MEI4

Summary

MEI4 (meiotic double-stranded break formation protein 4, HGNC:43638) is a protein-coding gene on chromosome 6q14.1, encoding Meiosis-specific protein MEI4 (A8MW99). Required for DNA double-strand breaks (DSBs) formation in unsynapsed regions during meiotic recombination.

Predicted to be involved in meiosis I cell cycle process; oogenesis; and spermatogenesis. Predicted to be located in chromosome. Predicted to be active in lateral element.

Source: NCBI Gene 101928601 — RefSeq curated summary.

At a glance

• Gene–disease (curated): infertility disorder (Strong, GenCC)
• GWAS associations: 5
• MANE Select transcript: NM_001322247

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:43638
Approved symbol	MEI4
Name	meiotic double-stranded break formation protein 4
Location	6q14.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000269964
Ensembl biotype	protein_coding
OMIM	618417
Entrez	101928601

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000602452, ENST00000649759, ENST00000684080

RefSeq mRNA: 2 — MANE Select: NM_001322247 NM_001282136, NM_001322247

CCDS: CCDS64463

Canonical transcript exons

ENST00000684080 — 5 exons

Exon	Start	End
ENSE00001700373	77690658	77690903
ENSE00001742538	77761130	77761665
ENSE00003287050	77828931	77829062
ENSE00003917806	77653039	77653092
ENSE00003917873	77923089	77927045

Expression profiles

Bgee: expression breadth broad, 52 present calls, max score 80.10.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0044 / max 3.9728, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
68654	0.0044	3

Top tissues by expression

111 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	80.10	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	70.85	gold quality
islet of Langerhans	UBERON:0000006	69.88	gold quality
pancreas	UBERON:0001264	64.73	gold quality
adrenal tissue	UBERON:0018303	63.05	gold quality
adult mammalian kidney	UBERON:0000082	62.96	gold quality
body of pancreas	UBERON:0001150	61.90	gold quality
testis	UBERON:0000473	61.59	gold quality
right testis	UBERON:0004534	61.14	gold quality
left testis	UBERON:0004533	60.85	gold quality
kidney	UBERON:0002113	59.56	gold quality
adenohypophysis	UBERON:0002196	56.25	gold quality
pituitary gland	UBERON:0000007	55.59	gold quality
right adrenal gland	UBERON:0001233	54.53	gold quality
right adrenal gland cortex	UBERON:0035827	54.52	gold quality
adrenal gland	UBERON:0002369	54.38	gold quality
left adrenal gland cortex	UBERON:0035825	53.81	gold quality
left adrenal gland	UBERON:0001234	53.66	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	53.65	gold quality
right atrium auricular region	UBERON:0006631	53.59	gold quality
cortex of kidney	UBERON:0001225	53.26	gold quality
thyroid gland	UBERON:0002046	53.02	gold quality
left lobe of thyroid gland	UBERON:0001120	52.97	gold quality
liver	UBERON:0002107	52.32	gold quality
metanephros cortex	UBERON:0010533	52.18	gold quality
gall bladder	UBERON:0002110	51.89	gold quality
right lobe of thyroid gland	UBERON:0001119	51.49	gold quality
ventricular zone	UBERON:0003053	51.24	gold quality
right lobe of liver	UBERON:0001114	51.04	gold quality
stromal cell of endometrium	CL:0002255	49.68	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

133 targeting MEI4, 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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-335-3P	99.93	73.36	4958

Literature-anchored findings (GeneRIF, showing 1)

• Bi-allelic missense variants in MEI4 cause preimplantation embryonic arrest and female infertility. (PMID:38252283)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mei4	ENSDARG00000043912
mus_musculus	Mei4	ENSMUSG00000043289
rattus_norvegicus	Mei4	ENSRNOG00000023794

Protein

Protein identifiers

Meiosis-specific protein MEI4 — A8MW99 (reviewed: A8MW99)

All UniProt accessions (1): A8MW99

UniProt curated annotations — full annotation on UniProt →

Function. Required for DNA double-strand breaks (DSBs) formation in unsynapsed regions during meiotic recombination. Probably acts by forming a complex with IHO1 and REC114, which activates DSBs formation in unsynapsed regions, an essential step to ensure completion of synapsis.

Subunit / interactions. Part of the MCD recombinosome complex, at least composed of IHO1, REC114 and MEI4. Forms a complex with REC114; the interaction is required for MEI4 stability. Interacts (via N-terminal domain) with REC114 (via C-terminal domain). Interacts with IHO1.

Subcellular location. Chromosome.

Similarity. Belongs to the MEI4L family.

RefSeq proteins (2): NP_001269065, NP_001309176* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR025888	MEI4	Family

Pfam: PF13971

UniProt features (4 total): region of interest 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A8MW99-F1	70.83	0.11

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 65 (showing top): GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_OOGENESIS, GOBP_MALE_GAMETE_GENERATION, GOBP_ORGANELLE_FISSION, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, GOBP_CHROMOSOME_ORGANIZATION_INVOLVED_IN_MEIOTIC_CELL_CYCLE, GOBP_FEMALE_GAMETE_GENERATION, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_HOMOLOGOUS_CHROMOSOME_SEGREGATION, GOBP_MEIOTIC_CELL_CYCLE_PROCESS, GOBP_HOMOLOGOUS_CHROMOSOME_PAIRING_AT_MEIOSIS, GOBP_NUCLEAR_CHROMOSOME_SEGREGATION, GOBP_MEIOTIC_CELL_CYCLE, GOCC_LATERAL_ELEMENT

GO Biological Process (6): DNA recombination (GO:0006310), homologous chromosome pairing at meiosis (GO:0007129), spermatogenesis (GO:0007283), meiotic DNA double-strand break formation (GO:0042138), oogenesis (GO:0048477), meiotic cell cycle (GO:0051321)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): lateral element (GO:0000800), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
homologous chromosome segregation	1
chromosome organization involved in meiotic cell cycle	1
developmental process involved in reproduction	1
male gamete generation	1
meiosis I cell cycle process	1
germ cell development	1
female gamete generation	1
cell cycle	1
sexual reproduction	1
reproductive process	1
meiotic nuclear division	1
binding	1
synaptonemal complex	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MEI4	REC114	Q7Z4M0	997
MEI4	CD151	P48509	980
MEI4	IHO1	Q8IYA8	913
MEI4	MEI1	Q5TIA1	793
MEI4	SPO11	Q9Y5K1	762
MEI4	ANKRD31	Q8N7Z5	743
MEI4	ADARB1	P78555	738
MEI4	HORMAD1	Q86X24	646
MEI4	TOP6BL	Q8N6T0	621
MEI4	SKIC8	Q9GZS3	620
MEI4	REC8	O95072	592
MEI4	PRDM9	Q9NQV7	546
MEI4	MAD2L2	Q9UI95	539
MEI4	BMP7	P18075	537
MEI4	HORMAD2	Q8N7B1	511

IntAct

118 interactions, top by confidence:

A	B	Type	Score
REC114	MEI4	psi-mi:“MI:0915”(physical association)	0.590
MEI4	REC114	psi-mi:“MI:0915”(physical association)	0.590
C19orf25	MEI4	psi-mi:“MI:0915”(physical association)	0.560
NME7	MEI4	psi-mi:“MI:0915”(physical association)	0.560
BAG4	MEI4	psi-mi:“MI:0915”(physical association)	0.560
TRIM59	MEI4	psi-mi:“MI:0915”(physical association)	0.560
MYO5B	MEI4	psi-mi:“MI:0915”(physical association)	0.560
MTMR9	MEI4	psi-mi:“MI:0915”(physical association)	0.560
CABP5	MEI4	psi-mi:“MI:0915”(physical association)	0.560
CPNE2	MEI4	psi-mi:“MI:0915”(physical association)	0.560
CDKN2D	MEI4	psi-mi:“MI:0915”(physical association)	0.560
GRB2	MEI4	psi-mi:“MI:0915”(physical association)	0.560
METTL21A	MEI4	psi-mi:“MI:0915”(physical association)	0.560
OSGIN1	MEI4	psi-mi:“MI:0915”(physical association)	0.560
TSSK3	MEI4	psi-mi:“MI:0915”(physical association)	0.560
MACO1	MEI4	psi-mi:“MI:0915”(physical association)	0.560
NGB	MEI4	psi-mi:“MI:0915”(physical association)	0.560
POLR1C	MEI4	psi-mi:“MI:0915”(physical association)	0.560
R3HDM2	MEI4	psi-mi:“MI:0915”(physical association)	0.560
CTTNBP2	MEI4	psi-mi:“MI:0915”(physical association)	0.560
AIRIM	MEI4	psi-mi:“MI:0915”(physical association)	0.560
CHAF1A	MEI4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (39): MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid), MEI4 (Two-hybrid)

ESM2 similar proteins: A0JM23, A4D1B5, A6NDU8, A8C754, A8MW99, A8Y5U1, O43149, O55036, O75901, O88480, P42695, P54274, P93820, Q14AT2, Q3U1D0, Q3UPC7, Q3URV1, Q4R7B1, Q5SSH7, Q5TIA1, Q5ZLS8, Q63517, Q642P2, Q68Y81, Q6P2C0, Q6TNU3, Q6ZQK0, Q86VV8, Q8AYS7, Q8BR90, Q8BRM6, Q8C6S9, Q8K1K4, Q8K2A7, Q8NG48, Q8R4Y8, Q8TDY2, Q8TEL6, Q8W4P9, Q91VB4

Diamond homologs: A8MW99, Q8BRM6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1340 predictions. Top by Δscore:

Variant	Effect	Δscore
6:77690899:GAGTG:G	donor_gain	1.0000
6:77690901:GTG:G	donor_gain	1.0000
6:77690905:T:A	donor_loss	1.0000
6:77923232:G:GT	donor_gain	1.0000
6:77690900:AGTG:A	donor_gain	0.9900
6:77690901:GTGG:G	donor_gain	0.9900
6:77690902:TG:T	donor_gain	0.9900
6:77690902:TGGT:T	donor_gain	0.9900
6:77690903:GG:G	donor_gain	0.9900
6:77690903:GGTG:G	donor_gain	0.9900
6:77690904:G:GG	donor_gain	0.9900
6:77761128:A:AG	acceptor_gain	0.9900
6:77761129:G:GG	acceptor_gain	0.9900
6:77761265:A:T	donor_gain	0.9900
6:77923239:G:GT	donor_gain	0.9900
6:77761124:TTTCA:T	acceptor_loss	0.9800
6:77761125:TTCA:T	acceptor_loss	0.9800
6:77761126:TCAG:T	acceptor_loss	0.9800
6:77761127:CAGG:C	acceptor_loss	0.9800
6:77761128:AG:A	acceptor_gain	0.9800
6:77761129:GG:G	acceptor_gain	0.9800
6:77761129:GGA:G	acceptor_gain	0.9800
6:77761129:GGAT:G	acceptor_gain	0.9800
6:77923199:TCATG:T	donor_gain	0.9800
6:77923201:A:AG	donor_gain	0.9800
6:77923263:G:GT	donor_gain	0.9800
6:77690906:GAGTA:G	donor_loss	0.9700
6:77761129:GGATA:G	acceptor_gain	0.9700
6:77816763:GACTT:G	donor_gain	0.9700
6:77816768:G:GG	donor_gain	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000003301 (6:77706218 G>A,C), RS1000015377 (6:77803820 C>G,T), RS1000041937 (6:77805808 GA>G,GAA), RS1000079841 (6:77822135 A>G), RS1000086450 (6:77838212 T>A), RS1000094105 (6:77799806 A>T), RS1000099961 (6:77700488 T>C), RS1000104222 (6:77690463 C>A), RS1000121546 (6:77831521 A>G), RS1000141165 (6:77892262 C>T), RS1000143489 (6:77662530 G>C), RS1000153997 (6:77729184 A>T), RS1000163877 (6:77827832 A>T), RS1000202386 (6:77747121 G>A,C), RS1000209781 (6:77729514 G>A)

Disease associations

OMIM: gene MIM:618417 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
infertility disorder	Strong	Semidominant

Mondo (1): infertility disorder (MONDO:0005047)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002936_3	Cadmium levels	5.000000e-06
GCST004795_3	Brain volume in infants (white matter)	9.000000e-07
GCST006976_119	Macular thickness	4.000000e-11
GCST011494_32	Daytime nap	3.000000e-06
GCST011743_44	HDL cholesterol levels in HIV infection	2.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008370	infant white matter volume measurement
EFO:0007828	daytime rest measurement
EFO:0004612	high density lipoprotein cholesterol measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007246	Infertility	C12.100.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

2 total (human), top 2 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01388907	PHASE4	COMPLETED	Efficacity Assessment of PREVADH® in Adhesion Prevention in Gynaecologic Surgery
NCT01430650	PHASE4	COMPLETED	Endometrial Priming for Embryo Transfer
NCT02607319	PHASE4	COMPLETED	Low Molecular Weight Heparin to Improve Pregnancy Outcome in Patients With Recurrent Implantation Failure
NCT03169166	PHASE4	COMPLETED	The Use of GnRH Agonist Trigger for Final Follicle Maturation in Women Undergoing Assisted Reproductive Technologies
NCT03177122	PHASE4	UNKNOWN	Myo-Inositol- Based Co-treatment in Women With PCOS Undergoing Assisted Reproductive Technology
NCT03477929	PHASE4	UNKNOWN	Cetrorelix and Ganirelix Flexible Protocol for (IVF)
NCT03619707	PHASE4	COMPLETED	Oral Versus Vaginal Progesterone in the Luteal Support in Cryo-warmed Embryo Transfer Cycles
NCT03846544	PHASE4	COMPLETED	Double Pick up in Poor Prognosis Women
NCT05725512	PHASE4	RECRUITING	Prednisolone Administration in Patients With Unexplained REcurrent MIscarriages
NCT06195163	PHASE4	NOT_YET_RECRUITING	TRAP Study: Testosterone for Androgen Receptor Polymorphism
NCT06763926	PHASE4	NOT_YET_RECRUITING	Intranasal Nafarelin For Triggering Oocyte Maturation
NCT00749853	PHASE3	SUSPENDED	Efficacy of Ovarian Stimulation Based on FSHR Genotype Status
NCT03238092	PHASE3	UNKNOWN	Comparison Between Testosterone and Estradiol Over the Homogenization of Follicular Cohort
NCT03803228	PHASE3	COMPLETED	Dual Ovarian Stimulation (DUOSTIM) for Poor Ovarian Responders
NCT04701034	PHASE2	COMPLETED	Intravenous Immunoglobulin and Prednisolone for RPL After ART.
NCT04850261	PHASE2	WITHDRAWN	Injection Free IVF
NCT06997900	PHASE2	RECRUITING	Menopur And Rekovelle Combination Study Version 2.0
NCT01330771	Not specified	COMPLETED	Assessment of the Therapeutic Utility of r-FSH in Association With hMG-HP
NCT01330784	Not specified	COMPLETED	Assessment of the Therapeutic Utility of hMG-HP
NCT01331720	Not specified	COMPLETED	Assessment of the Effectiveness and Tolerability of Ovarian Hyperstimulation
NCT01331733	Not specified	COMPLETED	Comparative Assessment of the Clinical Utility of Ovarian Stimulation With Menotropin Versus Menotropin Plus GnRH Antagonist
NCT01406964	Not specified	COMPLETED	Chlamidia Antibodies Test for Tubal Factor Screening
NCT01533350	Not specified	COMPLETED	Receptivity Assessment of Homogeneous Endometrium in Late Follicle Phase
NCT01955356	Not specified	COMPLETED	Embryo Implantation After Induced Endometrial Injury
NCT02081924	Not specified	RECRUITING	Reproductive Hormones During Sustained Administration of Kisspeptin
NCT02648555	Not specified	UNKNOWN	A Lifestyle Intervention to Improve in Vitro Fertilization Results
NCT03007043	Not specified	COMPLETED	Genetic Variation in Gonadotropin and Gonadotropin Receptor Genes and Suboptimal Response
NCT03023774	Not specified	COMPLETED	Use of Gcsf in Patients With Recurrent Ivf/Icsi Failure
NCT03065114	Not specified	COMPLETED	Retrospective Study on Clinical Results of Preimplantation Genetic Screening at Different Embryo Stage
NCT03085212	Not specified	ACTIVE_NOT_RECRUITING	Strategies for Pregnancy Achievement
NCT03085433	Not specified	COMPLETED	Sperm Selection by Microfluidic Separation Improves Embryo Quality
NCT03118219	Not specified	COMPLETED	Positive Adjustment Coping Intervention
NCT03156374	Not specified	COMPLETED	Timing Frozen Embryo Transfer by Following Two Different Methods
NCT03161873	Not specified	COMPLETED	Cycle and Pregnancy Monitoring With Wearable Sensor Technology (AVA)
NCT03173404	Not specified	COMPLETED	Benefits of Hysteroscopy Prior to Performing a Cycle of in Vitro Fertilization/Intracytoplasmic Sperm Injection
NCT03180827	Not specified	ACTIVE_NOT_RECRUITING	Female Fertility Preservation Using Ovarian Tissue Cryopreservation Before Highly Gonadotoxic Cancer Treatment
NCT03180918	Not specified	RECRUITING	Male Fertility Preservation Using Cryopreservation of Testicular Tissue Before Highly Gonadotoxic Cancer Treatment
NCT03250195	Not specified	TERMINATED	Non-invasive Detection of Male Infertility With FDG-PET/MRI (Spectroscopy and DWI)
NCT03269916	Not specified	UNKNOWN	Fertility and Ovarian Reserve Function in the Patient With Inflammatory Bowel Disease
NCT03290911	Not specified	COMPLETED	Retrospective Trial on Low Prognosis Infertile Patients