581
ENSE00000830678	75810697	75810807
ENSE00000830679	75806981	75807141
ENSE00000931976	75815021	75815136
ENSE00000931977	75816373	75816546
ENSE00001067035	75881246	75881370
ENSE00001067036	75897907	75898081
ENSE00001067037	75899618	75899706
ENSE00001067038	75890696	75890824
ENSE00001067039	75848209	75848276
ENSE00001067040	75880050	75880153
ENSE00001067041	75878149	75878318
ENSE00001067042	75883621	75883821
ENSE00001067044	75878992	75879128
ENSE00001067045	75889251	75889369
ENSE00001067046	75867514	75867588
ENSE00001067047	75876936	75877000
ENSE00001172584	75912696	75913242
ENSE00001172697	75803731	75803913
ENSE00001172702	75796882	75797229

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 82.06.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0565 / max 33.8314, expressed in 11 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
3554	0.0565	11

Top tissues by expression

281 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	82.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.18	gold quality
right coronary artery	UBERON:0001625	66.35	gold quality
gastrocnemius	UBERON:0001388	62.83	gold quality
right testis	UBERON:0004534	61.59	gold quality
cerebellar hemisphere	UBERON:0002245	61.56	gold quality
right hemisphere of cerebellum	UBERON:0014890	61.50	gold quality
cerebellar cortex	UBERON:0002129	61.46	gold quality
muscle of leg	UBERON:0001383	61.42	gold quality
testis	UBERON:0000473	60.62	gold quality
left testis	UBERON:0004533	60.55	gold quality
cerebellum	UBERON:0002037	59.61	gold quality
sperm	CL:0000019	58.75	gold quality
muscle organ	UBERON:0001630	58.33	gold quality
male germ cell	CL:0000015	58.26	gold quality
hindlimb stylopod muscle	UBERON:0004252	57.79	gold quality
decidua	UBERON:0002450	56.55	gold quality
popliteal artery	UBERON:0002250	56.23	gold quality
tibial artery	UBERON:0007610	56.16	gold quality
tibialis anterior	UBERON:0001385	55.94	silver quality
coronary artery	UBERON:0001621	55.51	gold quality
left coronary artery	UBERON:0001626	55.49	gold quality
right ovary	UBERON:0002118	55.26	gold quality
tibial nerve	UBERON:0001323	55.02	gold quality
cranial nerve II	UBERON:0000941	54.84	silver quality
left ovary	UBERON:0002119	54.50	gold quality
aorta	UBERON:0000947	53.59	gold quality
body of uterus	UBERON:0009853	53.43	gold quality
hair follicle	UBERON:0002073	52.72	gold quality
deltoid	UBERON:0001476	52.62	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SRY

miRNA regulators (miRDB)

31 targeting MSH4, 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-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-2053	99.57	69.15	1635
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-4452	99.50	68.45	1493
HSA-MIR-183-3P	99.41	69.41	1598
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-3675-3P	99.09	67.70	968
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-8066	99.05	68.66	1532
HSA-MIR-4521	97.73	67.64	684

Literature-anchored findings (GeneRIF, showing 18)

• Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha (PMID:11948175)
• The different properties associated with these two hMSH5 variants underscore the potential functional diversity of the human hMSH5 gene. (PMID:15907804)
• the GPS2 might function in concert with hMSH4-hMSH5 during the process of homologous recombination. (PMID:16122992)
• A review of the properties and functional roles of MSH4. (PMID:17127347)
• Dimerization of MSH4 and MSH5 facilitates their nuclear localization suggesting that dimerization may regulate the intracellular trafficking of these proteins. (PMID:17869244)
• Data have identified the interaction region between the individual subunits of hMSH4-hMSH5 that are likely involved in clamp formation and show that each subunit of the heterodimer binds ATP. (PMID:17977839)
• Data show that there is no association between MSH4 gene mutation and premature ovarian failure. (PMID:18166824)
• mutation analysis of SYCP3, DNMT3L and MSH4 in patients with maturation arrest of spermatogenesis and couples with recurrent miscarriages (PMID:21126912)
• Our current study has revealed a role for hMSH4 in the maintenance of genomic stability by suppressing NHEJ-mediated DSB repair. (PMID:23725059)
• hMSH4 interacts with HDAC3. (PMID:24145748)
• inactivation of MSH4 in germ cells may have played a role in the acquisition of additional TP53 and LATS1 germline mutations in a Li-Fraumeni family (PMID:25041856)
• Study describes the first MSH4 mutation associated with POI and increases the number of meiotic/DNA repair genes formally implicated as being responsible for this condition. (PMID:28541421)
• Semiquantitative promoter methylation of MLH1 and MSH2 genes and their impact on sperm DNA fragmentation and chromatin condensation in infertile men. (PMID:33112435)
• Rare missense variant in MSH4 associated with primary gonadal failure in both 46, XX and 46, XY individuals. (PMID:33448284)
• Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes. (PMID:34755185)
• Novel bi-allelic MSH4 variants causes meiotic arrest and non-obstructive azoospermia. (PMID:35090489)
• Identification of compound heterozygous variants in MSH4 as a novel genetic cause of diminished ovarian reserve. (PMID:37620942)
• A novel homozygote nonsense variant of MSH4 leads to primary ovarian insufficiency and non-obstructive azoospermia. (PMID:38175272)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	msh4	ENSDARG00000075826
mus_musculus	Msh4	ENSMUSG00000005493
rattus_norvegicus	Msh4	ENSRNOG00000010431
caenorhabditis_elegans		WBGENE00001872

Paralogs (4): MSH2 (ENSG00000095002), MSH3 (ENSG00000113318), MSH6 (ENSG00000116062), MSH5 (ENSG00000204410)

Protein

Protein identifiers

MutS protein homolog 4 — O15457 (reviewed: O15457)

All UniProt accessions (1): O15457

UniProt curated annotations — full annotation on UniProt →

Function. Involved in meiotic recombination. Required for reciprocal recombination and proper segregation of homologous chromosomes at meiosis.

Subunit / interactions. Heterooligomer of MSH4 and MSH5.

Subcellular location. Chromosome.

Tissue specificity. Highly expressed in testis. Also expressed in the ovary.

Disease relevance. Spermatogenic failure 2 (SPGF2) [MIM:108420] An autosomal recessive disorder characterized by male infertility due to non-obstructive azoospermia. Testicular histopathology reveals no round spermatids or spermatozoa in the seminiferous tubules of SPGF2 patients, consistent with meiotic arrest. The disease is caused by variants affecting the gene represented in this entry. Premature ovarian failure 20 (POF20) [MIM:619938] A form of premature ovarian failure, an ovarian disorder defined as the cessation of ovarian function under the age of 40 years. It is characterized by oligomenorrhea or amenorrhea, in the presence of elevated levels of serum gonadotropins and low estradiol. POF20 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the DNA mismatch repair MutS family.

RefSeq proteins (1): NP_002431* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000432	DNA_mismatch_repair_MutS_C	Domain
IPR007696	DNA_mismatch_repair_MutS_core	Domain
IPR007860	DNA_mmatch_repair_MutS_con_dom	Domain
IPR007861	DNA_mismatch_repair_MutS_clamp	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036187	DNA_mismatch_repair_MutS_sf	Homologous_superfamily
IPR036678	MutS_con_dom_sf	Homologous_superfamily
IPR045076	MutS	Family

Pfam: PF00488, PF05188, PF05190, PF05192

UniProt features (24 total): sequence variant 13, sequence conflict 5, region of interest 2, compositionally biased region 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15457-F1	75.12	0.27

Functional residue map

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

Ligand- & substrate-binding residues (1): 680–687

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-912446	Meiotic recombination
R-HSA-1474165	Reproduction
R-HSA-1500620	Meiosis
R-HSA-1640170	Cell Cycle

MSigDB gene sets: 171 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, REACTOME_MEIOTIC_RECOMBINATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_MALE_GAMETE_GENERATION, KAUFFMANN_DNA_REPAIR_GENES, MARTINEZ_RB1_TARGETS_UP, GOBP_OVARIAN_FOLLICLE_DEVELOPMENT, GOBP_ORGANELLE_FISSION, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, BLALOCK_ALZHEIMERS_DISEASE_UP, MODULE_99, GOBP_DNA_DAMAGE_RESPONSE, GOBP_FEMALE_SEX_DIFFERENTIATION, GOBP_CHROMOSOME_ORGANIZATION_INVOLVED_IN_MEIOTIC_CELL_CYCLE

GO Biological Process (7): ovarian follicle development (GO:0001541), mismatch repair (GO:0006298), homologous chromosome pairing at meiosis (GO:0007129), reciprocal meiotic recombination (GO:0007131), spermatogenesis (GO:0007283), female gamete generation (GO:0007292), meiotic cell cycle (GO:0051321)

GO Molecular Function (7): DNA binding (GO:0003677), double-stranded DNA binding (GO:0003690), ATP binding (GO:0005524), mismatched DNA binding (GO:0030983), ATP-dependent DNA damage sensor activity (GO:0140664), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (6): synaptonemal complex (GO:0000795), nucleus (GO:0005634), chromosome (GO:0005694), recombination nodule (GO:0005713), condensed chromosome (GO:0000793), condensed nuclear chromosome (GO:0000794)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Meiosis	1
Reproduction	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
female gonad development	1
anatomical structure development	1
DNA repair	1
homologous chromosome segregation	1
chromosome organization involved in meiotic cell cycle	1
meiosis I	1
reciprocal homologous recombination	1
meiotic cell cycle process	1
developmental process involved in reproduction	1
male gamete generation	1
gamete generation	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
nucleic acid binding	1
DNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
double-stranded DNA binding	1
ATP-dependent activity, acting on DNA	1
DNA damage sensor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
synaptonemal structure	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
condensed nuclear chromosome	1
cellular anatomical structure	1
chromosome	1
nuclear chromosome	1
condensed chromosome	1
nucleus	1

Protein interactions and networks

STRING

1588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSH4	MSH5	O43196	993
MSH4	HFM1	A2PYH4	981
MSH4	MLH3	P49751	960
MSH4	SYCP3	Q8IZU3	946
MSH4	HORMAD1	Q86X24	938
MSH4	HORMAD2	Q8N7B1	929
MSH4	RAD51	Q06609	877
MSH4	SPO11	Q9Y5K1	875
MSH4	C1orf146	Q5VVC0	861
MSH4	MLH1	P40692	856
MSH4	VBP1	P61758	827
MSH4	SLC39A1	Q9NY26	822
MSH4	RNF212	Q495C1	816
MSH4	TEX11	Q8IYF3	811
MSH4	PMS1	P54277	809

IntAct

14 interactions, top by confidence:

A	B	Type	Score
MSH5	MSH4	psi-mi:“MI:0915”(physical association)	0.630
MSH4	MSH5	psi-mi:“MI:0915”(physical association)	0.630
MSH4	EIF3F	psi-mi:“MI:0915”(physical association)	0.580
EIF3F	MSH4	psi-mi:“MI:0915”(physical association)	0.580
CFTR	MSH4	psi-mi:“MI:0915”(physical association)	0.370
JAZF1	TNPO2	psi-mi:“MI:0914”(association)	0.350

BioGRID (45): MSH5 (Reconstituted Complex), MSH5 (Affinity Capture-Western), EIF3F (Two-hybrid), MSH4 (Two-hybrid), EIF3F (Affinity Capture-Western), MSH4 (Affinity Capture-Western), MSH4 (Reconstituted Complex), RAD51 (Two-hybrid), DMC1 (Two-hybrid), MSH5 (Two-hybrid), RAD51 (Reconstituted Complex), DMC1 (Reconstituted Complex), MSH4 (Reconstituted Complex), VBP1 (Two-hybrid), MSH4 (Two-hybrid)

ESM2 similar proteins: A1DCB2, A2R1F6, A5PF48, B0YCF6, D3ZG52, D3ZVK1, E1BMP7, F4IFF3, F4JEP5, F4JP48, I0IUP3, O15457, O23617, O24617, O43196, O74773, O80738, O94065, O95573, P13705, P20585, P25847, P40965, P43248, P51530, Q0CPP9, Q0UXL8, Q0WUI9, Q1DQ73, Q1EG27, Q2UT70, Q4WGB7, Q5B6T1, Q5R668, Q5ZKG3, Q5ZPI9, Q63151, Q6DNF4, Q6MG62, Q6ZD95

Diamond homologs: A1BHN5, A1K764, A1V5I2, A1VDD9, A1WRJ3, A1WXK9, A2SAW7, A3ML57, A3NWZ4, A3PFD3, A4VJN9, A5CDU2, A5FQC0, A5UZK7, A6V1G8, A6W1Q6, A7GE45, A7HMG4, A7MTT8, A7NPT5, A8AZU4, A8F164, A8FDH3, A8FST7, A8GMX2, A8H1T4, A8I275, A8ZXH5, B0S1C1, B0TK13, B1KPS7, B1LQ55, B2SXQ9, B3CQY2, B3EEE1, B4UCY7, B5FAC8, B7NT79, B7VK59, B8CJQ5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MSH4	“form complex”	“MutSgamma meiotic recombination complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	7
Uncertain significance	127
Likely benign	4
Benign	8

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1256044	NM_002440.4(MSH4):c.2222_2225del (p.Lys741fs)	Pathogenic
1256045	NM_002440.4(MSH4):c.2728C>T (p.Arg910Ter)	Pathogenic
1693499	NM_002440.4(MSH4):c.2355+1G>A	Pathogenic
1693500	NM_002440.4(MSH4):c.1552C>T (p.Gln518Ter)	Pathogenic
1693502	NM_002440.4(MSH4):c.805_812del (p.Val269fs)	Pathogenic
1693503	NM_002440.4(MSH4):c.1950G>A (p.Trp650Ter)	Pathogenic
1693504	NM_002440.4(MSH4):c.2179del (p.Asp727fs)	Pathogenic
1255997	NM_002440.4(MSH4):c.1063A>G (p.Ile355Val)	Likely pathogenic
1256001	NM_002440.4(MSH4):c.2374A>G (p.Thr792Ala)	Likely pathogenic
1256012	NM_002440.4(MSH4):c.1855A>G (p.Met619Val)	Likely pathogenic
1256043	NM_002440.4(MSH4):c.1025C>T (p.Thr342Ile)	Likely pathogenic
992887	NM_002440.4(MSH4):c.1453C>T (p.Gln485Ter)	Likely pathogenic
992888	NM_002440.4(MSH4):c.1686del (p.Lys562_Val563insTer)	Likely pathogenic
992889	NM_002440.4(MSH4):c.2198C>A (p.Ser733Ter)	Likely pathogenic

SpliceAI

3963 predictions. Top by Δscore:

Variant	Effect	Δscore
1:75803878:GTTA:G	donor_gain	1.0000
1:75803879:TTAT:T	donor_gain	1.0000
1:75806980:GCTTC:G	acceptor_gain	1.0000
1:75822437:A:G	acceptor_gain	1.0000
1:75848207:A:AG	acceptor_gain	1.0000
1:75848208:G:GA	acceptor_gain	1.0000
1:75848208:GTT:G	acceptor_gain	1.0000
1:75848208:GTTAT:G	acceptor_gain	1.0000
1:75877029:A:AG	donor_gain	1.0000
1:75878134:T:TA	acceptor_gain	1.0000
1:75878314:AGCAG:A	donor_loss	1.0000
1:75878316:CAG:C	donor_loss	1.0000
1:75878317:AGG:A	donor_loss	1.0000
1:75878318:GG:G	donor_loss	1.0000
1:75878319:G:GA	donor_loss	1.0000
1:75878320:T:A	donor_loss	1.0000
1:75880154:G:GG	donor_gain	1.0000
1:75883619:A:G	acceptor_gain	1.0000
1:75898024:G:GT	donor_gain	1.0000
1:75898058:G:T	donor_gain	1.0000
1:75912688:A:AG	acceptor_gain	1.0000
1:75801080:A:AG	donor_gain	0.9900
1:75803724:A:G	acceptor_gain	0.9900
1:75803726:TTTA:T	acceptor_loss	0.9900
1:75803727:TTAG:T	acceptor_loss	0.9900
1:75803729:A:AC	acceptor_loss	0.9900
1:75803729:A:AG	acceptor_gain	0.9900
1:75803730:G:A	acceptor_loss	0.9900
1:75803730:G:GG	acceptor_gain	0.9900
1:75803730:GGTTC:G	acceptor_gain	0.9900

AlphaMissense

6095 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:75815069:G:A	G250R	0.999
1:75815069:G:C	G250R	0.999
1:75822471:T:C	L351P	0.999
1:75878283:G:C	R502T	0.999
1:75878284:A:C	R502S	0.999
1:75878284:A:T	R502S	0.999
1:75807068:G:A	G172E	0.998
1:75807073:G:C	A174P	0.998
1:75815046:G:C	R242T	0.998
1:75815046:G:T	R242M	0.998
1:75815047:G:C	R242S	0.998
1:75815047:G:T	R242S	0.998
1:75816399:C:A	A281D	0.998
1:75822458:G:T	G347W	0.998
1:75878243:G:C	A489P	0.998
1:75878244:C:A	A489E	0.998
1:75878271:T:C	L498P	0.998
1:75878279:G:C	A501P	0.998
1:75878291:T:G	Y505D	0.998
1:75879060:T:C	F537L	0.998
1:75879062:T:A	F537L	0.998
1:75879062:T:G	F537L	0.998
1:75883753:G:A	G680E	0.998
1:75883771:A:T	K686I	0.998
1:75889251:G:A	G703E	0.998
1:75889260:T:A	V706D	0.998
1:75807040:G:A	G163R	0.997
1:75807040:G:C	G163R	0.997
1:75807040:G:T	G163W	0.997
1:75815070:G:A	G250E	0.997

dbSNP variants (sampled 300 via entrez): RS1000020497 (1:75835104 C>T), RS1000031869 (1:75910351 G>T), RS1000049858 (1:75904531 T>TG), RS1000078829 (1:75872321 G>A), RS1000143208 (1:75823624 C>G), RS1000212151 (1:75871785 A>G), RS1000221255 (1:75825041 A>G), RS1000230331 (1:75903169 T>C), RS1000240122 (1:75897534 T>G), RS1000338300 (1:75809694 G>A), RS1000362095 (1:75829327 C>T), RS1000376777 (1:75859482 G>A), RS1000403372 (1:75834761 C>T), RS1000429326 (1:75859815 T>C), RS1000550396 (1:75811114 G>A,C,T)

Disease associations

OMIM: gene MIM:602105 | disease phenotypes: MIM:108420, MIM:619938

GenCC curated gene-disease

Disease	Classification	Inheritance
premature ovarian failure 20	Strong	Autosomal recessive

Mondo (4): spermatogenic failure 2 (MONDO:0007161), premature ovarian failure 20 (MONDO:0030975), premature menopause (MONDO:0001119), oligospermia (MONDO:0001913)

Orphanet (1): Rare genetic premature ovarian failure (Orphanet:485382)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000027	Azoospermia
HP:0000062	Ambiguous genitalia
HP:0000133	Gonadal dysgenesis
HP:0000144	Decreased fertility
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000786	Primary amenorrhea
HP:0000798	Oligozoospermia
HP:0000823	Delayed puberty
HP:0000837	Increased circulating gonadotropin level
HP:0000869	Secondary amenorrhea
HP:0000938	Osteopenia
HP:0001166	Arachnodactyly
HP:0001251	Ataxia
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002206	Pulmonary fibrosis
HP:0002225	Sparse pubic hair
HP:0002750	Delayed skeletal maturation
HP:0003251	Male infertility
HP:0004322	Short stature
HP:0004349	Reduced bone mineral density
HP:0005625	Osteoporosis of vertebrae
HP:0008209	Premature ovarian insufficiency
HP:0008214	Decreased serum estradiol
HP:0008222	Female infertility
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0008684	Aplasia/hypoplasia of the uterus
HP:0009888	Abnormality of secondary sexual hair
HP:0010311	Aplasia/Hypoplasia of the breasts

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST003025_13	Attention function in attention deficit hyperactive disorder	4.000000e-06
GCST003518_98	Daytime sleep phenotypes	3.000000e-06
GCST006249_15	Serum metabolite levels	8.000000e-28
GCST006249_16	Serum metabolite levels	1.000000e-24
GCST006249_5	Serum metabolite levels	4.000000e-32
GCST006249_6	Serum metabolite levels	6.000000e-30
GCST006249_71	Serum metabolite levels	3.000000e-19
GCST006249_72	Serum metabolite levels	1.000000e-18
GCST006249_81	Serum metabolite levels	5.000000e-16
GCST006249_82	Serum metabolite levels	4.000000e-15
GCST010396_168	Gut microbiota (bacterial taxa, hurdle binary method)	3.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007636	attention function measurement
EFO:0007828	daytime rest measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D009845	Oligospermia	C12.100.500.430.508; C12.100.750.700.508; C12.200.294.430.508

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Smoke	increases abundance, increases expression, decreases expression	2
aristolochic acid I	increases expression	1
bisphenol A	decreases expression	1
sodium arsenite	decreases expression, increases reaction	1
benzo(e)pyrene	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	increases expression	1
Decitabine	increases expression	1
Glyphosate	affects methylation	1
Air Pollutants	increases abundance, increases expression	1
Coal	increases abundance, increases expression	1
Estradiol	decreases expression, increases reaction	1
Formaldehyde	increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Methapyrilene	decreases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT02307994	PHASE4	UNKNOWN	Clinical Research on Effectiveness and Safety of Treatment of Severe Oligospermia or Azoospermia With uFSH
NCT05320536	PHASE4	UNKNOWN	A Clinical Study of Gulingji Capsule in the Treatment of Idiopathic Oligospermia, Asthenia, and Teratozoospermia
NCT06260007	PHASE4	RECRUITING	Efficacy and Safety Study of Products Based on Tribulus Terrestris, L. in Men With Oligospermia
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00440180	PHASE3	TERMINATED	Aromatase Inhibitors in the Treatment of Male Infertility
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT01409837	PHASE2	COMPLETED	The Effect and Safety of Lisinopril in Non-hypertensive Men With Infertility From Low Sperm Count
NCT02234206	PHASE2	COMPLETED	A Clinical Trial to Study the Safety and Efficacy of Chandrakanthi Choornam in Patients With Low Sperm Count
NCT07481370	PHASE2	ENROLLING_BY_INVITATION	Isotretinoin vs hCG for Male Infertility Due to Low or Absent Sperm
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT05158114	PHASE1	WITHDRAWN	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for Testicular Injury and Oligospermia
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.