MIB1

Summary

MIB1 (MIB E3 ubiquitin protein ligase 1, HGNC:21086) is a protein-coding gene on chromosome 18q11.2, encoding E3 ubiquitin-protein ligase MIB1 (Q86YT6). E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. It is a selective cancer dependency (DepMap: 15.6% of cell lines).

This gene encodes a protein containing multiple ankyrin repeats and RING finger domains that functions as an E3 ubiquitin ligase. The encoded protein positively regulates Notch signaling by ubiquitinating the Notch receptors, thereby facilitating their endocytosis. This protein may also promote the ubiquitination and degradation of death-associated protein kinase 1 (DAPK1).

Source: NCBI Gene 57534 — RefSeq curated summary.

At a glance

• Gene–disease (curated): left ventricular noncompaction 7 (Moderate, GenCC) — +4 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 650 total — 1 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 3
• Cancer dependency (DepMap): dependent in 15.6% of screened cell lines
• MANE Select transcript: NM_020774

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21086
Approved symbol	MIB1
Name	MIB E3 ubiquitin protein ligase 1
Location	18q11.2
Locus type	gene with protein product
Status	Approved
Aliases	DIP-1, MIB, KIAA1323, ZZANK2, ZZZ6
Ensembl gene	ENSG00000101752
Ensembl biotype	protein_coding
OMIM	608677
Entrez	57534

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000261537, ENST00000577749, ENST00000578260, ENST00000578646, ENST00000695486, ENST00000695487, ENST00000864012, ENST00000955830, ENST00000955831

RefSeq mRNA: 1 — MANE Select: NM_020774 NM_020774

CCDS: CCDS11871

Canonical transcript exons

ENST00000261537 — 21 exons

Exon	Start	End
ENSE00001146229	21864526	21870953
ENSE00001204680	21791374	21791557
ENSE00001240503	21740792	21741812
ENSE00003460126	21799841	21799974
ENSE00003477681	21773624	21773728
ENSE00003478350	21779481	21779685
ENSE00003481854	21798084	21798228
ENSE00003482999	21838365	21838497
ENSE00003496535	21846944	21847125
ENSE00003497912	21778103	21778169
ENSE00003511277	21815616	21815813
ENSE00003515707	21853140	21853218
ENSE00003515790	21803907	21804014
ENSE00003529398	21768623	21768752
ENSE00003606034	21843131	21843217
ENSE00003632075	21849196	21849388
ENSE00003654194	21765772	21765943
ENSE00003659433	21857130	21857243
ENSE00003667988	21819495	21819646
ENSE00003674018	21858546	21858646
ENSE00003684773	21844092	21844253

Expression profiles

Bgee: expression breadth ubiquitous, 262 present calls, max score 95.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.9676 / max 131.4301, expressed in 1801 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169610	8.6316	1691
169609	7.7369	1741
169607	0.7788	285
169611	0.7364	403
169612	0.6835	421
169608	0.4004	200

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	95.82	gold quality
kidney epithelium	UBERON:0004819	95.80	gold quality
tibia	UBERON:0000979	95.64	gold quality
nipple	UBERON:0002030	95.47	gold quality
caput epididymis	UBERON:0004358	95.38	gold quality
parietal pleura	UBERON:0002400	95.36	gold quality
cauda epididymis	UBERON:0004360	95.19	gold quality
cartilage tissue	UBERON:0002418	94.77	gold quality
corpus callosum	UBERON:0002336	94.56	gold quality
visceral pleura	UBERON:0002401	94.34	gold quality
oviduct epithelium	UBERON:0004804	94.34	gold quality
secondary oocyte	CL:0000655	94.27	gold quality
germinal epithelium of ovary	UBERON:0001304	94.05	gold quality
calcaneal tendon	UBERON:0003701	93.93	gold quality
renal medulla	UBERON:0000362	93.74	gold quality
cardia of stomach	UBERON:0001162	93.56	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.46	gold quality
ventricular zone	UBERON:0003053	93.11	gold quality
adrenal tissue	UBERON:0018303	93.10	gold quality
pylorus	UBERON:0001166	92.74	gold quality
urethra	UBERON:0000057	92.32	gold quality
ganglionic eminence	UBERON:0004023	92.07	gold quality
embryo	UBERON:0000922	92.06	gold quality
ventral tegmental area	UBERON:0002691	91.94	gold quality
epithelial cell of pancreas	CL:0000083	91.92	gold quality
inferior vagus X ganglion	UBERON:0005363	91.88	gold quality
skin of hip	UBERON:0001554	91.84	gold quality
thymus	UBERON:0002370	91.74	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.68	gold quality
mammary duct	UBERON:0001765	91.47	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.60
E-MTAB-7303	no	123.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BHLHA15, HNF1B, NEUROG3, PTF1A

miRNA regulators (miRDB)

336 targeting MIB1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4282	99.99	75.36	6408
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 15.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 37)

• Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1 (PMID:17003037)
• DAPK is found in two distinct immune complexes, one containing HSP90 and CHIP and a second complex containing only DIP1/Mib; strict modulation of DAPK activities by HSP90 heterocomplexes is critical for regulation of apoptosis and cellular homeostasis (PMID:17324930)
• The interaction between Mib1 and cFLIP decreases the association of caspase-8 with cFLIP, which activates caspase-8 and induces cell death (PMID:19710364)
• Data demonstrate that c-mip interacts with Dip1 and upregulates DAPK, which blocks the nuclear translocation of ERK1/2. (PMID:20018188)
• RYK interacts both physically and functionally with the E3 ubiquitin MIB1. MIB1 is sufficient to activate Wnt/CTNNB1 signaling and this activity depends on endogenous RYK. (PMID:21875946)
• MIB1 negatively regulates TNFalpha- and IL1beta-induced NF-kappaB target gene activation (PMID:22184009)
• implicate NOTCH signaling in left ventricular noncompaction and indicate that MIB1 mutations arrest chamber myocardium development, preventing trabecular maturation and compaction (PMID:23314057)
• MIB-1 was found to be associated with estrogen receptors in the stromal component (PMID:23442362)
• Data show that the E3 ubiquitin ligase, mind bomb 1 (Mib1), interacts with and ubiquitinates SMN and facilitates its degradation. (PMID:23615451)
• Invasive adenomas have a higher inducible nitric oxide synthase, and this correlated with the MIB-1 (PMID:24008756)
• This is the first published study ever assessing the expression of COX-2, p16 and Ki67 markers in ductal carcinoma in situ breast tumors. (PMID:25077370)
• a significant survival benefit for p16-positive vaginal cancers compared with p16-negative cancers for stages I and II. No difference was observed in survival for MIB-1-positive tumors (PMID:25319982)
• Data show how E3 ubiquitin protein ligase Mind bomb protein recognizes notch receptor ligands. (PMID:25747658)
• these results identify the interaction between Mib1 and Plk4 as a new and important element in the control of centriole homeostasis. (PMID:25795303)
• Expression of MIB1 ligase protein, human was correlated with tumor grade and Figo stages. (PMID:26204652)
• provided evidences that miR-10 regulates human endothelial cells behaviour through targeting Mib1 as well (PMID:26825552)
• The aim of the study was to evaluate the caspase-3 and survivin expression in correlation with MIB-1 expression in gliomas of various grade. (PMID:26995334)
• In the absence of PCM1, Mib1 destabilizes Talpid3 through poly-ubiquitylation and suppresses cilium assembly. (PMID:27146717)
• M1B-1 antigen was shown to increase the risk. High birth weight, pesticide exposure (childhood exposure, and parental occupational exposure) and maternal consumption of cured meat during pregnancy may also increase the risk of onset of childhood brain tumours (PMID:27212451)
• MIB1 mutations reduce Notch signaling activation and contribute to the development of congenital heart disease. (PMID:30322850)
• CYLD marshals the centriolar satellites by deubiquitinating and preventing the E3 ligase Mindbomb 1 (MIB1) from marking PCM1 for proteasomal degradation. (PMID:31067453)
• High MIB1 expression is associated with prostate cancer progression. (PMID:31322262)
• Proximity interactions of the ubiquitin ligase Mind bomb 1 reveal a role in regulation of epithelial polarity complex proteins. (PMID:31462741)
• MIB1-mediated degradation of WRN promotes cellular senescence in response to camptothecin treatment. (PMID:32652764)
• Mind Bomb 1 Promotes Pancreatic Cancer Proliferation by Activating beta-Catenin Signaling. (PMID:32711591)
• E3 ubiquitin ligase Mindbomb 1 facilitates nuclear delivery of adenovirus genomes. (PMID:33443154)
• Maintenance of type 2 glycolytic myofibers with age by Mib1-Actn3 axis. (PMID:33637766)
• MicroRNA1955p is associated with cell proliferation, migration and invasion in prostate cancer and targets MIB1. (PMID:34698358)
• A Novel Long-Noncoding RNA LncZFAS1 Prevents MPP(+)-Induced Neuroinflammation Through MIB1 Activation. (PMID:34775541)
• Associations of the Methylation Levels of NFAT5, PVT1, RPS6KA1, and MIB1 with Steroid-Resistant Asthma. (PMID:35417913)
• Increased MIB-1 expression in salivary gland pleomorphic adenoma that recurs and undergoes malignant transformation. (PMID:35637257)
• CEMIP, acting as a scaffold protein for bridging GRAF1 and MIB1, promotes colorectal cancer metastasis via activating CDC42/MAPK pathway. (PMID:36849460)
• EHD1 promotes CP110 ubiquitination by centriolar satellite delivery of HERC2 to the mother centriole. (PMID:37074924)
• The E3 ubiquitin ligase MIB1 suppresses breast cancer cell migration through regulating CTNND1 protein level. (PMID:37209565)
• Novel Association of the NOTCH Pathway Regulator MIB1 Gene With the Development of Bicuspid Aortic Valve. (PMID:37405741)
• N[6]-methyladenosine-modified MIB1 promotes stemness properties and peritoneal metastasis of gastric cancer cells by ubiquitinating DDX3X. (PMID:38252226)
• Structural requirements for activity of Mind bomb1 in Notch signaling. (PMID:39121852)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mib1	ENSDARG00000102184
mus_musculus	Mib1	ENSMUSG00000024294
rattus_norvegicus	Mib1	ENSRNOG00000013281
drosophila_melanogaster	mib1	FBGN0263601

Paralogs (1): MIB2 (ENSG00000197530)

Protein

Protein identifiers

E3 ubiquitin-protein ligase MIB1 — Q86YT6 (reviewed: Q86YT6)

Alternative names: DAPK-interacting protein 1, Mind bomb homolog 1, RING-type E3 ubiquitin transferase MIB1, Zinc finger ZZ type with ankyrin repeat domain protein 2

All UniProt accessions (1): Q86YT6

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. Probably mediates ubiquitination and subsequent proteasomal degradation of DAPK1, thereby antagonizing anti-apoptotic effects of DAPK1 to promote TNF-induced apoptosis. Involved in ubiquitination of centriolar satellite CEP131, CEP290 and PCM1 proteins and hence inhibits primary cilium formation in proliferating cells. Mediates ‘Lys-63’-linked polyubiquitination of TBK1, which probably participates in kinase activation. (Microbial infection) During adenovirus infection, mediates ubiquitination of Core-capsid bridging protein. This allows viral genome delivery into nucleus for infection.

Subunit / interactions. Interacts with CEP131 and PCM1.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Centriolar satellite. Cell membrane.

Tissue specificity. Widely expressed at low level. Expressed at higher level in spinal cord, ovary, whole brain, and all specific brain regions examined.

Post-translational modifications. Ubiquitinated; possibly via autoubiquitination. Ubiquitinated; this modification is inhibited in response to cellular stress, such as ultraviolet light (UV) radiation or heat shock.

Disease relevance. Left ventricular non-compaction 7 (LVNC7) [MIM:615092] A form of left ventricular non-compaction, a cardiomyopathy due to myocardial morphogenesis arrest and characterized by a hypertrophic left ventricle, a severely thickened 2-layered myocardium, numerous prominent trabeculations, deep intertrabecular recesses, and poor systolic function. Clinical manifestations are variable. Some affected individuals experience no symptoms at all, others develop heart failure. In some cases, left ventricular non-compaction is associated with other congenital heart anomalies. LVNC7 is an autosomal dominant condition. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Miscellaneous. In epilepsy brain tissue, levels of expression are increased in the cytoplasm and microsomal fractions (endoplasmic reticulum).

RefSeq proteins (1): NP_065825* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000433	Znf_ZZ	Domain
IPR001841	Znf_RING	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR010606	Mib_Herc2	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR037252	Mib_Herc2_sf	Homologous_superfamily
IPR040847	SH3_15	Domain
IPR042056	MIB1/2_ZZ	Domain
IPR043145	Znf_ZZ_sf	Homologous_superfamily

Pfam: PF00023, PF00569, PF06701, PF12796, PF13920, PF18346

UniProt features (98 total): helix 35, strand 26, repeat 9, binding site 8, turn 7, zinc finger region 4, domain 2, sequence variant 2, sequence conflict 2, chain 1, coiled-coil region 1, modified residue 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4XI6	X-RAY DIFFRACTION	2.04
4XI7	X-RAY DIFFRACTION	2.05
4TSE	X-RAY DIFFRACTION	2.06
4XIB	X-RAY DIFFRACTION	2.15
8V0E	X-RAY DIFFRACTION	2.39
8V0D	X-RAY DIFFRACTION	2.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86YT6-F1	84.09	0.62

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 (8): 85; 88; 100; 103; 109; 112; 118; 122

Post-translational modifications (1): 408

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2691232	Constitutive Signaling by NOTCH1 HD Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2691230	Signaling by NOTCH1 HD Domain Mutants in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-9012852	Signaling by NOTCH3

MSigDB gene sets: 288 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, REACTOME_SIGNALING_BY_NOTCH, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, AAGCAAT_MIR137, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_NEURON_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, TGCGCANK_UNKNOWN, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, TGCACTT_MIR519C_MIR519B_MIR519A, SP3_Q3, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_NEURAL_TUBE_DEVELOPMENT, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (13): blood vessel development (GO:0001568), in utero embryonic development (GO:0001701), somitogenesis (GO:0001756), neural tube formation (GO:0001841), heart looping (GO:0001947), ubiquitin-dependent protein catabolic process (GO:0006511), endocytosis (GO:0006897), Notch signaling pathway (GO:0007219), protein ubiquitination (GO:0016567), central nervous system neuron differentiation (GO:0021953), negative regulation of neuron differentiation (GO:0045665), positive regulation of endocytosis (GO:0045807), heart development (GO:0007507)

GO Molecular Function (6): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (10): cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), cytoplasmic vesicle (GO:0031410), centriolar satellite (GO:0034451), glutamatergic synapse (GO:0098978), cytoskeleton (GO:0005856), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Signaling by NOTCH	3
Signaling by NOTCH1 in Cancer	3
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Signaling by NOTCH2	1
Signaling by NOTCH3	1
Signal Transduction	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
chordate embryonic development	2
neuron differentiation	2
cytoplasm	2
vasculature development	1
anatomical structure development	1
anterior/posterior pattern specification	1
segmentation	1
anatomical structure formation involved in morphogenesis	1
somite development	1
embryonic epithelial tube formation	1
neural tube development	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
cell surface receptor signaling pathway	1
protein modification by small protein conjugation	1
central nervous system development	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
endocytosis	1
regulation of endocytosis	1
positive regulation of transport	1
positive regulation of cellular component organization	1
animal organ development	1
circulatory system development	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
centriole	1

Protein interactions and networks

STRING

1727 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MIB1	BRD2	P25440	767
MIB1	DAPK1	P53355	657
MIB1	DAPK2	Q9UIK4	486
MIB1	DAPK3	O43293	481
MIB1	HES5	Q5TA89	479
MIB1	NHS	Q6T4R5	458
MIB1	TRIP11	Q15643	422
MIB1	HPGD	P15428	395
MIB1	ZWILCH	Q9H900	389
MIB1	FADD	Q13158	388
MIB1	ABHD3	Q8WU67	384
MIB1	CALML3	P27482	367
MIB1	CALML5	Q9NZT1	367
MIB1	UBA5	Q9GZZ9	366
MIB1	CALM1	P02593	361
MIB1	CALML6	Q8TD86	361

IntAct

132 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
CEP290	CCP110	psi-mi:“MI:2364”(proximity)	0.890
TBK1	TBKBP1	psi-mi:“MI:0914”(association)	0.860
rep	MIB1	psi-mi:“MI:0915”(physical association)	0.750
MIB1	rep	psi-mi:“MI:0915”(physical association)	0.750
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
rep	GTF2F2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PCM1	MIB1	psi-mi:“MI:0915”(physical association)	0.650
LPXN	PCNT	psi-mi:“MI:0914”(association)	0.640
FAM171B	FAM171A2	psi-mi:“MI:0914”(association)	0.530
FSD1	UBFD1	psi-mi:“MI:0914”(association)	0.530
SH3PXD2A	FGD1	psi-mi:“MI:0914”(association)	0.530
RYK	PCDH7	psi-mi:“MI:0914”(association)	0.530
GABARAP	MIB1	psi-mi:“MI:0915”(physical association)	0.520
Azi2	N4BP1	psi-mi:“MI:0914”(association)	0.500
MIB1	Azi2	psi-mi:“MI:0915”(physical association)	0.500
TBK1	MIB1	psi-mi:“MI:0915”(physical association)	0.500
Cep131	IPO5	psi-mi:“MI:0915”(physical association)	0.400
COASY	MIB1	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
UBE2D1	MIB1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (421): MIB1 (Affinity Capture-MS), MIB1 (Co-localization), MIB1 (Affinity Capture-Western), PLK4 (Affinity Capture-Western), MIB1 (Affinity Capture-MS), MIB1 (Proximity Label-MS), MIB1 (Proximity Label-MS), MIB1 (Affinity Capture-MS), MIB1 (Affinity Capture-MS), MIB1 (Affinity Capture-MS), MIB1 (Affinity Capture-MS), MIB1 (Proximity Label-MS), MIB1 (Proximity Label-MS), MIB1 (Proximity Label-MS), MIB1 (Proximity Label-MS)

ESM2 similar proteins: A4IFF3, A4IG72, A6QQ71, A7MB11, D3ZQF4, E9PY46, F6PHZ6, O02697, O75344, O95801, P27124, P30416, P48736, P54729, Q02790, Q0P5H9, Q17QZ7, Q1RLX4, Q3UR70, Q3V3E1, Q4U2V3, Q5EA11, Q5F3K0, Q5RBW9, Q5RGL7, Q62018, Q6GM65, Q6GN68, Q6GNY1, Q6GPE5, Q6P3X3, Q7DMA9, Q7ZXV5, Q80SY4, Q86YT6, Q8BTI9, Q8CD92, Q8N0Z6, Q8R3H9, Q8WUH2

Diamond homologs: A1E2V0, A1L020, A1L3F4, A5D8Q0, A9JTP3, A9ULZ2, D3ZDI6, E3SCZ8, O08863, O10296, O10324, O14064, O15392, O62640, O70201, O88738, P40629, P41435, P41436, P41437, P41454, P47732, P98170, Q05AK5, Q0WPJ7, Q13489, Q13490, Q28ER3, Q28H51, Q50L39, Q557E7, Q5BKL8, Q5R881, Q5RAH9, Q60989, Q62210, Q69Z36, Q6I6F4, Q6J1J1, Q6NTT6

SIGNOR signaling

17 interactions.

A	Effect	B	Mechanism
MIB1	“up-regulates activity”	JAG1	ubiquitination
MIB1	down-regulates	RYK	ubiquitination
MIB1	“up-regulates activity”	DLL4	ubiquitination
MIB1	“up-regulates activity”	DLL3	ubiquitination
MIB1	“up-regulates activity”	DLL1	ubiquitination
MIB1	“down-regulates quantity by destabilization”	SMN1	ubiquitination
Ub:E2	“up-regulates activity”	MIB1	ubiquitination
MIB1	“down-regulates quantity by destabilization”	DAPK1	polyubiquitination
MIB1	“down-regulates quantity by destabilization”	SMN1	polyubiquitination
MIB1	down-regulates	CEP131	ubiquitination
MIB1	down-regulates	PCM1	ubiquitination
MIB1	“down-regulates quantity by destabilization”	BLM	ubiquitination
MIB1	“down-regulates quantity by destabilization”	SNRPN	ubiquitination
MIB1	“down-regulates quantity by destabilization”	KIAA0586	ubiquitination
CDK5	“up-regulates activity”	MIB1	phosphorylation
MIB1	“down-regulates quantity by destabilization”	MIB1	polyubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 166 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
Loss of Nlp from mitotic centrosomes	13	18.9×	4e-11
Loss of proteins required for interphase microtubule organization from the centrosome	13	18.9×	4e-11
AURKA Activation by TPX2	13	18.2×	5e-11
Recruitment of mitotic centrosome proteins and complexes	13	16.2×	1e-10
Regulation of PLK1 Activity at G2/M Transition	13	15.1×	3e-10
Anchoring of the basal body to the plasma membrane	14	14.5×	1e-10
Regulation of TNFR1 signaling	7	14.4×	4e-05
Centrosome maturation	6	14.0×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	23
Uncertain significance	348
Likely benign	221
Benign	26

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
4070967	NM_020774.4(MIB1):c.2550C>A (p.Cys850Ter)	Pathogenic
1028190	NM_020774.4(MIB1):c.2878C>T (p.Gln960Ter)	Likely pathogenic
1175114	NM_020774.4(MIB1):c.198C>A (p.Tyr66Ter)	Likely pathogenic
1334019	NM_020774.4(MIB1):c.2039del (p.Gln680fs)	Likely pathogenic
1677955	NM_020774.4(MIB1):c.2309del (p.Asn770fs)	Likely pathogenic
1678126	NM_020774.4(MIB1):c.1246_1247del (p.Ser416fs)	Likely pathogenic
1678131	NM_020774.4(MIB1):c.1349T>A (p.Leu450Ter)	Likely pathogenic
1678132	NM_020774.4(MIB1):c.2049+1G>A	Likely pathogenic
1678139	NM_020774.4(MIB1):c.1622del (p.Gly541fs)	Likely pathogenic
1678140	NM_020774.4(MIB1):c.1541_1559del (p.Glu514fs)	Likely pathogenic
1678141	NM_020774.4(MIB1):c.2482_2483del (p.Asp828fs)	Likely pathogenic
1678151	NM_020774.4(MIB1):c.864del (p.Ile288fs)	Likely pathogenic
1678162	NM_020774.4(MIB1):c.1176C>A (p.Tyr392Ter)	Likely pathogenic
1678164	NM_020774.4(MIB1):c.2687del (p.Lys896fs)	Likely pathogenic
3027436	NM_020774.4(MIB1):c.2250_2259del (p.Lys750fs)	Likely pathogenic
3067834	NM_020774.4(MIB1):c.531+1G>A	Likely pathogenic
3338302	NM_020774.4(MIB1):c.2665+1G>A	Likely pathogenic
3366937	NM_020774.4(MIB1):c.2779+2dup	Likely pathogenic
3776133	NM_020774.4(MIB1):c.1305_1306insAA (p.Val436fs)	Likely pathogenic
4055773	NM_020774.4(MIB1):c.838_841del (p.Thr280fs)	Likely pathogenic
4056619	NM_020774.4(MIB1):c.1471G>T (p.Glu491Ter)	Likely pathogenic
4074747	NM_020774.4(MIB1):c.2212-2A>T	Likely pathogenic
418296	NM_020774.4(MIB1):c.265C>T (p.Arg89Cys)	Likely pathogenic
4686729	NM_020774.4(MIB1):c.2803C>T (p.Gln935Ter)	Likely pathogenic

SpliceAI

4195 predictions. Top by Δscore:

Variant	Effect	Δscore
18:21741809:ACCGG:A	donor_loss	1.0000
18:21741811:CGGTA:C	donor_loss	1.0000
18:21741812:GGT:G	donor_loss	1.0000
18:21741813:G:T	donor_loss	1.0000
18:21741814:T:G	donor_loss	1.0000
18:21765761:T:TA	acceptor_gain	1.0000
18:21765767:A:AG	acceptor_gain	1.0000
18:21765767:AATAG:A	acceptor_gain	1.0000
18:21765768:A:G	acceptor_gain	1.0000
18:21765769:TA:T	acceptor_loss	1.0000
18:21765770:A:AG	acceptor_gain	1.0000
18:21765770:A:C	acceptor_loss	1.0000
18:21765770:AG:A	acceptor_gain	1.0000
18:21765771:G:GA	acceptor_gain	1.0000
18:21765771:GG:G	acceptor_gain	1.0000
18:21765771:GGC:G	acceptor_gain	1.0000
18:21765771:GGCA:G	acceptor_gain	1.0000
18:21765771:GGCAT:G	acceptor_gain	1.0000
18:21765836:G:GT	donor_gain	1.0000
18:21765934:G:GT	donor_gain	1.0000
18:21765934:G:T	donor_gain	1.0000
18:21765941:GAG:G	donor_gain	1.0000
18:21765943:GGTAG:G	donor_loss	1.0000
18:21765944:G:C	donor_loss	1.0000
18:21768621:AG:A	acceptor_gain	1.0000
18:21768622:GG:G	acceptor_gain	1.0000
18:21768739:G:GT	donor_gain	1.0000
18:21768752:GGTAC:G	donor_loss	1.0000
18:21768753:G:GC	donor_loss	1.0000
18:21768754:T:A	donor_loss	1.0000

AlphaMissense

6640 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:21741644:G:C	G21R	1.000
18:21741653:T:A	W24R	1.000
18:21741653:T:C	W24R	1.000
18:21741655:G:C	W24C	1.000
18:21741655:G:T	W24C	1.000
18:21741659:T:A	W26R	1.000
18:21741659:T:C	W26R	1.000
18:21741661:G:C	W26C	1.000
18:21741661:G:T	W26C	1.000
18:21741671:G:C	D30H	1.000
18:21741692:G:C	G37R	1.000
18:21741693:G:A	G37D	1.000
18:21741699:T:A	V39D	1.000
18:21741737:T:A	W52R	1.000
18:21741737:T:C	W52R	1.000
18:21741738:G:C	W52S	1.000
18:21741739:G:C	W52C	1.000
18:21741739:G:T	W52C	1.000
18:21741760:C:A	N59K	1.000
18:21741760:C:G	N59K	1.000
18:21741761:T:C	Y60H	1.000
18:21741761:T:G	Y60D	1.000
18:21741789:G:C	R69P	1.000
18:21765795:T:A	C85S	1.000
18:21765795:T:C	C85R	1.000
18:21765796:G:A	C85Y	1.000
18:21765796:G:C	C85S	1.000
18:21765796:G:T	C85F	1.000
18:21765797:T:G	C85W	1.000
18:21765804:T:C	C88R	1.000

dbSNP variants (sampled 300 via entrez): RS1000023180 (18:21767714 A>G), RS1000037997 (18:21725672 A>G), RS1000108612 (18:21706088 T>C), RS1000112129 (18:21751340 G>A), RS1000135165 (18:21839934 A>C), RS1000155266 (18:21764420 C>G), RS1000176576 (18:21834918 G>A), RS1000219796 (18:21745143 A>G), RS1000243426 (18:21855000 T>C), RS1000263551 (18:21837836 G>A,C), RS1000269067 (18:21707148 A>C), RS1000289890 (18:21833371 A>G), RS1000304927 (18:21824333 G>A,T), RS1000316319 (18:21838218 C>T), RS1000323695 (18:21869098 A>G)

Disease associations

OMIM: gene MIM:608677 | disease phenotypes: MIM:615092, MIM:192600, MIM:143890

GenCC curated gene-disease

Disease	Classification	Inheritance
left ventricular noncompaction 7	Moderate	Autosomal dominant
left ventricular noncompaction	Supportive	Autosomal dominant
neurodevelopmental disorder	Limited	Autosomal dominant
isolated cleft palate	No Known Disease Relationship	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
dilated cardiomyopathy	Limited	AD

Mondo (9): left ventricular noncompaction 7 (MONDO:0014042), familial hypertrophic cardiomyopathy (MONDO:0024573), paroxysmal atrial fibrillation (MONDO:1030011), autism spectrum disorder (MONDO:0005258), dilated cardiomyopathy (MONDO:0005021), hypercholesterolemia, familial, 1 (MONDO:0007750), isolated cleft palate (MONDO:0007336), left ventricular noncompaction (MONDO:0018901), neurodevelopmental disorder (MONDO:0700092)

Orphanet (6): Left ventricular noncompaction (Orphanet:54260), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Dilated cardiomyopathy (Orphanet:217604), Homozygous familial hypercholesterolemia (Orphanet:391665), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

3 total (4 of 3 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0011664	Left ventricular noncompaction cardiomyopathy
HP:0030682	Left ventricular noncompaction
HP:0001644	Dilated cardiomyopathy

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004998_1	Severe progression in rheumatoid arthritis	5.000000e-06
GCST010703_44	Brain morphology (MOSTest)	1.000000e-08
GCST011365_156	Myocardial infarction	5.000000e-06
GCST90002397_383	Mean spheric corpuscular volume	9.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008336	disease progression measurement
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects cotreatment, decreases expression, increases abundance	2
Valproic Acid	decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
avobenzone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
sanggenone C	decreases reaction, increases degradation, increases ubiquitination, affects cotreatment, decreases expression	1
enzalutamide	affects expression	1
jinfukang	decreases expression	1
(+)-JQ1 compound	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	decreases expression, increases abundance, affects cotreatment	1
Cadmium	increases abundance, increases expression	1
Calcitriol	increases expression	1
Doxorubicin	increases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1
Manganese	increases abundance, affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_D1XM	Abcam A-549 MIB1 KO	Cancer cell line	Male
CVCL_D2BX	Abcam HCT 116 MIB1 KO	Cancer cell line	Male
CVCL_UN00	LVNC-FiPS-MIB1STOP1	Induced pluripotent stem cell	Female
CVCL_UN01	LVNC-FiPS-MIB1VF2	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00540787	PHASE4	COMPLETED	A Comparison of Antiarrhythmic Drug Therapy and Radio Frequency Catheter Ablation in Patients With Paroxysmal Atrial Fibrillation
NCT00744874	PHASE4	COMPLETED	Ablation of the Pulmonary Veins for Paroxysmal Afib
NCT00964392	PHASE4	COMPLETED	NAVISTAR® THERMOCOOL® Catheter Post Approval Registry
NCT01057394	PHASE4	TERMINATED	Post-Market Randomized Trial: Endoscopically- Guided Ablation vs. Radiofrequency Ablation
NCT01058980	PHASE4	COMPLETED	ADenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination: the ADVICE Trial
NCT01070667	PHASE4	UNKNOWN	Dronedarone in Pacemakers Patients With Paroxysmal Atrial Fibrillation
NCT01504451	PHASE4	UNKNOWN	Left Atrial Ablation of Paroxysmal Atrial Fibrillation With Implantable Loop Recorder Follow Up Study: The LAAPITUP 2 Study
NCT01527279	PHASE4	COMPLETED	Antazoline in Rapid Cardioversion of Paroxysmal Atrial Fibrillation
NCT01645917	PHASE4	COMPLETED	Durability of Pulmonary Vein Isolation Following Cryoablation for Treatment of Paroxysmal Atrial Fibrillation
NCT01959425	PHASE4	TERMINATED	Oral Anticoagulation Therapy Pilot Study
NCT02502110	PHASE4	UNKNOWN	Study of Statin for Reduction of Postoperative Paroxysmal Atrial Fibrillation
NCT03005366	PHASE4	COMPLETED	Predictive Factors to Effectively Terminate Paroxysmal Atrial Fibrillation by Blocking Atrial Selective Ionic Currents
NCT03624881	PHASE4	COMPLETED	Evaluation of VISITAG SURPOINT™ Module With External Processing Unit (EPU)
NCT04704986	PHASE4	ACTIVE_NOT_RECRUITING	Comparison of PolarX and the Arctic Front Cryoballoons for PVI in Patients With Symptomatic Paroxysmal AF
NCT05534581	PHASE4	ACTIVE_NOT_RECRUITING	SINGLE SHOT CHAMPION
NCT06168994	PHASE4	NOT_YET_RECRUITING	Role of Eplerenone in Reducing Recurrence of Atrial Fibrillation in Patient With Structural Heart Disease
NCT06765356	PHASE4	ACTIVE_NOT_RECRUITING	Pragmatic Evaluation of a Pentaspline Pulsed Field Ablation System to Treat Atrial Fibrillation and Related Arrhythmias
NCT07487714	PHASE4	ENROLLING_BY_INVITATION	Comparative Efficacy of 100-, 200-, & 400-mg Amiodarone in Patients With Paroxysmal AF Depending on Plasma Concentration
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD