MIF4GD

Summary

MIF4GD (MIF4G domain containing, HGNC:24030) is a protein-coding gene on chromosome 17q25.1, encoding MIF4G domain-containing protein (A9UHW6). Functions in replication-dependent translation of histone mRNAs which differ from other eukaryotic mRNAs in that they do not end with a poly-A tail but a stem-loop.

This gene encodes a protein which interacts with the N-terminus of the stem-loop binding protein (SLBP) and the 3’ end of histone mRNA. This interaction facilitates the activation of histone mRNA translation. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 57409 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 50 total
• MANE Select transcript: NM_001370592

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24030
Approved symbol	MIF4GD
Name	MIF4G domain containing
Location	17q25.1
Locus type	gene with protein product
Status	Approved
Aliases	AD023, MGC45027, SLIP1
Ensembl gene	ENSG00000125457
Ensembl biotype	protein_coding
OMIM	612072
Entrez	57409

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 32 protein_coding, 3 retained_intron

ENST00000245551, ENST00000325102, ENST00000577240, ENST00000577542, ENST00000578305, ENST00000579119, ENST00000579194, ENST00000579297, ENST00000579612, ENST00000580099, ENST00000580571, ENST00000580717, ENST00000581777, ENST00000618645, ENST00000649805, ENST00000678201, ENST00000886601, ENST00000886602, ENST00000886603, ENST00000886604, ENST00000886605, ENST00000886606, ENST00000886607, ENST00000886608, ENST00000886609, ENST00000886610, ENST00000886611, ENST00000886612, ENST00000886613, ENST00000886614, ENST00000886615, ENST00000941498, ENST00000941499, ENST00000941500, ENST00000941501

RefSeq mRNA: 12 — MANE Select: NM_001370592 NM_001242498, NM_001242500, NM_001242501, NM_001363806, NM_001365751, NM_001365752, NM_001365753, NM_001365754, NM_001365755, NM_001370592, NM_001411093, NM_020679

CCDS: CCDS11719, CCDS56044, CCDS58598, CCDS92390, CCDS92391

Canonical transcript exons

ENST00000325102 — 6 exons

Exon	Start	End
ENSE00000855713	75267746	75267901
ENSE00000855714	75268083	75268192
ENSE00002705855	75271144	75271231
ENSE00002723024	75266228	75266967
ENSE00003482026	75270114	75270245
ENSE00003519892	75267538	75267630

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 95.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.3414 / max 104.6527, expressed in 1769 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168055	6.6239	1634
168057	2.3574	1361
168056	0.7849	499
168054	0.2628	130
168053	0.1903	85
168052	0.1222	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	95.76	gold quality
saphenous vein	UBERON:0007318	95.21	gold quality
granulocyte	CL:0000094	93.70	gold quality
nipple	UBERON:0002030	93.29	gold quality
gastrocnemius	UBERON:0001388	93.15	gold quality
penis	UBERON:0000989	92.95	gold quality
tibialis anterior	UBERON:0001385	92.64	gold quality
superior surface of tongue	UBERON:0007371	92.57	gold quality
muscle of leg	UBERON:0001383	92.50	gold quality
tibial artery	UBERON:0007610	92.47	gold quality
popliteal artery	UBERON:0002250	92.46	gold quality
medial globus pallidus	UBERON:0002477	92.21	gold quality
quadriceps femoris	UBERON:0001377	92.11	gold quality
tendon of biceps brachii	UBERON:0008188	91.92	gold quality
endothelial cell	CL:0000115	91.90	gold quality
tongue	UBERON:0001723	91.86	gold quality
aorta	UBERON:0000947	91.79	gold quality
vastus lateralis	UBERON:0001379	91.75	gold quality
mucosa of stomach	UBERON:0001199	91.66	gold quality
pharyngeal mucosa	UBERON:0000355	91.46	gold quality
lymph node	UBERON:0000029	91.39	gold quality
right coronary artery	UBERON:0001625	91.38	gold quality
parotid gland	UBERON:0001831	91.26	gold quality
kidney epithelium	UBERON:0004819	91.22	gold quality
body of tongue	UBERON:0011876	91.17	gold quality
leukocyte	CL:0000738	91.05	gold quality
oocyte	CL:0000023	90.96	gold quality
ascending aorta	UBERON:0001496	90.94	gold quality
thoracic aorta	UBERON:0001515	90.94	gold quality
coronary artery	UBERON:0001621	90.88	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-110499	no	819.75
E-MTAB-6524	no	83.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting MIF4GD, 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-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-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-5571-5P	99.49	66.99	1764
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-593-5P	99.34	69.50	965

Literature-anchored findings (GeneRIF, showing 5)

• downregulation of endogenous SLIP1 reduces the rate of translation of endogenous histone mRNA and also reduces cell viability. (PMID:18025107)
• INT6 and MIF4GD were observed to colocalize in cytoplasmic foci. It was concluded that INT6, by establishing interactions with MIF4GD and SLBP, plays an important role in translation of poly(A) minus histone mRNAs. (PMID:22532700)
• Data suggest that oligomerization and SLBP phosphorylation regulate SLBP-SLIP1-histone-mRNA complex formation/disassociation; sequential and ordered assembly is required. (PMID:23286197)
• This paper describes the oligomeric state of SLIP1 and the SLIP1-SLBP complex and how it is regulated by SLBP phosphorylation. Using alanine scanning mutagenesis, the authors demonstrate that the binding site on SLIP1 for SLBP lies close to the dimer interface. A single-point mutant near the SLIP1 homodimer interface abolished interaction with SLBP in vitro and reduced the abundance of histone mRNA in vivo. (PMID:23286197)
• Results suggest that MIF4GD is a potential regulator of p27-dependent cell proliferation in HCC. (PMID:24336329)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	mif4gda	ENSDARG00000102080
danio_rerio	mif4gdb	ENSDARG00000102578
mus_musculus	Mif4gd	ENSMUSG00000020743
rattus_norvegicus	Mif4gd	ENSRNOG00000081690
drosophila_melanogaster	CG13124	FBGN0032156
caenorhabditis_elegans		WBGENE00018405

Paralogs (2): CTIF (ENSG00000134030), PAIP1 (ENSG00000172239)

Protein

Protein identifiers

MIF4G domain-containing protein — A9UHW6 (reviewed: A9UHW6)

Alternative names: SLBP-interacting protein 1

All UniProt accessions (12): A9UHW6, A0A0S2Z5K9, A0A0S2Z5S7, A0A0S2Z5T5, A0A3B3IU65, J3KSB8, J3KSU6, J3QKW3, J3QLD1, J3QLJ5, J3QLN4, J3QRZ6

UniProt curated annotations — full annotation on UniProt →

Function. Functions in replication-dependent translation of histone mRNAs which differ from other eukaryotic mRNAs in that they do not end with a poly-A tail but a stem-loop. May participate in circularizing those mRNAs specifically enhancing their translation.

Subunit / interactions. Interacts with EIF4G1, EIF4G2 and SLBP; probably tethered by SLBP to the 3’-end of mRNAs ending with the histone stem-loop, it also interacts with EIF4G1 which is bound to their 5’-end.

Subcellular location. Cytoplasm. Nucleus.

Miscellaneous. Depletion of MIF4GD results in cell death and reduced histone mRNA translation.

Similarity. Belongs to the MIF4GD family.

Isoforms (3)

UniProt ID	Names	Canonical?
A9UHW6-1	1	yes
A9UHW6-2	2
A9UHW6-3	3

RefSeq proteins (12): NP_001229427, NP_001229429, NP_001229430, NP_001350735, NP_001352680, NP_001352681, NP_001352682, NP_001352683, NP_001352684, NP_001357521, NP_001398022, NP_065730 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003890	MIF4G-like_typ-3	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR051367	mRNA_TranslReg/HistoneTransl	Family

Pfam: PF02854

UniProt features (4 total): splice variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A9UHW6-F1	92.03	0.83

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 157 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOBP_TRANSLATIONAL_INITIATION, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOMF_TRANSLATION_REGULATOR_ACTIVITY, MARTINEZ_RB1_TARGETS_UP, MODULE_256, GOBP_CYTOPLASMIC_TRANSLATIONAL_INITIATION, MODULE_480, DOUGLAS_BMI1_TARGETS_DN, HU_GENOTOXIN_ACTION_DIRECT_VS_INDIRECT_24HR, ACEVEDO_LIVER_CANCER_UP, MODULE_333, NIKOLSKY_BREAST_CANCER_17Q21_Q25_AMPLICON, MODULE_427

GO Biological Process (4): cap-dependent translational initiation (GO:0002191), regulation of translational initiation (GO:0006446), regulation of translation (GO:0006417), positive regulation of translation (GO:0045727)

GO Molecular Function (4): RNA binding (GO:0003723), translation activator activity (GO:0008494), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (6): nucleolus (GO:0005730), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), cytosol (GO:0005829), histone mRNA stem-loop binding complex (GO:0062073), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
regulation of translation	2
translation	2
cellular anatomical structure	2
intracellular membrane-bounded organelle	2
cytoplasmic translational initiation	1
cap-dependent translation initiation factor activity	1
translational initiation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
nucleic acid binding	1
translation regulator activity	1
positive regulation of translation	1
protein binding	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
endomembrane system	1
protein-containing complex	1

Protein interactions and networks

STRING

428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MIF4GD	SLBP	Q14493	988
MIF4GD	EIF4G1	Q04637	825
MIF4GD	PABPC1	P11940	559
MIF4GD	EIF4E	P06730	550
MIF4GD	NCBP1	Q09161	547
MIF4GD	EIF4A1	P04765	532
MIF4GD	TNFAIP1	Q13829	506
MIF4GD	PCNX3	Q9H6A9	505
MIF4GD	GLE1	Q53GS7	473
MIF4GD	PAIP1	Q9H074	447
MIF4GD	UPF1	Q92900	396
MIF4GD	EIF3G	O75821	392
MIF4GD	MPHOSPH9	Q99550	386
MIF4GD	ZNF473	Q8WTR7	380
MIF4GD	STARD9	Q9P2P6	378

IntAct

70 interactions, top by confidence:

A	B	Type	Score
MIF4GD	DDX19B	psi-mi:“MI:0915”(physical association)	0.870
DDX19B	MIF4GD	psi-mi:“MI:0915”(physical association)	0.870
DDX19B	MIF4GD	psi-mi:“MI:0407”(direct interaction)	0.870
DDX19B	MIF4GD	psi-mi:“MI:0914”(association)	0.870
MIF4GD	DDX19A	psi-mi:“MI:0915”(physical association)	0.860
DDX19A	MIF4GD	psi-mi:“MI:0915”(physical association)	0.860
DDX19A	MIF4GD	psi-mi:“MI:0914”(association)	0.860
MIF4GD	SLBP	psi-mi:“MI:0407”(direct interaction)	0.760
MIF4GD	SLBP	psi-mi:“MI:0915”(physical association)	0.760

BioGRID (70): MIF4GD (Two-hybrid), MIF4GD (Two-hybrid), MIF4GD (Two-hybrid), MIF4GD (Two-hybrid), CTIF (Affinity Capture-MS), KLK3 (Affinity Capture-MS), MIF4GD (Two-hybrid), MIF4GD (Two-hybrid), MIF4GD (Affinity Capture-MS), MIF4GD (Affinity Capture-MS), MIF4GD (Two-hybrid), MIF4GD (Affinity Capture-MS), MIF4GD (Affinity Capture-Western), MIF4GD (Two-hybrid), CTIF (Affinity Capture-MS)

ESM2 similar proteins: A0JMZ3, A7YWD2, A9UHW6, F4IRR2, F4J738, O35841, O43592, O75031, O94829, O95373, Q05AL1, Q15386, Q2KI54, Q3UBZ5, Q3UFS0, Q3ZC21, Q53I77, Q5R644, Q5R6S3, Q5R974, Q5RA02, Q5SPJ8, Q5TYQ1, Q5ZIC8, Q5ZJZ6, Q6AXU7, Q6NTZ5, Q6P2B1, Q6QI06, Q6R327, Q7Z3V4, Q80U95, Q8BHL5, Q8IUR7, Q8K0C1, Q8QHJ8, Q8R5L3, Q91W86, Q924Z6, Q96JC1

Diamond homologs: A3KND5, A9UHW6, B0UXU6, O43310, Q0V9S3, Q28H63, Q3UBZ5, Q3ZC21, Q5EAQ1, Q6AXU7, Q6PEE2, Q801N6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1047 predictions. Top by Δscore:

Variant	Effect	Δscore
17:75266964:CCAC:C	acceptor_gain	1.0000
17:75266965:CAC:C	acceptor_gain	1.0000
17:75266965:CACC:C	acceptor_gain	1.0000
17:75266966:ACC:A	acceptor_loss	1.0000
17:75266967:CCT:C	acceptor_loss	1.0000
17:75266968:C:CC	acceptor_gain	1.0000
17:75266968:CTGC:C	acceptor_loss	1.0000
17:75266969:T:A	acceptor_loss	1.0000
17:75267440:T:TA	donor_gain	1.0000
17:75267452:T:TA	donor_gain	1.0000
17:75267533:CCCA:C	donor_loss	1.0000
17:75267534:CCA:C	donor_loss	1.0000
17:75267535:CA:C	donor_loss	1.0000
17:75267539:T:TA	donor_gain	1.0000
17:75267545:T:TA	donor_gain	1.0000
17:75267628:CAC:C	acceptor_gain	1.0000
17:75267631:C:CC	acceptor_gain	1.0000
17:75267631:C:G	acceptor_loss	1.0000
17:75267632:T:A	acceptor_loss	1.0000
17:75267744:AC:A	donor_gain	1.0000
17:75267745:CC:C	donor_gain	1.0000
17:75267745:CCCT:C	donor_gain	1.0000
17:75267785:G:C	donor_gain	1.0000
17:75267793:AGC:A	donor_gain	1.0000
17:75267898:CTGC:C	acceptor_gain	1.0000
17:75267910:C:CT	acceptor_gain	1.0000
17:75267910:C:T	acceptor_gain	1.0000
17:75267911:A:T	acceptor_gain	1.0000
17:75268098:G:C	donor_gain	1.0000
17:75268107:T:TA	donor_gain	1.0000

AlphaMissense

1454 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:75266793:A:G	W206R	0.998
17:75266793:A:T	W206R	0.998
17:75266945:A:G	L155P	0.998
17:75267593:A:T	V129D	0.997
17:75267793:A:G	W101R	0.997
17:75267793:A:T	W101R	0.997
17:75267846:A:G	L83P	0.997
17:75267870:A:G	F75S	0.997
17:75266791:C:A	W206C	0.996
17:75266791:C:G	W206C	0.996
17:75266924:A:G	L162P	0.996
17:75266933:C:T	G159E	0.996
17:75266934:C:A	G159W	0.996
17:75267608:G:T	A124D	0.996
17:75270122:G:T	A25E	0.996
17:75266766:A:G	Y215H	0.995
17:75266876:C:G	R178P	0.995
17:75267581:A:G	L133P	0.995
17:75267605:A:G	L125P	0.995
17:75267750:A:G	L115P	0.995
17:75268100:A:G	C59R	0.995
17:75266763:A:C	Y216D	0.994
17:75266804:C:G	R202P	0.994
17:75266933:C:A	G159V	0.994
17:75266934:C:G	G159R	0.994
17:75266934:C:T	G159R	0.994
17:75267605:A:T	L125Q	0.994
17:75267769:A:G	C109R	0.994
17:75267858:A:G	L79P	0.994
17:75268108:C:T	G56E	0.994

dbSNP variants (sampled 300 via entrez): RS1000358412 (17:75272310 G>A), RS1000698590 (17:75270333 G>T), RS1001213876 (17:75270639 A>G), RS1001841922 (17:75269935 C>T), RS1002894066 (17:75268269 G>A,C), RS1003250830 (17:75268434 T>G), RS1003327591 (17:75270519 C>T), RS1003712003 (17:75271741 G>A), RS1004218259 (17:75273159 T>C), RS1004480508 (17:75269534 T>A), RS1004748622 (17:75270044 C>G), RS1006224675 (17:75270945 G>A,T), RS1006628961 (17:75271169 T>C,G), RS1006946567 (17:75267813 C>A,T), RS1007920171 (17:75266126 T>C)

Disease associations

OMIM: gene MIM:612072 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	3
mercuric bromide	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
alpha-pinene	increases expression, increases abundance, affects cotreatment	1
bisphenol A	affects cotreatment, increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression, increases abundance	1
nickel sulfate	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression, affects cotreatment	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Acetaminophen	affects response to substance	1
Acrolein	increases expression, increases abundance, affects cotreatment	1
Air Pollutants	increases expression, affects cotreatment, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, decreases expression	1
Cisplatin	affects expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4D4	SEES3-1V human MIF4GD, clone1	Embryonic stem cell	Male
CVCL_A4D5	SEES3-1V human MIF4GD, clone2	Embryonic stem cell	Male
CVCL_A4D6	SEES3-1V human MIF4GD, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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