MBNL1

Summary

MBNL1 (muscleblind like splicing regulator 1, HGNC:6923) is a protein-coding gene on chromosome 3q25.1-q25.2, encoding Muscleblind-like protein 1 (Q9NR56). Mediates pre-mRNA alternative splicing regulation. It is a selective cancer dependency (DepMap: 14.1% of cell lines).

This gene encodes a member of the muscleblind protein family which was initially described in Drosophila melanogaster. The encoded protein is a C3H-type zinc finger protein that modulates alternative splicing of pre-mRNAs. Muscleblind proteins bind specifically to expanded dsCUG RNA but not to normal size CUG repeats and may thereby play a role in the pathophysiology of myotonic dystrophy. Mice lacking this gene exhibited muscle abnormalities and cataracts. Several alternatively spliced transcript variants have been described but the full-length natures of only some have been determined. The different isoforms are thought to have different binding specificities and/or splicing activities.

Source: NCBI Gene 4154 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 65 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 14.1% of screened cell lines
• MANE Select transcript: NM_021038

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6923
Approved symbol	MBNL1
Name	muscleblind like splicing regulator 1
Location	3q25.1-q25.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0428, EXP42, EXP40, EXP35, EXP
Ensembl gene	ENSG00000152601
Ensembl biotype	protein_coding
OMIM	606516
Entrez	4154

Gene structure

Transcript identifiers

Ensembl transcripts: 46 — 41 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000282486, ENST00000282488, ENST00000324196, ENST00000324210, ENST00000355460, ENST00000357472, ENST00000459747, ENST00000460166, ENST00000460591, ENST00000461436, ENST00000463374, ENST00000464596, ENST00000465907, ENST00000466565, ENST00000477171, ENST00000478535, ENST00000485509, ENST00000485910, ENST00000492948, ENST00000493459, ENST00000495875, ENST00000497971, ENST00000498502, ENST00000545754, ENST00000868242, ENST00000868243, ENST00000868244, ENST00000868245, ENST00000868246, ENST00000868247, ENST00000868248, ENST00000868249, ENST00000868250, ENST00000868251, ENST00000911754, ENST00000911755, ENST00000970058, ENST00000970059, ENST00000970060, ENST00000970061, ENST00000970062, ENST00000970063, ENST00000970064, ENST00000970065, ENST00000970066, ENST00000970067

RefSeq mRNA: 97 — MANE Select: NM_021038 NM_001314057, NM_001363870, NM_001376818, NM_001376819, NM_001376820, NM_001376821, NM_001376822, NM_001376823, NM_001376824, NM_001376825, NM_001376826, NM_001376827, NM_001376828, NM_001376829, NM_001376830, NM_001376831, NM_001376832, NM_001376833, NM_001376834, NM_001376835, NM_001376836, NM_001376837, NM_001376838, NM_001376839, NM_001376840, NM_001376841, NM_001376842, NM_001376843, NM_001376844, NM_001376845, NM_001376846, NM_001376847, NM_001376848, NM_001376849, NM_001376851, NM_001376853, NM_001387781, NM_001387782, NM_001387783, NM_001387784, NM_001387785, NM_001387786, NM_001387787, NM_001387788, NM_001387789, NM_001387790, NM_001387791, NM_001387792, NM_001387793, NM_001387794, NM_001387795, NM_001387796, NM_001387797, NM_001387798, NM_001387799, NM_001387800, NM_001387801, NM_001387802, NM_001387803, NM_001387804, NM_001387805, NM_001387806, NM_001387807, NM_001387808, NM_001387809, NM_001387810, NM_001387811, NM_001387812, NM_001387813, NM_001387814, NM_001387815, NM_001387816, NM_001387817, NM_001387818, NM_001387819, NM_001387820, NM_001387821, NM_001387822, NM_001387823, NM_001387824, NM_001387825, NM_001387826, NM_001387827, NM_001387828, NM_001387829, NM_001387830, NM_001387831, NM_001387832, NM_001387833, NM_001387834, NM_021038, NM_207292, NM_207293, NM_207294, NM_207295, NM_207296, NM_207297

CCDS: CCDS3163, CCDS3164, CCDS3165, CCDS3166, CCDS3167, CCDS3168, CCDS54656, CCDS82864, CCDS87156, CCDS93409

Canonical transcript exons

ENST00000324210 — 10 exons

Exon	Start	End
ENSE00001006104	152447620	152447773
ENSE00001818157	152268929	152269092
ENSE00001876421	152462385	152465780
ENSE00003538574	152445282	152445539
ENSE00003566215	152456267	152456361
ENSE00003572953	152299405	152300367
ENSE00003608902	152432717	152432920
ENSE00003644929	152455542	152455577
ENSE00003677383	152414941	152415111
ENSE00003683471	152459271	152459345

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 184.6203 / max 2366.9306, expressed in 1827 samples.

FANTOM5 promoters (31 alternative TSS)

Promoter ID	TPM avg	Samples expressed
39269	144.5210	1827
39268	8.4558	1687
39270	6.0767	1333
39273	5.1011	1200
39285	3.5211	971
39271	3.4516	1098
39287	2.7123	763
39258	1.9024	132
39256	1.5119	148
39267	1.0151	597

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	99.63	gold quality
blood vessel layer	UBERON:0004797	99.42	gold quality
superficial temporal artery	UBERON:0001614	99.35	gold quality
saphenous vein	UBERON:0007318	99.32	gold quality
trabecular bone tissue	UBERON:0002483	99.28	gold quality
cauda epididymis	UBERON:0004360	99.21	gold quality
lower lobe of lung	UBERON:0008949	99.17	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.05	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.03	gold quality
urethra	UBERON:0000057	98.95	gold quality
biceps brachii	UBERON:0001507	98.91	gold quality
skin of hip	UBERON:0001554	98.84	gold quality
bone element	UBERON:0001474	98.83	gold quality
bone marrow	UBERON:0002371	98.78	gold quality
synovial joint	UBERON:0002217	98.76	gold quality
visceral pleura	UBERON:0002401	98.76	gold quality
mononuclear cell	CL:0000842	98.74	gold quality
monocyte	CL:0000576	98.73	gold quality
leukocyte	CL:0000738	98.69	gold quality
bone marrow cell	CL:0002092	98.68	gold quality
colonic epithelium	UBERON:0000397	98.65	gold quality
vena cava	UBERON:0004087	98.63	gold quality
tendon	UBERON:0000043	98.58	gold quality
penis	UBERON:0000989	98.56	gold quality
right coronary artery	UBERON:0001625	98.56	gold quality
epithelium of nasopharynx	UBERON:0001951	98.56	gold quality
nasopharynx	UBERON:0001728	98.54	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.48	gold quality
vastus lateralis	UBERON:0001379	98.47	gold quality
popliteal artery	UBERON:0002250	98.43	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	32.82
E-HCAD-35	yes	31.89
E-CURD-119	yes	12.48
E-MTAB-6678	yes	9.47
E-MTAB-5061	no	3.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

283 targeting MBNL1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6867-5P	100.00	82.21	3464
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-4668-3P	100.00	68.74	2635
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548P	99.98	72.25	3784

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 14.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• MBNL proteins promote opposite splicing patterns for cardiac troponin T and insulin receptor alternative exons (PMID:15257297)
• small interfering RNA-mediated down-regulation of MBNL1 in normal myoblasts results in abnormal insulin receptor splicing (PMID:15546872)
• The GFP-MBNL1 in CUG and CAG foci have similar half-times of recovery and fractions of immobile molecules, suggesting GFP-MBNL1 is bound by both CUG and CAG repeats and formation of RNA foci and disruption of MBNL1-regulated splicing are separable events. (PMID:15961406)
• localized expression of the integrin alpha3 protein is regulated at the level of RNA localization by MBNL1; integrin alpha3 transcripts are physically associated with MLP1 in cells and MLP1 binds to a specific ACACCC motif in the integrin alpha3 3’ UTR (PMID:16273094)
• The fact that a human protein works in a Drosophila cellular context illustrates the use of an in vivo test to prove functional conservation. (PMID:16394256)
• findings show that MBNL1 nuclear sequestration in protein foci is a molecular pathology marker of DM1 and DM2 patients where ribonuclear inclusions of transcripts with expanded CUG/CCUG repeats are also present (PMID:16920640)
• Elevated levels of MBNL1 show RNA-independent interaction with hnRNP H and dampen the inhibitory activity of increased hnRNP H levels on IR splicing in normal myoblasts. (PMID:16946708)
• MBNL1 (muscleblind-like protein 1) is an alternative splicing factor that becomes highly concentrated with mutant RNA foci. (PMID:17846170)
• MBNL may bind all of its RNA substrates, both normal and pathogenic, as structured stem-loops containing pyrimidine mismatches. (PMID:17942744)
• Examination of dynamics of MBNL1 in response to stress, and suggestion of a role for MBNL1 in mRNA metabolism in the cytoplasm. (PMID:18335541)
• Both the ZnF3 and the ZnF4 zinc-finger domains target GC steps, with site-specific recognition mediated by a network of hydrogen bonds formed primarily with main chain groups of the protein. (PMID:19043415)
• MBNL1 and MBNL2 always co-distributed. Functional differences between MBNL1 and MBNL2 have not yet been found (PMID:19095965)
• Our data seem indicate that the presence of ribonuclear inclusions and MBNL1 nuclear foci are involved in alteration of alternative splicing but do not impair DM2 myogenic differentiation. (PMID:19345584)
• Data show that ligand 1 selectively destabilizes the MBNL1N-poly(CUG) complex. (PMID:19805260)
• Findings demonstrate a role for Mbnl1 in controlling insulin receptor exon 11 inclusion via binding to a downstream intronic enhancer element. (PMID:20519504)
• results indicate the occurrence of a mis-splicing event in myotonic dystrophy type 1 that is induced neither by a loss of muscleblind-like 1 (MBNL1) function nor by a gain of CUGBP1 (PMID:21439371)
• the abnormally high inclusion of the exon 5 and 7 regions in DM1 is expected to enhance the potential of MBNL1 of being sequestered with nuclear CUG expansions, which provides new insight into DM1 pathophysiology. (PMID:21454535)
• Although MBNL1 contains four Zn fingers, it appears that only two Zn fingers binding GC motifs are necessary for high affinity RNA binding. (PMID:21548961)
• MBNL1 regulates pre-miR-1 biogenesis. (PMID:21685920)
• Deletion of the MBNL1 response element eliminated MBNL1 splicing regulation and led to complete inclusion of exon 5, which is consistent with the suppressive effect of MBNL1 on splicing. (PMID:21832083)
• Expanded CUG repeats Dysregulate RNA splicing by altering the stoichiometry of the muscleblind 1 complex (PMID:21900255)
• The removal of one pair of zinc fingers greatly impairs the binding affinity of MBNL1, which indicates that the two pairs of zinc fingers might possibly interact with RNA targets cooperatively. (PMID:22106026)
• congenital myotonic dystrophy muscle has nuclear foci that contain muscleblind-like 1 (MBNL1) protein. (PMID:22113158)
• Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis. (PMID:22306654)
• study suggests that regulation of CUGBP1 and MBNL1 is essential for accurate control of destabilization of a broad spectrum of mRNAs as well as of alternative splicing events (PMID:22355723)
• The present results show that the MBNL1 protein is expressed and more or less sequestered into the CCUGexp nuclear foci also in analyzed non-muscle tissues of DM2 patients. (PMID:22520280)
• It was demonstrated that functionally distinct classes of MBNL1-mediated splicing events exist as defined by requirements for zinc finger-RNA interactions. (PMID:22890842)
• This report demonistrated that the association of several genetic variants of the MBNL1 gene with DM1 or with the severity of the disease. (PMID:23161457)
• MBNL1 loss shows a graded effect on the number and severity of the ensuing RNA splice defects. (PMID:23166594)
• consistent with a central and negative regulatory role for MBNL proteins in pluripotency, their knockdown significantly enhances the expression of key pluripotency genes and the formation of induced pluripotent stem cells during somatic cell reprogramming (PMID:23739326)
• in both dystrophic and sarcopenic muscles MBNL1 undergoes intranuclear relocation, accumulating in its usual functional sites but also ectopically moving to domains which are usually devoid of this protein in healthy adults (PMID:23807294)
• MBNL142-43 bind the Src-homology 3 domain of Src family kinases (SFKs) via their proline-rich motifs. (PMID:23949219)
• MBNL1 and RBFOX2 cooperate to establish a splicing programme involved in pluripotent stem cell differentiation. (PMID:24048253)
• MBNL1 is highly mobile and changes localization in response to altered transcription and splicing activity, providing an insight into the sensitivity of the lens to changes in MBNL1 distribution. (PMID:24354850)
• Results highlight the importance of RNA binding by MBNL Zinc Finger domains 1 and 2 for splicing regulatory activity, even when the protein is artificially recruited to its regulatory location on target RNAs. (PMID:24373687)
• both MBNL1 and MBNL2 are involved in the regulation of Tau exon 2 splicing and the mis-splicing of Tau in DM1 is due to the combined inactivation of both. (PMID:24440524)
• Reduced RBFOX1 activity in myotonic dystrophy type 1 tissues may amplify several of the splicing alterations caused by the deficiency in MBNL1. (PMID:25211016)
• Results show that nuclear localization is a major determinant of MBNL1 function. It promotes the nuclear retention of repeat-containing transcripts, which results in repression of aberrant protein expression from the expanded repeats. (PMID:25274774)
• The result is consistent with the hypothesis that MBNL proteins are trapped by expanded CUG repeats and inactivated in myotonic dystrophy type 1 (DM1) and that CELF1 is activated in DM1. (PMID:25403273)
• MBNL1 binds with C allelic pre-miR-1307 leading to low expression of miR-1307-3p in colorectal cancer. (PMID:25977444)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mbnl1	ENSDARG00000052978
mus_musculus	Mbnl1	ENSMUSG00000027763
rattus_norvegicus	Mbnl1	ENSRNOG00000014076
drosophila_melanogaster	mbl	FBGN0265487
caenorhabditis_elegans		WBGENE00019347

Paralogs (3): MBNL3 (ENSG00000076770), ZC3H10 (ENSG00000135482), MBNL2 (ENSG00000139793)

Protein

Protein identifiers

Muscleblind-like protein 1 — Q9NR56 (reviewed: Q9NR56)

Alternative names: Triplet-expansion RNA-binding protein

All UniProt accessions (9): Q9NR56, A0A0A0MQX8, C9J4T8, C9J7P7, C9JCX1, C9JP00, H7C4T5, H7C4Y1, Q86VM6

UniProt curated annotations — full annotation on UniProt →

Function. Mediates pre-mRNA alternative splicing regulation. Acts either as activator or repressor of splicing on specific pre-mRNA targets. Inhibits cardiac troponin-T (TNNT2) pre-mRNA exon inclusion but induces insulin receptor (IR) pre-mRNA exon inclusion in muscle. Antagonizes the alternative splicing activity pattern of CELF proteins. Regulates the TNNT2 exon 5 skipping through competition with U2AF2. Inhibits the formation of the spliceosome A complex on intron 4 of TNNT2 pre-mRNA. Binds to the stem-loop structure within the polypyrimidine tract of TNNT2 intron 4 during spliceosome assembly. Binds to the 5’-YGCU(U/G)Y-3’consensus sequence. Binds to the IR RNA. Binds to expanded CUG repeat RNA, which folds into a hairpin structure containing GC base pairs and bulged, unpaired U residues. Together with RNA binding proteins RBPMS and RBFOX2, activates vascular smooth muscle cells alternative splicing events. Regulates NCOR2 alternative splicing.

Subunit / interactions. Interacts with DDX1 and YBX1. Interacts with HNRNPH1; the interaction in RNA-independent. Interacts with RBPMS; the interaction allows cooperative assembly of RNA-bound stable cell-specific alternative splicing regulatory complexes.

Subcellular location. Nucleus. Cytoplasm. Cytoplasmic granule.

Tissue specificity. Highly expressed in cardiac, skeletal muscle and during myoblast differentiation. Weakly expressed in other tissues (at protein level). Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.

Disease relevance. Dystrophia myotonica 1 (DM1) [MIM:160900] A muscular disorder characterized by myotonia, muscle wasting in the distal extremities, cataract, hypogonadism, defective endocrine functions, male baldness and cardiac arrhythmias. The protein represented in this entry may be involved in disease pathogenesis. In muscle cells from patients, MBNL1 is sequestered by DMPK RNAs containing pathogenic CUG triplet repeat expansions. MBNL1 binding is proportional to repeat length consistent with the direct correlation between the length of repeat expansion and disease severity. Corneal dystrophy, Fuchs endothelial, 3 (FECD3) [MIM:613267] A late-onset form of Fuchs endothelial corneal dystrophy, a disease caused by loss of endothelium of the central cornea. It is characterized by focal wart-like guttata that arise from Descemet membrane and develop in the central cornea, epithelial blisters, reduced vision and pain. Descemet membrane is thickened by abnormal collagenous deposition. The protein represented in this entry is involved in disease pathogenesis. In corneal endothelial cells from patients, MBNL1 is sequestered by TCF4 RNAs containing pathogenic CUG triplet repeat expansions. This results in missplicing of essential MBNL1-regulated mRNAs.

Similarity. Belongs to the muscleblind family.

Isoforms (7)

UniProt ID	Names	Canonical?
Q9NR56-1	1, EXP42	yes
Q9NR56-2	2, EXP40
Q9NR56-3	3, EXP35
Q9NR56-4	4, EXP36
Q9NR56-5	5, EXP41
Q9NR56-6	6, EXP41S
Q9NR56-7	7

RefSeq proteins (97): NP_001300986, NP_001350799, NP_001363747, NP_001363748, NP_001363749, NP_001363750, NP_001363751, NP_001363752, NP_001363753, NP_001363754, NP_001363755, NP_001363756, NP_001363757, NP_001363758, NP_001363759, NP_001363760, NP_001363761, NP_001363762, NP_001363763, NP_001363764, NP_001363765, NP_001363766, NP_001363767, NP_001363768, NP_001363769, NP_001363770, NP_001363771, NP_001363772, NP_001363773, NP_001363774, NP_001363775, NP_001363776, NP_001363777, NP_001363778, NP_001363780, NP_001363782, NP_001374710, NP_001374711, NP_001374712, NP_001374713, NP_001374714, NP_001374715, NP_001374716, NP_001374717, NP_001374718, NP_001374719, NP_001374720, NP_001374721, NP_001374722, NP_001374723, NP_001374724, NP_001374725, NP_001374726, NP_001374727, NP_001374728, NP_001374729, NP_001374730, NP_001374731, NP_001374732, NP_001374733, NP_001374734, NP_001374735, NP_001374736, NP_001374737, NP_001374738, NP_001374739, NP_001374740, NP_001374741, NP_001374742, NP_001374743, NP_001374744, NP_001374745, NP_001374746, NP_001374747, NP_001374748, NP_001374749, NP_001374750, NP_001374751, NP_001374752, NP_001374753, NP_001374754, NP_001374755, NP_001374756, NP_001374757, NP_001374758, NP_001374759, NP_001374760, NP_001374761, NP_001374762, NP_001374763, NP_066368, NP_997175, NP_997176, NP_997177, NP_997178, NP_997179, NP_997180 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000571	Znf_CCCH	Domain
IPR054429	Znf-CCCH_Muscleblind-like	Domain

Pfam: PF00642, PF14608, PF22628

UniProt features (38 total): strand 9, helix 8, turn 6, splice variant 5, zinc finger region 4, sequence variant 3, chain 1, sequence conflict 1, modified residue 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3D2Q	X-RAY DIFFRACTION	1.5
3D2S	X-RAY DIFFRACTION	1.7
3D2N	X-RAY DIFFRACTION	2.7
5U6H	SOLUTION NMR
5U6L	SOLUTION NMR
5U9B	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NR56-F1	67.48	0.25

Functional residue map

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

Post-translational modifications (1): 6

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 493 (showing top): ATF_B, AHRARNT_01, RRAGTTGT_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, HORIUCHI_WTAP_TARGETS_DN, FREAC2_01, WWTAAGGC_UNKNOWN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GNF2_CASP8, TGCACTT_MIR519C_MIR519B_MIR519A, GCANCTGNY_MYOD_Q6, MITSIADES_RESPONSE_TO_APLIDIN_DN, CREBP1_Q2, FOXO4_01

GO Biological Process (7): in utero embryonic development (GO:0001701), mRNA processing (GO:0006397), nervous system development (GO:0007399), RNA splicing (GO:0008380), embryonic limb morphogenesis (GO:0030326), regulation of RNA splicing (GO:0043484), myoblast differentiation (GO:0045445)

GO Molecular Function (5): RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
RNA processing	2
chordate embryonic development	1
mRNA metabolic process	1
system development	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
RNA splicing	1
regulation of gene expression	1
regulation of primary metabolic process	1
cell differentiation	1
muscle structure development	1
nucleic acid binding	1
RNA binding	1
transition metal ion binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
cytoplasmic ribonucleoprotein granule	1

Protein interactions and networks

STRING

2294 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MBNL1	CELF1	Q92879	969
MBNL1	CNBP	P20694	954
MBNL1	DMPK	Q09013	939
MBNL1	CLCN1	P35523	933
MBNL1	QKI	Q96PU8	896
MBNL1	ATP2A1	O14983	835
MBNL1	LDB3	O75112	801
MBNL1	TNNT2	P45379	784
MBNL1	CEBPD	P49716	780
MBNL1	PURA	Q00577	759
MBNL1	SLC6A11	P48066	756
MBNL1	TNNT3	P45378	752
MBNL1	SIX5	Q8N196	751
MBNL1	HNRNPH1	P31943	745
MBNL1	HNRNPH2	P55795	745

IntAct

68 interactions, top by confidence:

A	B	Type	Score
	VPS39	psi-mi:“MI:0914”(association)	0.960
DAB1	MBNL1	psi-mi:“MI:0915”(physical association)	0.670
MBNL1	DAB1	psi-mi:“MI:0915”(physical association)	0.670
FHL2	CNOT1	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
SSBP4	GM2A	psi-mi:“MI:0914”(association)	0.530
ROPN1	PRKAR2B	psi-mi:“MI:0914”(association)	0.530
HSPA2	DNAJC13	psi-mi:“MI:0914”(association)	0.530
HNRNPH1	MBNL1	psi-mi:“MI:0915”(physical association)	0.500
MBNL1	HNRNPH1	psi-mi:“MI:0914”(association)	0.500
rep	MBNL1	psi-mi:“MI:0915”(physical association)	0.490
MBNL1		psi-mi:“MI:0915”(physical association)	0.370
MBNL1	IDH3A	psi-mi:“MI:0915”(physical association)	0.370
MBNL1	ZNHIT3	psi-mi:“MI:0915”(physical association)	0.370
ABI3BP	MBNL1	psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
ATXN1		psi-mi:“MI:0914”(association)	0.350
	TNFRSF10A	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
MBNL1	SAP30	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
BAG1	PSMD11	psi-mi:“MI:0914”(association)	0.350
MBNL1	MBNL2	psi-mi:“MI:0914”(association)	0.350
HSPA8	SBNO1	psi-mi:“MI:0914”(association)	0.350
WIF1	SMCHD1	psi-mi:“MI:0914”(association)	0.350
MBNL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
DNAJB6	SCAMP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (280): MBNL1 (Two-hybrid), MBNL1 (Two-hybrid), AEN (Two-hybrid), MBNL2 (Affinity Capture-MS), MBNL3 (Affinity Capture-MS), MBNL1 (Affinity Capture-MS), MBNL1 (Affinity Capture-MS), MBNL1 (Affinity Capture-MS), MBNL1 (Affinity Capture-MS), MBNL3 (Affinity Capture-MS), MBNL2 (Affinity Capture-MS), MBNL1 (Affinity Capture-MS), MBNL1 (Affinity Capture-MS), MBNL1 (Affinity Capture-MS), IARS2 (Affinity Capture-MS)

ESM2 similar proteins: A0A8I6B1J2, A0AV96, A8XND8, B3M3R5, B3NGA1, B4HUE4, B4IX08, B4KX02, B4LFQ9, B4MM23, B4PIS2, B4QRJ0, F2Z3T4, G5EFF1, O01367, P16914, P31367, Q0V9L3, Q24312, Q32NN2, Q56V19, Q5R4F5, Q5R5P4, Q5VZF2, Q5W9D5, Q5W9D6, Q5W9D7, Q5ZKW9, Q66H68, Q6IRN2, Q6P0D0, Q6P104, Q6Q2B2, Q7JJZ8, Q7TSY6, Q8C181, Q8MSV2, Q8R003, Q8R205, Q91WT8

Diamond homologs: A0A8I6B1J2, A8XND8, F2Z3T4, O16011, Q0JD07, Q56V19, Q5R4F5, Q5VZF2, Q5ZKW9, Q6Q2B2, Q8C181, Q8R003, Q94250, Q9JKP5, Q9NR56, Q9NUK0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of HSF1-mediated heat shock response	5	13.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

2891 predictions. Top by Δscore:

Variant	Effect	Δscore
3:152299570:GCTC:G	donor_gain	1.0000
3:152320549:GAC:G	donor_gain	1.0000
3:152320550:ACA:A	donor_gain	1.0000
3:152414930:T:TA	acceptor_gain	1.0000
3:152414936:TCTA:T	acceptor_loss	1.0000
3:152414937:CTA:C	acceptor_loss	1.0000
3:152414938:TA:T	acceptor_loss	1.0000
3:152414939:A:AC	acceptor_loss	1.0000
3:152414939:A:AG	acceptor_gain	1.0000
3:152414939:AG:A	acceptor_gain	1.0000
3:152414939:AGG:A	acceptor_gain	1.0000
3:152414940:G:GT	acceptor_gain	1.0000
3:152414940:GG:G	acceptor_gain	1.0000
3:152414940:GGG:G	acceptor_gain	1.0000
3:152414940:GGGC:G	acceptor_gain	1.0000
3:152414940:GGGCC:G	acceptor_gain	1.0000
3:152415107:CCGTG:C	donor_gain	1.0000
3:152415108:CGTGG:C	donor_loss	1.0000
3:152415109:GTG:G	donor_gain	1.0000
3:152415110:TG:T	donor_gain	1.0000
3:152415111:GG:G	donor_gain	1.0000
3:152415111:GGT:G	donor_loss	1.0000
3:152415112:G:GC	donor_loss	1.0000
3:152415112:G:GG	donor_gain	1.0000
3:152415113:T:TC	donor_loss	1.0000
3:152432715:A:AG	acceptor_gain	1.0000
3:152432716:G:GG	acceptor_gain	1.0000
3:152432716:GC:G	acceptor_gain	1.0000
3:152432716:GCC:G	acceptor_gain	1.0000
3:152432716:GCCA:G	acceptor_gain	1.0000

AlphaMissense

2492 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:152300221:G:C	D10H	1.000
3:152300222:A:T	D10V	1.000
3:152300230:T:A	W13R	1.000
3:152300230:T:C	W13R	1.000
3:152300231:G:C	W13S	1.000
3:152300232:G:C	W13C	1.000
3:152300232:G:T	W13C	1.000
3:152300234:T:A	L14Q	1.000
3:152300234:T:C	L14P	1.000
3:152300240:T:A	L16Q	1.000
3:152300240:T:C	L16P	1.000
3:152300242:G:A	E17K	1.000
3:152300243:A:T	E17V	1.000
3:152300246:T:A	V18E	1.000
3:152300248:T:A	C19S	1.000
3:152300248:T:C	C19R	1.000
3:152300248:T:G	C19G	1.000
3:152300249:G:A	C19Y	1.000
3:152300249:G:C	C19S	1.000
3:152300249:G:T	C19F	1.000
3:152300250:T:G	C19W	1.000
3:152300251:A:G	R20G	1.000
3:152300252:G:C	R20T	1.000
3:152300252:G:T	R20I	1.000
3:152300253:A:C	R20S	1.000
3:152300253:A:T	R20S	1.000
3:152300257:T:C	F22L	1.000
3:152300259:C:A	F22L	1.000
3:152300259:C:G	F22L	1.000
3:152300264:G:C	R24T	1.000

dbSNP variants (sampled 300 via entrez): RS1000006212 (3:152278617 T>C,G), RS1000013288 (3:152355959 C>T), RS1000028244 (3:152362815 G>T), RS1000036446 (3:152404656 A>C,G), RS1000037955 (3:152310473 G>A), RS1000041164 (3:152271659 C>T), RS1000048769 (3:152411377 G>A,C), RS1000080043 (3:152373621 T>C), RS1000083122 (3:152332658 A>G), RS1000105713 (3:152404919 T>C), RS1000109594 (3:152404942 T>C), RS1000110350 (3:152316415 C>T), RS1000118586 (3:152362105 T>A), RS1000124279 (3:152378303 C>T), RS1000127533 (3:152464029 A>G)

Disease associations

OMIM: gene MIM:606516 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001399_1	Infantile hypertrophic pyloric stenosis	2.000000e-17
GCST003983_10	Male-pattern baldness	5.000000e-19
GCST006085_117	Prostate cancer	4.000000e-11
GCST006611_115	HDL cholesterol	1.000000e-10
GCST006814_1	End-stage renal disease	6.000000e-07
GCST006867_26	Type 2 diabetes	2.000000e-10
GCST006979_306	Heel bone mineral density	4.000000e-09
GCST006988_113	Blond vs. brown/black hair color	2.000000e-09
GCST009379_137	Type 2 diabetes	8.000000e-13
GCST009379_138	Type 2 diabetes	1.000000e-08
GCST009379_139	Type 2 diabetes	8.000000e-08
GCST010118_27	Type 2 diabetes	1.000000e-09
GCST010241_426	Apolipoprotein A1 levels	3.000000e-12
GCST011320_7	Type 2 diabetes or prostate cancer (pleiotropy)	2.000000e-12
GCST90000025_954	Appendicular lean mass	2.000000e-09
GCST90002407_415	White blood cell count	6.000000e-10
GCST90013405_15	Liver enzyme levels (alanine transaminase)	4.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009270	heel bone mineral density
EFO:0003924	hair color
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1293317 (SINGLE PROTEIN)

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.96	Kd	0.011	nM	CHEMBL1710607
9.60	Kd	0.25	nM	MYRICETIN
8.40	Kd	4	nM	CHEMBL5286270
7.03	Kd	93	nM	CHEMBL5276958
6.52	Kd	300	nM	CHEMBL3102959

PubChem BioAssay actives

5 with measured affinity, of 8 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-(2-fluorophenyl)-3-methylquinoline	1922356: Binding affinity to MBNL1 (unknown origin)	kd	<0.0001	uM
3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chromen-4-one	1922356: Binding affinity to MBNL1 (unknown origin)	kd	0.0003	uM
3-amino-9-bromo-2-(4-methoxybenzoyl)-4-phenylchromeno[4,3-b]pyridin-5-one	1922356: Binding affinity to MBNL1 (unknown origin)	kd	0.0040	uM
3-amino-2-(4-methoxybenzoyl)-4-phenylchromeno[4,3-b]pyridin-5-one	1922356: Binding affinity to MBNL1 (unknown origin)	kd	0.0930	uM
2-N-[4-[(6-chloro-2-methoxyacridin-9-yl)amino]butyl]-1,3,5-triazine-2,4,6-triamine	2064585: Binding affinity to MBNL1 (unknown origin) (1 to 272 residues) assessed as dissociation constant	kd	0.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	5
trichostatin A	affects cotreatment, increases expression	3
bisphenol A	increases methylation, affects cotreatment, affects methylation, increases expression	2
sodium arsenite	decreases expression, affects cotreatment, affects splicing, increases abundance	2
methacrylaldehyde	decreases expression, increases oxidation, increases abundance, affects cotreatment	2
Acetaminophen	decreases expression, increases expression	2
Acrolein	affects cotreatment, decreases expression, increases oxidation, increases abundance	2
Estradiol	decreases expression, increases expression	2
Ozone	increases oxidation, increases abundance, affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Particulate Matter	increases expression, increases abundance	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
shuanghuang shengbai	decreases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases oxidation, increases abundance	1
testosterone undecanoate	affects cotreatment, decreases expression	1
kojic acid	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	increases methylation	1
brequinar	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1614166	Binding	PubChem BioAssay. qHTS Assay for Inhibitors of MBNL1-poly(CUG) RNA binding. (Class of assay: confirmatory)	PubChem BioAssay data set

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1XK	Abcam A-549 MBNL1 KO	Cancer cell line	Male
CVCL_D2BV	Abcam HCT 116 MBNL1 KO	Cancer cell line	Male
CVCL_D2NP	Abcam THP-1 MBNL1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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