MIS12

Summary

MIS12 (MIS12 kinetochore complex component, HGNC:24967) is a protein-coding gene on chromosome 17p13.2, encoding Protein MIS12 homolog (Q9H081). Part of the MIS12 complex which is required for normal chromosome alignment and segregation and for kinetochore formation during mitosis. It is a common-essential gene (DepMap: required in 94.3% of cancer cell lines).

Involved in attachment of mitotic spindle microtubules to kinetochore and kinetochore assembly. Located in kinetochore and nucleus. Part of MIS12/MIND type complex.

Source: NCBI Gene 79003 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 26 total
• Cancer dependency (DepMap): dependent in 94.3% of screened cell lines (common-essential)
• MANE Select transcript: NM_001258217

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24967
Approved symbol	MIS12
Name	MIS12 kinetochore complex component
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC2488, hMIS12, KNTC2AP, MTW1
Ensembl gene	ENSG00000167842
Ensembl biotype	protein_coding
OMIM	609178
Entrez	79003

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 26 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000381165, ENST00000573759, ENST00000574186, ENST00000576570, ENST00000576988, ENST00000611091, ENST00000891287, ENST00000891288, ENST00000891289, ENST00000891290, ENST00000891291, ENST00000891292, ENST00000891293, ENST00000891294, ENST00000891295, ENST00000891296, ENST00000891297, ENST00000916906, ENST00000916907, ENST00000916908, ENST00000916909, ENST00000960710, ENST00000960711, ENST00000960712, ENST00000960713, ENST00000960714, ENST00000960715

RefSeq mRNA: 5 — MANE Select: NM_001258217 NM_001258217, NM_001258218, NM_001258219, NM_001258220, NM_024039

CCDS: CCDS11074

Canonical transcript exons

ENST00000611091 — 3 exons

Exon	Start	End
ENSE00001117575	5488196	5488589
ENSE00003727833	5488823	5490811
ENSE00003746052	5486566	5486684

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 91.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.1610 / max 247.2464, expressed in 1770 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159038	5.7127	1593
159037	3.5594	1509
159039	2.3604	1225
159040	1.6098	856
159036	0.9187	523

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	91.35	gold quality
germinal epithelium of ovary	UBERON:0001304	90.20	gold quality
parietal pleura	UBERON:0002400	89.53	gold quality
bronchial epithelial cell	CL:0002328	89.06	gold quality
pleura	UBERON:0000977	88.50	gold quality
visceral pleura	UBERON:0002401	88.40	gold quality
tibia	UBERON:0000979	88.38	gold quality
superficial temporal artery	UBERON:0001614	88.34	gold quality
ventricular zone	UBERON:0003053	88.16	gold quality
palpebral conjunctiva	UBERON:0001812	87.92	gold quality
epithelium of nasopharynx	UBERON:0001951	87.55	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.53	gold quality
caput epididymis	UBERON:0004358	87.44	gold quality
granulocyte	CL:0000094	87.19	gold quality
vermiform appendix	UBERON:0001154	87.12	gold quality
islet of Langerhans	UBERON:0000006	87.03	gold quality
cauda epididymis	UBERON:0004360	87.00	gold quality
secondary oocyte	CL:0000655	86.97	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.92	gold quality
amniotic fluid	UBERON:0000173	86.91	gold quality
ganglionic eminence	UBERON:0004023	86.77	gold quality
body of pancreas	UBERON:0001150	86.35	gold quality
lymph node	UBERON:0000029	86.28	gold quality
spleen	UBERON:0002106	86.18	gold quality
pancreas	UBERON:0001264	85.95	gold quality
endometrium	UBERON:0001295	85.91	gold quality
lower lobe of lung	UBERON:0008949	85.75	gold quality
esophagus squamous epithelium	UBERON:0006920	85.68	gold quality
rectum	UBERON:0001052	85.61	gold quality
colonic mucosa	UBERON:0000317	85.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.93
E-GEOD-110499	no	578.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

55 targeting MIS12, 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-574-5P	100.00	66.01	989
HSA-MIR-513A-5P	100.00	69.77	2465
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-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-129-5P	99.88	70.26	3273
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-516A-3P	99.46	67.96	1378
HSA-MIR-516B-3P	99.46	67.96	1378
HSA-MIR-7162-5P	99.46	68.08	1368

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 94.3% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• hMIS12 has a role in mitosis and localizes at kinetochores (PMID:12515822)
• These results indicate that a four-subunit Mis12 complex plays an essential role in chromosome segregation in vertebrates and contributes to mitotic kinetochore assembly. (PMID:16585270)
• These findings support a novel role for Hsp90-Sgt1 chaperones in ensuring the fidelity of Mis12 multiprotein complex assembly. (PMID:20404110)
• Direct binding of Cenp-C to the Mis12 complex joins the inner and outer kinetochore. (PMID:21353556)
• RWD-containing proteins interact with the Mis12 complex to shape KMN network topology, as revealed by structural analysis (PMID:24530301)
• Mechanisms of mitosis-specific assembly of the checkpoint platform Knl1/MIS12/NDC80 at human kinetochores. (PMID:25601404)
• Whereas CENP-C recruits a single MIS12:NDC80 complex, the authors show here that CENP-T binds one MIS12:NDC80 and two NDC80 complexes upon phosphorylation by the mitotic CDK1:Cyclin B complex at three distinct CENP-T sites. (PMID:28012276)
• METTL3 counteracts premature aging via m6A-dependent stabilization of MIS12 mRNA. (PMID:33035345)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mis12	ENSDARG00000026454
mus_musculus	Mis12	ENSMUSG00000040599
rattus_norvegicus	Mis12	ENSRNOG00000066036

Protein

Protein identifiers

Protein MIS12 homolog — Q9H081 (reviewed: Q9H081)

All UniProt accessions (3): Q9H081, I3L244, I3L4K6

UniProt curated annotations — full annotation on UniProt →

Function. Part of the MIS12 complex which is required for normal chromosome alignment and segregation and for kinetochore formation during mitosis. Essential for proper kinetochore microtubule attachments.

Subunit / interactions. Component of the MIS12 complex composed of MIS12, DSN1, NSL1 and PMF1. Also interacts with KNL1, CBX3, CBX5, NDC80 and ZWINT.

Subcellular location. Chromosome. Centromere. Kinetochore.

Similarity. Belongs to the mis12 family.

RefSeq proteins (5): NP_001245146, NP_001245147, NP_001245148, NP_001245149, NP_076944 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008685	Centromere_Mis12	Family

Pfam: PF05859

UniProt features (10 total): helix 6, chain 1, coiled-coil region 1, sequence variant 1, strand 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8PPR	ELECTRON MICROSCOPY	3
5LSJ	X-RAY DIFFRACTION	3.25
5LSK	X-RAY DIFFRACTION	3.5
8Q5H	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H081-F1	88.12	0.53

Function

Pathways and Gene Ontology

Reactome pathways

18 pathways

ID	Pathway
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-68877	Mitotic Prometaphase
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-141424	Amplification of signal from the kinetochores
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-68882	Mitotic Anaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-69618	Mitotic Spindle Checkpoint
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 147 (showing top): GOBP_CHROMOSOME_ORGANIZATION, MYAATNNNNNNNGGC_UNKNOWN, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, GOBP_CHROMOSOME_LOCALIZATION, GEORGES_CELL_CYCLE_MIR192_TARGETS, GGGTGGRR_PAX4_03, MARTINEZ_RB1_TARGETS_UP, GOBP_ORGANELLE_FISSION, GOBP_MITOTIC_NUCLEAR_DIVISION, GOBP_ORGANELLE_ASSEMBLY, MCBRYAN_PUBERTAL_BREAST_5_6WK_UP, GOBP_MITOTIC_CELL_CYCLE, FISCHER_DREAM_TARGETS, GOBP_ORGANELLE_LOCALIZATION, GOBP_KINETOCHORE_ORGANIZATION

GO Biological Process (7): mitotic sister chromatid segregation (GO:0000070), chromosome segregation (GO:0007059), attachment of spindle microtubules to kinetochore (GO:0008608), cell division (GO:0051301), attachment of mitotic spindle microtubules to kinetochore (GO:0051315), kinetochore assembly (GO:0051382), mitotic cell cycle (GO:0000278)

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

GO Cellular Component (8): MIS12/MIND type complex (GO:0000444), kinetochore (GO:0000776), spindle pole (GO:0000922), outer kinetochore (GO:0000940), nucleus (GO:0005634), cytosol (GO:0005829), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Mitotic Prometaphase	2
M Phase	2
Cell Cycle	2
Amplification of signal from the kinetochores	1
Mitotic Anaphase	1
RHO GTPase Effectors	1
Mitotic Spindle Checkpoint	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Mitotic Metaphase and Anaphase	1
Cell Cycle, Mitotic	1
Cell Cycle Checkpoints	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mitotic nuclear division	2
mitotic cell cycle process	2
cell cycle process	2
intracellular membraneless organelle	2
cellular anatomical structure	2
sister chromatid segregation	1
microtubule binding	1
metaphase chromosome alignment	1
cellular process	1
mitotic metaphase chromosome alignment	1
attachment of spindle microtubules to kinetochore	1
kinetochore organization	1
protein-containing complex assembly	1
membraneless organelle assembly	1
cell cycle	1
binding	1
outer kinetochore	1
condensed chromosome, centromeric region	1
supramolecular complex	1
spindle	1
kinetochore	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
cytoplasm	1
chromosomal region	1

Protein interactions and networks

STRING

740 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MIS12	DSN1	Q9H410	984
MIS12	KNL1	Q8NG31	973
MIS12	CENPC	Q03188	851
MIS12	NDC80	O14777	836
MIS12	SPC24	Q8NBT2	817
MIS12	CENPI	Q92674	802
MIS12	CENPH	Q9H3R5	769
MIS12	NUF2	Q9BZD4	767
MIS12	ZWINT	O95229	731
MIS12	CENPT	Q96BT3	729
MIS12	CENPA	P49450	620
MIS12	CENPS	Q8N2Z9	577
MIS12	AURKB	Q96GD4	570
MIS12	CENPB	P07199	555
MIS12	BUB1	O43683	514

IntAct

113 interactions, top by confidence:

A	B	Type	Score
MIS12	PMF1	psi-mi:“MI:0915”(physical association)	0.950
PMF1	MIS12	psi-mi:“MI:0915”(physical association)	0.950
PMF1	MIS12	psi-mi:“MI:2364”(proximity)	0.950
MIS12	PMF1	psi-mi:“MI:2364”(proximity)	0.950
NUF2	NDC80	psi-mi:“MI:0914”(association)	0.950
ZWINT	NDC80	psi-mi:“MI:0914”(association)	0.940
SPC25	NDC80	psi-mi:“MI:0914”(association)	0.940
DSN1	MIS12	psi-mi:“MI:2364”(proximity)	0.930

BioGRID (205): MIS12 (Two-hybrid), MIS12 (Affinity Capture-MS), MIS12 (Affinity Capture-MS), MIS12 (Affinity Capture-MS), MIS12 (Affinity Capture-MS), MIS12 (Affinity Capture-MS), MIS12 (Affinity Capture-MS), MIS12 (Affinity Capture-MS), MIS12 (Affinity Capture-MS), PMF1 (Co-purification), MIS12 (Affinity Capture-MS), CDKN2A (Affinity Capture-MS), CENPC (Affinity Capture-MS), NDC80 (Affinity Capture-MS), ZWINT (Affinity Capture-MS)

ESM2 similar proteins: A4D1B5, A8MW99, A8Y5U1, O70173, O88480, Q12769, Q1LV50, Q1T769, Q1T7B7, Q1T7B8, Q28HU3, Q3MHH2, Q3TCV3, Q3U1D0, Q3ZAU7, Q402B2, Q5EA49, Q5PNP6, Q5R9W0, Q5RB52, Q5ZL79, Q63517, Q6DRL4, Q6IPU0, Q6P2C0, Q6TNU3, Q7TQ72, Q7Z2Z1, Q7Z4M0, Q8AYS7, Q8BJW5, Q8BKT8, Q8BMG1, Q8BQ33, Q8BR90, Q8BRM6, Q8K2A7, Q8NG48, Q91VB4, Q92674

Diamond homologs: Q1T769, Q5EA49, Q5R9W0, Q7TQ72, Q9CY25, Q9H081

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MIS12	“form complex”	“MIS12 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 56 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
Amplification of signal from the kinetochores	8	39.4×	5e-10
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	13	37.9×	1e-15
Mitotic Spindle Checkpoint	8	31.7×	2e-09
EML4 and NUDC in mitotic spindle formation	13	30.2×	1e-14
Resolution of Sister Chromatid Cohesion	13	28.1×	2e-14
RHO GTPases Activate Formins	13	25.2×	6e-14
Mitotic Prometaphase	13	22.5×	2e-13
Cell Cycle Checkpoints	9	19.9×	9e-09

GO biological processes:

GO term	Partners	Fold	FDR
attachment of spindle microtubules to kinetochore	8	162.8×	1e-14
mitotic spindle assembly checkpoint signaling	7	85.5×	1e-10
chromosome segregation	7	26.4×	3e-07
cell division	13	13.1×	6e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

509 predictions. Top by Δscore:

Variant	Effect	Δscore
17:5488282:A:T	donor_gain	1.0000
17:5488813:A:AG	acceptor_gain	1.0000
17:5488814:C:G	acceptor_gain	1.0000
17:5488815:A:AG	acceptor_gain	1.0000
17:5488815:ATTT:A	acceptor_gain	1.0000
17:5488816:T:G	acceptor_gain	1.0000
17:5488818:TGCA:T	acceptor_loss	1.0000
17:5488819:GCAG:G	acceptor_loss	1.0000
17:5488820:CAG:C	acceptor_loss	1.0000
17:5488821:A:AG	acceptor_gain	1.0000
17:5488821:A:AT	acceptor_loss	1.0000
17:5488821:AG:A	acceptor_gain	1.0000
17:5488822:G:GT	acceptor_gain	1.0000
17:5488822:GG:G	acceptor_gain	1.0000
17:5488822:GGT:G	acceptor_gain	1.0000
17:5488822:GGTT:G	acceptor_gain	1.0000
17:5488822:GGTTT:G	acceptor_gain	1.0000
17:5487100:G:GT	donor_gain	0.9900
17:5488281:G:GT	donor_gain	0.9900
17:5488302:GC:G	donor_gain	0.9900
17:5488818:T:TA	acceptor_gain	0.9900
17:5488265:GCC:G	donor_gain	0.9800
17:5488274:GAA:G	donor_gain	0.9800
17:5487088:GAGT:G	donor_gain	0.9700
17:5487087:G:GT	donor_gain	0.9600
17:5487101:A:T	donor_gain	0.9600
17:5486682:CCGGT:C	donor_loss	0.9500
17:5486683:CGGT:C	donor_loss	0.9500
17:5486684:GGTA:G	donor_loss	0.9500
17:5486685:G:GG	donor_gain	0.9500

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000334647 (17:5487321 G>A,T), RS1000863037 (17:5487478 T>C), RS1000873701 (17:5487584 T>C), RS1000969450 (17:5486755 C>G), RS1001075134 (17:5486363 C>CA,CG,CT), RS1001858131 (17:5489326 C>G,T), RS1002241079 (17:5485758 G>A), RS1002312057 (17:5488867 C>T), RS1002739768 (17:5489585 A>G), RS1002890012 (17:5485401 G>A), RS1002908833 (17:5490544 A>G), RS1003934686 (17:5485433 T>G), RS1005092559 (17:5487014 A>G), RS1005150452 (17:5486920 A>C,G), RS1005412399 (17:5491040 T>C)

Disease associations

OMIM: gene MIM:609178 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST009303_2	Abstraction and mental flexibility	9.000000e-06
GCST009391_1683	Metabolite levels	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009332	executive function measurement
EFO:0010343	cholesteryl ester 18:0 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Particulate Matter	increases abundance, decreases reaction, increases expression, decreases expression	4
Air Pollutants	increases abundance, increases expression, decreases expression	2
Vehicle Emissions	decreases reaction, increases expression, increases abundance	2
Tunicamycin	increases expression	2
Valproic Acid	decreases expression, affects cotreatment, increases expression	2
Zinc	affects cotreatment, increases expression, decreases expression	2
Cyclosporine	increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
jinfukang	decreases expression	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Atrazine	decreases expression	1
Cannabidiol	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydralazine	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Selenium	decreases expression	1
Smoke	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1

Clinical trials (associated diseases)

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