MEIS2

Summary

MEIS2 (Meis homeobox 2, HGNC:7001) is a protein-coding gene on chromosome 15q14, encoding Homeobox protein Meis2 (O14770). Involved in transcriptional regulation. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a homeobox protein belonging to the TALE (’three amino acid loop extension’) family of homeodomain-containing proteins. TALE homeobox proteins are highly conserved transcription regulators, and several members have been shown to be essential contributors to developmental programs. Multiple transcript variants encoding distinct isoforms have been described for this gene.

Source: NCBI Gene 4212 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 239 total — 21 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 56
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 10 downstream targets (CollecTRI)
• MANE Select transcript: NM_170675

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7001
Approved symbol	MEIS2
Name	Meis homeobox 2
Location	15q14
Locus type	gene with protein product
Status	Approved
Aliases	MRG1, HsT18361
Ensembl gene	ENSG00000134138
Ensembl biotype	protein_coding
OMIM	601740
Entrez	4212

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 19 protein_coding, 10 retained_intron, 9 protein_coding_CDS_not_defined, 5 nonsense_mediated_decay

ENST00000314177, ENST00000338564, ENST00000340545, ENST00000397620, ENST00000397624, ENST00000424352, ENST00000557796, ENST00000557992, ENST00000558643, ENST00000559085, ENST00000559129, ENST00000559371, ENST00000559408, ENST00000559561, ENST00000559972, ENST00000560570, ENST00000560617, ENST00000560697, ENST00000560702, ENST00000561163, ENST00000561208, ENST00000561264, ENST00000561284, ENST00000561422, ENST00000606653, ENST00000607277, ENST00000699898, ENST00000699899, ENST00000699900, ENST00000699901, ENST00000699902, ENST00000699903, ENST00000699904, ENST00000699905, ENST00000699906, ENST00000699955, ENST00000699956, ENST00000699957, ENST00000861683, ENST00000861684, ENST00000950915, ENST00000950916, ENST00000950917

RefSeq mRNA: 8 — MANE Select: NM_170675 NM_001220482, NM_002399, NM_170674, NM_170675, NM_170676, NM_170677, NM_172315, NM_172316

CCDS: CCDS10044, CCDS10045, CCDS42014, CCDS45217, CCDS45218, CCDS45219

Canonical transcript exons

ENST00000561208 — 12 exons

Exon	Start	End
ENSE00001929803	37099455	37100549
ENSE00003487762	36895151	36895261
ENSE00003544519	37036814	37036959
ENSE00003565296	37093581	37093730
ENSE00003594817	37096289	37096430
ENSE00003601407	36950324	36950400
ENSE00003626491	36896628	36896686
ENSE00003642793	37095564	37095614
ENSE00003684036	37097967	37098199
ENSE00003699736	37083771	37083885
ENSE00003728167	36889204	36892459
ENSE00003759114	37094527	37094577

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.3869 / max 656.5232, expressed in 1527 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149351	6.7191	1286
149348	3.5684	1119
149340	2.3804	865
149352	2.2650	1128
149341	1.3667	741
149344	1.1278	455
149339	0.9593	527
149338	0.8677	495
149350	0.8468	447
149346	0.8313	404

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	99.45	gold quality
ganglionic eminence	UBERON:0004023	99.25	gold quality
pancreatic ductal cell	CL:0002079	98.47	gold quality
parotid gland	UBERON:0001831	98.43	gold quality
palpebral conjunctiva	UBERON:0001812	98.42	gold quality
embryo	UBERON:0000922	98.37	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.77	gold quality
cauda epididymis	UBERON:0004360	97.48	gold quality
lateral globus pallidus	UBERON:0002476	97.34	gold quality
cortical plate	UBERON:0005343	97.24	gold quality
parietal pleura	UBERON:0002400	96.92	gold quality
body of uterus	UBERON:0009853	96.57	gold quality
urethra	UBERON:0000057	96.44	gold quality
germinal epithelium of ovary	UBERON:0001304	96.05	gold quality
pericardium	UBERON:0002407	95.80	gold quality
nucleus accumbens	UBERON:0001882	95.69	gold quality
islet of Langerhans	UBERON:0000006	95.50	gold quality
caudate nucleus	UBERON:0001873	95.19	gold quality
seminal vesicle	UBERON:0000998	95.11	gold quality
myometrium	UBERON:0001296	95.08	gold quality
pleura	UBERON:0000977	94.95	gold quality
prostate gland	UBERON:0002367	94.88	gold quality
putamen	UBERON:0001874	94.79	gold quality
sural nerve	UBERON:0015488	94.72	gold quality
adrenal tissue	UBERON:0018303	94.40	gold quality
nasal cavity mucosa	UBERON:0001826	94.32	gold quality
pylorus	UBERON:0001166	94.29	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.18	gold quality
heart right ventricle	UBERON:0002080	93.91	gold quality
epithelial cell of pancreas	CL:0000083	93.85	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	5594.66
E-CURD-119	yes	3850.27
E-HCAD-5	yes	1796.94
E-MTAB-11121	yes	1253.67
E-MTAB-9906	yes	903.47
E-HCAD-31	yes	792.71
E-HCAD-10	yes	791.03
E-MTAB-9154	yes	759.38
E-GEOD-114530	yes	717.94
E-ENAD-27	yes	627.85
E-MTAB-5061	yes	560.03
E-ANND-5	yes	464.34
E-HCAD-13	yes	143.06
E-GEOD-81608	yes	16.27
E-GEOD-93593	yes	15.78

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

10 targets.

Target	Regulation
CDH1	Activation
CDKN2A	Activation
CDKN2B	Activation
DRD1	Activation
EPHA8	Activation
IL17RB	Unknown
KRT19	Activation
NOTCH1
PAX6	Unknown
TGFBR2	Repression

JASPAR motifs

Motif	Name	Family
MA0774.1	MEIS2	TALE-type homeo domain factors
MA1640.1	MEIS2	TALE-type homeo domain factors
MA1640.2	MEIS2	TALE-type homeo domain factors

JASPAR matrix evidence (PMIDs): PMID:9405651, PMID:23602564

Upstream regulators (CollecTRI, top): MYC, RNF2, SATB2

miRNA regulators (miRDB)

194 targeting MEIS2, 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-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-8068	99.98	73.85	2376
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6825-5P	99.96	69.81	3431

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 38)

• Analysis of an Affymetrix data set in the public domain showed high expression of MEIS1 in human endometrium (PMID:18408019)
• co-expression of PBX1 and MEIS1/2 in granulosa cells in normal human ovaries suggested that MEIS1/2 might control PBX1 sublocalization, as seen in other systems (PMID:18973687)
• co-operation between TLX1 and MEIS proteins may have a significant role in T-cell leukemogenesis. (PMID:19559479)
• The Single Nucleotide Polymorphism in Meis homeobox 2 (MEIS2) mediated the effects of risperidone on hip circumference (q=0.004). (PMID:20195266)
• Data demonstrate by in situ hybridization and immunohistochemistry that the two homeobox genes Pax6 and MEIS2 are expressed during early fetal brain development in humans. (PMID:20523026)
• This work suggests that the transcriptional activity of all members of the Meis/Prep Hth protein family is subject to autoinhibition by their Hth domains, and that the Meis3.2 splice variant encodes a protein that bypasses this autoinhibitory effect. (PMID:20553494)
• Transgenic mice lacking microRNAs miR-9-2 and miR-9-3 exhibit multiple defects of telencephalic structures which may be brought about by dysregulation of Foxg1, Nr2e1, Gsh2, and Meis2 expression. (PMID:21368052)
• Klf4 recruits a complex of Meis and Pbx proteins to DNA, resulting in Meis2 transcriptional activation domain-dependent activation of a subset of Klf4 target genes. (PMID:21746878)
• The data suggest existence of a complex regulatory pathway in the trabecular meshwork part of which includes interactions between FOXC1, miR-204, MEIS2, and ITGbeta1. (PMID:23541832)
• Our results show that MEIS2 is a gene needed for palate closure. In syndromic cases of cleft palate, MEIS2 should be considered among the candidate genes, for example, in cases without 22q11.2 deletions. (PMID:24678003)
• FOXM1 is a direct target gene of MEIS2 and is required for MEIS2 to upregulate mitotic genes. (PMID:25210800)
• This is the first report showing a de novo small intragenic mutation in MEIS2 and further confirms the important role of this gene in normal development. (PMID:25712757)
• Meis2 as the target of miR-134 in the regulation of cardiomyocyte progenitor cell proliferation. (PMID:26512644)
• we have identified a novel nonsense MEIS2 mutation in a female patient with cleft palate, cardiac septal defect, severe ID, developmental delay and feeding difficulty with gastro-esophageal reflux. Our findings strongly suggest neurocristopathy be included in the clinical features associated with MEIS2 alterations. (PMID:27225850)
• High expression of MEIS2 impairs repressive DNA binding of AML1-ETO, inducing increased expression of genes such as the druggable proto-oncogene YES1. (PMID:27346355)
• Mechanistic analyses integrate this unrecognized anti-atrial function of ISL1 with known and newly identified atrial inducers. In this revised view, ISL1 is antagonized by retinoic acid signaling via a novel player, MEIS2. (PMID:29337667)
• Moderate elevation of MEIS2A expression reduced proliferation of MYCN-amplified human neuroblastoma cells, induced neuronal differentiation and impaired the ability of these cells to form tumors in mice (PMID:29382709)
• These data implicate a functional role for MEIS proteins in regulating cancer progression, and support a hypothesis whereby tumor expression of MEIS1 and MEIS2 expression confers a more indolent prostate cancer phenotype, with a decreased propensity for metastatic progression (PMID:29716922)
• these are the first described de novo missense variants in MEIS2, expanding the known mutation spectrum of the newly recognized human disorder caused by aberrations in this gene. (PMID:30055086)
• Loss-of-function MEIS2 mutations were identified in nine patients with palatal defects, congenital heart defects, and intellectual disability. (PMID:30291340)
• TAL1 acts as a downstream gene mediating the function of MEIS2 during early hematopoiesis. (PMID:30526668)
• The present study indicated that Meis2 repress the osteoblastic transdifferentiation of aortic valve interstitial cells through the Notch1/Twist1 signaling pathway. (PMID:30594396)
• Study shows that MEIS2 expression is regulated in bladder neoplasm via alternative splicing by PTBP1. (PMID:30742945)
• MEIS2 might be involved in the Wnt/beta-catenin pathway. (PMID:30859572)
• Study demonstrated that MEIS2 acted as a promoter of metastasis in colorectal cancer (CRC). Knockdown of MEIS2 significantly suppressed CRC migration, invasion and EMT. MEIS2 was associated with a shorter overall survival time for patients with CRC. These results suggest that MEIS2 may serve as a novel biomarker for CRC. (PMID:31115559)
• Inhibition of Senescence-Associated Genes Rb1 and Meis2 in Adult Cardiomyocytes Results in Cell Cycle Reentry and Cardiac Repair Post-Myocardial Infarction. (PMID:31315484)
• MEISC/D promote hepatocellular carcinoma development via Wnt/beta-catenin and Hippo/YAP signaling pathways (PMID:31623651)
• Results strongly indicate that aberrant DNA hypermethylation is associated with epigenetic silencing of MEIS2 transcriptional expression in prostate cancer (PC) and validate MEIS2 as a potential prognostic biomarker for PC. (PMID:31640805)
• MEIS2 sequence variant in a child with intellectual disability and cardiac defects: Expansion of the phenotypic spectrum and documentation of low-level mosaicism in an unaffected parent. (PMID:33091211)
• Intellectual disability associated with craniofacial dysmorphism, cleft palate, and congenital heart defect due to a de novo MEIS2 mutation: A clinical longitudinal study. (PMID:33427397)
• Expression of ISL1 and its partners in prostate cancer progression and neuroendocrine differentiation. (PMID:33864110)
• Meis homeobox 2 (MEIS2) inhibits the proliferation and promotes apoptosis of thyroid cancer cell and through the NF-kappaB signaling pathway. (PMID:33975520)
• IGF2BP2 promotes the progression of ovarian endometriosis by regulating m6A-modified MEIS2 and GATA6. (PMID:36113831)
• CircDHRS3 inhibits prostate cancer cell proliferation and metastasis through the circDHRS3/miR-421/MEIS2 axis. (PMID:36840946)
• LINC-PINT suppresses breast cancer cell proliferation and migration via MEIS2/PPP3CC/NF-kappaB pathway by sponging miR-576-5p. (PMID:37660994)
• Cellular Ligand-Receptor Perturbations Unravel MEIS2 as a Key Factor for the Aggressive Progression and Prognosis in Stage II/III Colorectal Cancer. (PMID:38153233)
• Novel genetic markers for chronic kidney disease in a geographically isolated population of Indigenous Australians: Individual and multiple phenotype genome-wide association study. (PMID:38347632)
• MEIS2 suppresses breast cancer development by downregulating IL10. (PMID:38711262)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	meis2a	ENSDARG00000098240
mus_musculus	Meis2	ENSMUSG00000027210
rattus_norvegicus	Meis2	ENSRNOG00000004730
drosophila_melanogaster	exd	FBGN0000611
drosophila_melanogaster	hth	FBGN0001235
drosophila_melanogaster	vis	FBGN0033748
drosophila_melanogaster	achi	FBGN0033749
caenorhabditis_elegans		WBGENE00000443
caenorhabditis_elegans		WBGENE00006796
caenorhabditis_elegans		WBGENE00017690

Paralogs (13): MEIS3 (ENSG00000105419), PBX4 (ENSG00000105717), TGIF2 (ENSG00000118707), MEIS1 (ENSG00000143995), TGIF2LX (ENSG00000153779), PKNOX1 (ENSG00000160199), PKNOX2 (ENSG00000165495), PBX3 (ENSG00000167081), TGIF2LY (ENSG00000176679), TGIF1 (ENSG00000177426), PBX1 (ENSG00000185630), MEIS3P2 (ENSG00000188013), PBX2 (ENSG00000204304)

Protein

Protein identifiers

Homeobox protein Meis2 — O14770 (reviewed: O14770)

Alternative names: Meis1-related protein 1

All UniProt accessions (10): O14770, A0A8V8TPB7, A0A8V8TPM6, A0A8V8TQU6, A0A9H3ZWV7, H0YKE5, H0YKN2, H0YM65, U3KQ95, U3KQI2

UniProt curated annotations — full annotation on UniProt →

Function. Involved in transcriptional regulation. Binds to HOX or PBX proteins to form dimers, or to a DNA-bound dimer of PBX and HOX proteins and thought to have a role in stabilization of the homeoprotein-DNA complex. Isoform 3 is required for the activity of a PDX1:PBX1b:MEIS2b complex in pancreatic acinar cells involved in the transcriptional activation of the ELA1 enhancer; the complex binds to the enhancer B element and cooperates with the transcription factor 1 complex (PTF1) bound to the enhancer A element; MEIS2 is not involved in complex DNA-binding. Probably in complex with PBX1, is involved in transcriptional regulation by KLF4. Isoform 3 and isoform 4 can bind to a EPHA8 promoter sequence containing the DNA motif 5’-CGGTCA-3’; in cooperation with a PBX protein (such as PBX2) is proposed to be involved in the transcriptional activation of EPHA8 in the developing midbrain. May be involved in regulation of myeloid differentiation. Can bind to the DNA sequence 5’-TGACAG-3’in the activator ACT sequence of the D(1A) dopamine receptor (DRD1) promoter and activate DRD1 transcription; isoform 5 cannot activate DRD1 transcription.

Subunit / interactions. Monomer and homodimer. Heterodimer with HOXB13 (Ref.16). Isoform 2 interacts with TLX1. Isoform 3 interacts with HOXA13 and PBX1 isoform PBX1b. Isoform 4 interacts with SP1, SP3 and KLF4. Isoform 4 and isoform 5 interact with PBX1 isoform PBX1a; the interaction partially relieves MEIS2 autoinhibition. Isoform 3 also known as MEIS2b is part of a PDX1:PBX1b:Meis2B complex; Meis2B is recruited by PBX1b and can be replaced by isoform 4 in a small fraction of complexes. Can form trimeric complexes including HOXB8 and PBX2 or PBX3.

Subcellular location. Nucleus. Cytoplasm. Perinuclear region.

Tissue specificity. Expressed in various tissues. Expressed at high level in the lymphoid organs of hematopoietic tissues. Also expressed in some regions of the brain, such as the putamen.

Disease relevance. Cleft palate, cardiac defects, and impaired intellectual development (CPCMR) [MIM:600987] An autosomal dominant disease characterized by multiple congenital malformations, mild-to-severe intellectual disability with poor speech, and delayed psychomotor development. Congenital malformations include heart defects, cleft lip/palate, distally-placed thumbs and toes, and cutaneous syndactyly between the second and third toes. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TALE/MEIS homeobox family.

Isoforms (8)

UniProt ID	Names	Canonical?
O14770-1	1, Meis2C	yes
O14770-2	2, Meis2A
O14770-3	3, Meis2B
O14770-4	4, Meis2D
O14770-5	5, Meis2E
O14770-6	6
O14770-7	7
O14770-8	8

RefSeq proteins (8): NP_001207411, NP_002390, NP_733774, NP_733775, NP_733776, NP_733777, NP_758526, NP_758527 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001356	HD	Domain
IPR008422	KN_HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR032453	PKNOX/Meis_N	Domain
IPR050224	TALE_homeobox	Family

Pfam: PF05920, PF16493

UniProt features (32 total): mutagenesis site 8, splice variant 7, helix 4, region of interest 4, compositionally biased region 3, sequence variant 2, chain 1, domain 1, DNA-binding region 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4XRM	X-RAY DIFFRACTION	1.6
3K2A	X-RAY DIFFRACTION	1.95
5EG0	X-RAY DIFFRACTION	3.1
5BNG	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14770-F1	63.16	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.

Mutagenesis-validated functional residues (8):

Position	Phenotype
85	impairs interaction with pbx1; when associated with a-88.
88	impairs interaction with pbx1; when associated with a-85. helix 285 297.
94–97	impairs interaction with pbx1.
151	impairs interaction with pbx1; when associated with a-154.
154	impairs interaction with pbx1; when associated with a-151.
158–159	impairs interaction with pbx1; when associated with a-161.
161	impairs interaction with pbx1; when associated with 158-a-a-159.
332	impairs dna binding and pbx1-dependent transcriptional activation. no effect on interaction with pbx1.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 583 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, RNGTGGGC_UNKNOWN, E2F_Q4, E2F_Q4_01, AAGCAAT_MIR137, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_COGNITION, GOBP_BEHAVIOR, NKX25_02, GOBP_ASSOCIATIVE_LEARNING, AREB6_03, BOYAULT_LIVER_CANCER_SUBCLASS_G2, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, chr15q14

GO Biological Process (15): negative regulation of transcription by RNA polymerase II (GO:0000122), eye development (GO:0001654), brain development (GO:0007420), positive regulation of cell population proliferation (GO:0008284), visual learning (GO:0008542), response to mechanical stimulus (GO:0009612), embryonic pattern specification (GO:0009880), animal organ morphogenesis (GO:0009887), pancreas development (GO:0031016), negative regulation of myeloid cell differentiation (GO:0045638), positive regulation of mitotic cell cycle (GO:0045931), positive regulation of transcription by RNA polymerase II (GO:0045944), response to growth factor (GO:0070848), positive regulation of cardiac muscle myoblast proliferation (GO:0110024), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA binding (GO:0003677), transcription factor binding (GO:0008134), sequence-specific DNA binding (GO:0043565), sequence-specific double-stranded DNA binding (GO:1990837), protein binding (GO:0005515)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of transcription by RNA polymerase II	3
animal organ development	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
transcription by RNA polymerase II	2
negative regulation of DNA-templated transcription	1
sensory organ development	1
visual system development	1
central nervous system development	1
head development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
visual behavior	1
associative learning	1
response to external stimulus	1
response to abiotic stimulus	1
pattern specification process	1
embryo development	1
anatomical structure morphogenesis	1
myeloid cell differentiation	1
negative regulation of cell differentiation	1
regulation of myeloid cell differentiation	1
mitotic cell cycle	1
regulation of mitotic cell cycle	1
positive regulation of cell cycle	1
positive regulation of DNA-templated transcription	1
response to endogenous stimulus	1
cardiac muscle myoblast proliferation	1
regulation of cardiac muscle myoblast proliferation	1
positive regulation of myoblast proliferation	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1

Protein interactions and networks

STRING

1794 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MEIS2	PBX1	P40424	837
MEIS2	PAX6	P26367	820
MEIS2	DLX2	Q07687	807
MEIS2	CRBN	Q96SW2	683
MEIS2	HOXB7	P09629	658
MEIS2	OTX2	P32243	615
MEIS2	PBX2	P40425	614
MEIS2	HOXA9	P31269	611
MEIS2	HOXB3	P14651	604
MEIS2	MEF2C	Q06413	572
MEIS2	HOXA10	P31260	563
MEIS2	HOXB8	P17481	552
MEIS2	DDB1	Q16531	546
MEIS2	GSX2	Q9BZM3	543
MEIS2	TLE4	Q04727	538

IntAct

44 interactions, top by confidence:

A	B	Type	Score
OSGIN1	MEIS2	psi-mi:“MI:0915”(physical association)	0.670
MEIS2	OSGIN1	psi-mi:“MI:0915”(physical association)	0.670
MEIS2	PBX1	psi-mi:“MI:0915”(physical association)	0.660
MEIS2	PBX1	psi-mi:“MI:0914”(association)	0.660
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
CCDC196	MEIS2	psi-mi:“MI:0915”(physical association)	0.560
ANXA1	MEIS2	psi-mi:“MI:0915”(physical association)	0.560
C1orf94	MEIS2	psi-mi:“MI:0915”(physical association)	0.560
MEIS2	CCDC196	psi-mi:“MI:0915”(physical association)	0.560
MEIS2	ANXA1	psi-mi:“MI:0915”(physical association)	0.560
MEIS2	C1orf94	psi-mi:“MI:0915”(physical association)	0.560
MEIS2	gag-pro-pol	psi-mi:“MI:0915”(physical association)	0.560
DNAAF8	CCDC85C	psi-mi:“MI:0914”(association)	0.530
MAB21L1	MEIS1	psi-mi:“MI:0914”(association)	0.530
MAB21L2	MEIS1	psi-mi:“MI:0914”(association)	0.530
FAM222A	MEIS1	psi-mi:“MI:0914”(association)	0.530
	MEIS2	psi-mi:“MI:0407”(direct interaction)	0.440
	MEIS2	psi-mi:“MI:0915”(physical association)	0.400
MEIS2	MEIS2	psi-mi:“MI:0915”(physical association)	0.370
XCL1	MEIS2	psi-mi:“MI:0915”(physical association)	0.370
MEIS2	TRIM25	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (128): MEIS2 (Two-hybrid), MEIS2 (Two-hybrid), OSGIN1 (Two-hybrid), C1orf94 (Two-hybrid), LINC00238 (Two-hybrid), MEIS2 (Affinity Capture-MS), MEIS2 (Affinity Capture-MS), MEIS3 (Affinity Capture-MS), MEIS1 (Affinity Capture-MS), PBX1 (Affinity Capture-MS), PBX2 (Affinity Capture-MS), PBX4 (Affinity Capture-MS), PBX3 (Affinity Capture-MS), GNB4 (Affinity Capture-MS), PIGL (Affinity Capture-MS)

ESM2 similar proteins: A1YFU7, A8WL06, O14770, O35740, O42368, O46250, O76971, O77215, P07548, P09077, P09081, P20482, P20822, P23023, P25822, P31264, P40657, P40791, P43699, P54231, P54269, P56672, P83949, P83950, P91607, P91613, P91686, P91697, P91698, P91705, P91716, P92203, P97367, Q05201, Q0VCT9, Q24248, Q24255, Q24573, Q2Z1R2, Q5XGW7

Diamond homologs: A1YER0, A2D5H2, A6NDR6, A8K0S8, A8WL06, B3DM47, B4F6V6, O00470, O04134, O04135, O14770, O17894, O22299, O35317, O35984, O42406, O46339, O65034, O73916, O80416, O93307, O95343, O95475, P10842, P24345, P40424, P40425, P40426, P40427, P41778, P41779, P41817, P46608, P46609, P46639, P46640, P48731, P53147, P56661, P56662

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
KLF4	“up-regulates activity”	MEIS2	binding
MEIS2	“up-regulates quantity by expression”	CDKN2A	“transcriptional regulation”
MEIS2	“up-regulates quantity by expression”	CDH1	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 32 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.

GO biological processes:

GO term	Partners	Fold	FDR
eye development	6	84.3×	2e-08
brain development	5	15.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	23
Uncertain significance	110
Likely benign	51
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1199240	NM_170675.5(MEIS2):c.992G>A (p.Arg331Lys)	Pathogenic
1285573	NM_170675.5(MEIS2):c.977+2T>G	Pathogenic
1343136	NM_170675.5(MEIS2):c.751C>T (p.Gln251Ter)	Pathogenic
1527861	NM_170675.5(MEIS2):c.639+1G>A	Pathogenic
1708881	NM_170675.5(MEIS2):c.104dup (p.Val36fs)	Pathogenic
2502862	NM_170675.5(MEIS2):c.122_126delinsTGA (p.His41fs)	Pathogenic
2575990	NM_170675.5(MEIS2):c.977+1G>A	Pathogenic
2662809	NM_170675.5(MEIS2):c.991A>G (p.Arg331Gly)	Pathogenic
3376268	NM_170675.5(MEIS2):c.454C>T (p.Gln152Ter)	Pathogenic
3600288	NM_170675.5(MEIS2):c.654G>A (p.Trp218Ter)	Pathogenic
3600577	NM_170675.5(MEIS2):c.889C>T (p.Gln297Ter)	Pathogenic
4074781	NM_170675.5(MEIS2):c.777_795dup (p.Asp266delinsSerPheThrTrpTyrArgTer)	Pathogenic
427214	NG_029108.1:g.120078_181902dup	Pathogenic
427215	NM_170675.5(MEIS2):c.611C>G (p.Ser204Ter)	Pathogenic
4685559	NM_170675.5(MEIS2):c.505_512dup (p.Phe171fs)	Pathogenic
489082	NM_170675.5(MEIS2):c.520C>T (p.Arg174Ter)	Pathogenic
545068	NM_170675.5(MEIS2):c.978-2A>G	Pathogenic
559625	NM_170675.5(MEIS2):c.825dup (p.Arg276fs)	Pathogenic
620448	NM_170675.5(MEIS2):c.424G>T (p.Glu142Ter)	Pathogenic
685290	GRCh37/hg19 15q14(chr15:37299667-37409497)x1	Pathogenic
686274	GRCh37/hg19 15q14(chr15:37328530-37383148)x1	Pathogenic
1033183	NM_170675.5(MEIS2):c.877G>C (p.Ala293Pro)	Likely pathogenic
1334732	NM_170675.5(MEIS2):c.968T>G (p.Val323Gly)	Likely pathogenic
1683752	NM_170675.5(MEIS2):c.1025C>G (p.Ser342Ter)	Likely pathogenic
1700237	NM_170675.5(MEIS2):c.973A>G (p.Asn325Asp)	Likely pathogenic
1706599	NM_170675.5(MEIS2):c.907T>A (p.Tyr303Asn)	Likely pathogenic
1709727	NM_170675.5(MEIS2):c.999A>C (p.Arg333Ser)	Likely pathogenic
1804899	NM_170675.5(MEIS2):c.986A>G (p.Asn329Ser)	Likely pathogenic
2442198	NM_170675.5(MEIS2):c.777_781del (p.Ala260fs)	Likely pathogenic
2575802	NM_170675.5(MEIS2):c.994A>G (p.Arg332Gly)	Likely pathogenic

SpliceAI

3414 predictions. Top by Δscore:

Variant	Effect	Δscore
15:36896613:C:CT	donor_gain	1.0000
15:36896614:T:TT	donor_gain	1.0000
15:36908288:C:T	acceptor_gain	1.0000
15:36908294:C:CT	acceptor_gain	1.0000
15:37036807:GACTT:G	donor_loss	1.0000
15:37036808:ACTTA:A	donor_loss	1.0000
15:37036809:CT:C	donor_loss	1.0000
15:37036810:TT:T	donor_loss	1.0000
15:37036811:T:TG	donor_loss	1.0000
15:37036812:A:AC	donor_gain	1.0000
15:37036812:ACTGT:A	donor_loss	1.0000
15:37036813:C:CC	donor_gain	1.0000
15:37036813:CT:C	donor_gain	1.0000
15:37036956:TCCC:T	acceptor_gain	1.0000
15:37036957:CCC:C	acceptor_gain	1.0000
15:37036957:CCCC:C	acceptor_gain	1.0000
15:37036958:CCC:C	acceptor_gain	1.0000
15:37036959:CC:C	acceptor_loss	1.0000
15:37036959:CCTAG:C	acceptor_gain	1.0000
15:37036960:C:CC	acceptor_gain	1.0000
15:37036960:C:CG	acceptor_loss	1.0000
15:37083932:C:CT	acceptor_gain	1.0000
15:37083933:A:T	acceptor_gain	1.0000
15:37083935:CAA:C	acceptor_gain	1.0000
15:37083936:A:T	acceptor_gain	1.0000
15:37083937:A:AC	acceptor_gain	1.0000
15:37083946:C:CT	acceptor_gain	1.0000
15:37083946:C:T	acceptor_gain	1.0000
15:37083947:A:T	acceptor_gain	1.0000
15:37083955:C:CT	acceptor_gain	1.0000

AlphaMissense

3177 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:36896648:A:C	I339S	1.000
15:36896648:A:T	I339N	1.000
15:36896650:C:A	M338I	1.000
15:36896650:C:G	M338I	1.000
15:36896650:C:T	M338I	1.000
15:36896651:A:G	M338T	1.000
15:36896651:A:T	M338K	1.000
15:36896654:G:A	P337L	1.000
15:36896654:G:C	P337R	1.000
15:36896654:G:T	P337H	1.000
15:36896655:G:A	P337S	1.000
15:36896655:G:T	P337T	1.000
15:36896656:C:A	Q336H	1.000
15:36896656:C:G	Q336H	1.000
15:36896660:A:G	V335A	1.000
15:36896660:A:T	V335E	1.000
15:36896663:A:C	I334R	1.000
15:36896663:A:G	I334T	1.000
15:36896663:A:T	I334K	1.000
15:36896665:T:A	R333S	1.000
15:36896665:T:G	R333S	1.000
15:36896666:C:A	R333I	1.000
15:36896666:C:G	R333T	1.000
15:36896667:T:C	R333G	1.000
15:36896668:T:A	R332S	1.000
15:36896668:T:G	R332S	1.000
15:36896669:C:A	R332I	1.000
15:36896669:C:G	R332T	1.000
15:36896670:T:C	R332G	1.000
15:36896671:T:A	R331S	1.000

dbSNP variants (sampled 300 via entrez): RS1000006493 (15:36963035 G>A), RS1000008897 (15:36916619 G>C), RS1000010544 (15:37076831 T>C), RS1000017696 (15:37035748 C>G), RS1000020036 (15:36904523 C>T), RS1000031445 (15:36955201 C>T), RS1000035423 (15:36991217 C>G,T), RS1000037557 (15:36899001 A>G), RS1000059034 (15:36948630 T>C), RS1000078210 (15:36961489 G>A), RS1000103713 (15:37040765 G>T), RS1000121330 (15:36891225 C>A,G), RS1000121985 (15:36916406 G>A), RS1000127358 (15:36950196 G>A), RS1000148455 (15:37047422 T>C)

Disease associations

OMIM: gene MIM:601740 | disease phenotypes: MIM:600987

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies	Definitive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (4): cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies (MONDO:0010970), cleft palate (MONDO:0016064), syndromic intellectual disability (MONDO:0000508), cleft lip/palate (MONDO:0016044)

Orphanet (3): Cleft palate (Orphanet:2014), Rare genetic syndromic intellectual disability (Orphanet:183763), Cleft lip/palate (Orphanet:199306)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000204	Cleft upper lip
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000307	Pointed chin
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000426	Prominent nasal bridge
HP:0000444	Convex nasal ridge
HP:0000490	Deeply set eye
HP:0000582	Upslanted palpebral fissure
HP:0000717	Autism
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001061	Acne
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001601	Laryngomalacia
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001680	Coarctation of aorta
HP:0001684	Secundum atrial septal defect

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000278_14	Hyperactive-impulsive symptoms	4.000000e-06
GCST000618_22	Response to antipsychotic treatment	1.000000e-08
GCST002168_4	Intraocular pressure	1.000000e-06
GCST003263_44	Post bronchodilator FEV1 in COPD	5.000000e-06
GCST004029_17	Angiotensin-converting enzyme inhibitor intolerance	2.000000e-06
GCST005042_14	Restless legs syndrome	3.000000e-27
GCST006041_11	Major depressive disorder	1.000000e-08
GCST008491_12	Voxel-wise structural brain imaging measurements in Alzheimer’s disease	2.000000e-06
GCST011050_5	Postprandial triglyceride response	2.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0004314	forced expiratory volume
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0004346	neuroimaging measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
C563414	Cardiac Malformation, Cleft Lip-Palate, Microcephaly and Digital Anomalies (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
trichostatin A	affects cotreatment, increases expression	3
Air Pollutants	decreases expression, decreases methylation, increases abundance	3
Tretinoin	increases expression, affects cotreatment	3
bisphenol A	affects cotreatment, increases methylation, increases expression	2
sodium arsenite	decreases expression, increases abundance	2
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, decreases expression	2
(+)-JQ1 compound	affects expression, increases reaction, decreases expression	2
Ethanol	affects cotreatment, increases expression, decreases expression	2
Arsenic	increases response to substance, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression, decreases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
4-oxoretinoic acid	increases expression	1
methylmercuric chloride	decreases expression	1
apocarotenal	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
ferrous chloride	decreases expression	1
nickel sulfate	increases expression	1
4-oxoretinol	increases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
pomalidomide	decreases reaction, increases degradation, increases ubiquitination, affects binding	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A4C8	SEES3-1V human MEIS2, clone1	Embryonic stem cell	Male
CVCL_A4C9	SEES3-1V human MEIS2, clone2	Embryonic stem cell	Male
CVCL_A4D0	SEES3-1V human MEIS2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02422056	PHASE4	COMPLETED	Acid Tranexamic Effectiveness in Reducing the Intraoperative Bleeding in Palatoplasty
NCT02915042	PHASE4	WITHDRAWN	Dexmedetomidine vs Placebo for Pediatric Cleft Palate Repair
NCT02953145	PHASE4	WITHDRAWN	The Use of Fibrin Sealant to Reduce Post Operative Pain in Cleft Palate Surgery
NCT03632044	PHASE4	ACTIVE_NOT_RECRUITING	Evaluation of Trigeminal Nerve Blockade
NCT06962306	PHASE4	RECRUITING	Optimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT04234971	PHASE4	RECRUITING	Cost Effectiveness in Alveolar Bone Grafting in Patients With Cleft Lip and Palate
NCT04771156	PHASE4	RECRUITING	Ketorolac in Palatoplasty
NCT00098319	PHASE3	COMPLETED	Oral Cleft Prevention Trial in Brazil
NCT00397917	PHASE3	COMPLETED	Oral Cleft Prevention Program
NCT04928352	PHASE3	RECRUITING	Nebulized Bupivacaine Analgesia for Cleft Palate Repair
NCT04928391	PHASE3	COMPLETED	A Single Bolus of Dexmedetomidine Versus Normal Saline in Postoperative Agitation
NCT03766217	PHASE3	COMPLETED	Bone Tissue Engineering With Dental Pulp Stem Cells for Alveolar Cleft Repair
NCT06284434	PHASE3	RECRUITING	Liposomal Bupivacaine Use in Alveolar Bone Graft Patients
NCT00004639	PHASE2	COMPLETED	Cleft Palate Surgery and Speech Development
NCT00760006	PHASE2	COMPLETED	Preventing Complications in Cleft Palate Repair With Antibiotics
NCT01760330	PHASE2	WITHDRAWN	IV Acetaminophen in Children Undergoing Palatoplasty
NCT02350803	PHASE2	COMPLETED	Does Use of Rigid Fixation After Removing Distraction Osteogenesis Device Reduce the Relapse?
NCT03412474	PHASE2	COMPLETED	Suprazygomatic Block in Cleft Palate Surgery in Children
NCT00930124	PHASE2	COMPLETED	Cleft Orthognathic Surgery Versus Distraction Osteogenesis - Which is Better?
NCT01616953	PHASE1/PHASE2	COMPLETED	Cell Therapy for Craniofacial Bone Defects
NCT02247193	PHASE1/PHASE2	COMPLETED	Botulinum Toxin to Improve Cosmesis of Primary Cleft Lip Repair
NCT00097149	Not specified	COMPLETED	Systematic Pediatric Care for Oral Clefts - South America
NCT00285714	Not specified	UNKNOWN	3D Imaging of Hard and Soft Tissue in Orthognathic Surgery
NCT00340977	Not specified	COMPLETED	Svangerskap, Arv, Og Miljo (Pregnancy, Heredity and Environment)
NCT00423072	Not specified	COMPLETED	Middle Ear Pressure Disregulation in Cleft Palate Patients
NCT00584272	Not specified	COMPLETED	Retrospective Study on the Outcome of Cleft Palate Repair: Comparing US Surgical and Ethicon Suture Materials
NCT00773994	Not specified	COMPLETED	Pilot Study Evaluating Characteristic Closure Patterns of the Normal Velopharyngeal Portal
NCT00779961	Not specified	UNKNOWN	An Investigation for the Optimal Timing of a Cleft Palate Repair
NCT00829101	Not specified	COMPLETED	Articulation and Phonology in Children With Unilateral Cleft Lip and Palate
NCT00993551	Not specified	COMPLETED	Timing of Primary Surgery for Cleft Palate
NCT00993993	Not specified	COMPLETED	Relational Development in Children With Cleft Lips and Palates: Influence of the Waiting Period Prior to the First Surgical Intervention and the Parents’ Psychological Perception of the Abnormality
NCT01046591	Not specified	COMPLETED	Sleep and Behavior in Children With Cleft Palate
NCT01252264	Not specified	COMPLETED	FaceBase Biorepository
NCT01380171	Not specified	COMPLETED	Primary Palatoplasty in Pediatric Patients - A Retrospective Review of Surgical Outcomes
NCT01500109	Not specified	COMPLETED	Efficacy of Oral Versus Intravenous Acetaminophen for Primary Pediatric Cleft Palate Repair
NCT01535131	Not specified	COMPLETED	Furlow Palatoplasty With Tensor Tenopexy
NCT01601171	Not specified	RECRUITING	Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate
NCT01867632	Not specified	COMPLETED	Acellular Dermal Matrix in Primary Palatoplasty
NCT02329509	Not specified	COMPLETED	Evaluation of Facial Growth in Two Primary Protocols Used in the Surgical Treatment of Unilateral Cleft Lip and Palate Patients
NCT02415361	Not specified	COMPLETED	Follow Ups of Parents With Infants With Cleft Lip and Palate