MEIS2
protein-codingMeis homeobox 2, the group of TALE class homeoboxes and pseudogenes|MicroRNA protein coding host genes
Gene summary
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. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~212.1 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0010970
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0000508
Submitter: ClinGen
Variants in *MEIS2* were first reported in relation to syndromic intellectual disability by Johannson et al. in 2014 (PMID: 24678003). The authors identified a 58 kb intragenic, tandem duplication of exon 9 and the flanking intronic region that was predicted to result in a frameshift and protein truncation in a mother and three children with syndromic intellectual disability. Since that time, additional publications have described individuals with variants in the *MEIS2* gene. Clinical features in affected individuals with *MEIS2* variants include palatal defects, intellectual disability, autism spectrum disorder, dysmorphic features, gastroesophageal reflux, and various types of structural congenital heart disease, including atrial septal defect, ventricular septal defect, coarctation of aorta, and tetralogy of Fallot. *MEIS2* is a member of the Three Amino-acid Loop Extension (TALE) family and encodes a homeodomain-containing transcription factor. At least 27 probands with *MEIS2* variants have been reported in the literature. At least three intragenic copy number variants have been reported in three probands (PMIDs: 20425846, 24678003, 28934986), 13 unique nonsense, canonical splice-site, and frameshift variants have been reported in 15 probands (PMIDs: 27225850, 27479907, 30291340, 30735726, 31452935, 32345733, 33004838, 33722742), six unique missense variants have been reported in seven probands (PMIDs: 29322350, 30055086, 30291340, 33427397), and one in-frame deletion in two probands (PMIDs: 25712757, 33091211). Missense variants cluster in the homeodomain alpha helices (PMID: 30055086). The mechanism of pathogenicity is loss of function. Variants are *de novo* in a majority of probands though inheritance from an unaffected parent with low-level mosaicism and mildly affected parent have been reported (PMIDs: 24678003, 33091211, 33722742). This gene-disease association is also supported by experimental evidence, including mouse (PMIDs: 26545946, 32169905) and zebrafish models (PMIDs: 22981225, 23559552). In summary, there is definitive evidence to support the relationship between *MEIS2* and autosomal dominant syndromic intellectual disability. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on April 22, 2022 (SOP Version 8). As of June 2024, this record underwent administrative updates to include additional information about the cardiac presentation oif this condition which was provided by the Congenital Heart Disease GCEP. No new evidence was added or scored.
Inheritance Pattern: AD
Disease ID:MONDO:0010970
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0010970
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0010970
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early identifcation and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MEIS2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_170675.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 42 | 1 | 47 | ||
| missense | 4 | 12 | 100 | 11 | 4 | 131 |
| nonsense | 7 | 3 | 1 | 11 | ||
| start loss | 0 | |||||
| frameshift | 5 | 7 | 3 | 15 | ||
| splice donor/acceptor (+/-2bp) | 4 | 4 | 4 | 12 | ||
| Total | 20 | 26 | 112 | 53 | 5 | 216 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_733775.1 | 12 | MANE Select | |
| Ensembl | ENSP00000453793.1 | 12 | MANE Select | |
| RefSeq | NP_001207411.1 | 12 | Standard | |
| RefSeq | NP_002390.1 | 11 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| meis2a | Danio rerio | Structure: cranial cartilage Quality: mislocalised abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- negative regulation of transcription by RNA polymerase II
- eye development
- transcription by RNA polymerase II
- visual learning
- response to mechanical stimulus
Molecular Function
- RNA polymerase II proximal promoter sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA binding
- DNA-binding transcription factor activity
Cellular Component
- nucleus
- perinuclear region of cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000561208
- Coding exons
- 12
- Length
- 212099
- Individuals with no LoFs
- 125642
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125647
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.46 | 171 | 288 | 0.593 | 0.0000145 | 3167 |
| Missense (PolyPhen) | 19 | 76.782 | 0.24745 | 928 | ||
| Synonymous | -0.239 | 113 | 110 | 1.03 | 0.00000657 | 901 |
| Loss of Function | 4.52 | 1 | 25.7 | 0.0389 | 0.00000126 | 284 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000019 | 0.000018 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- 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. {ECO:0000269|PubMed:10764806, ECO:0000269|PubMed:11279116, ECO:0000269|PubMed:21746878}.;
- Disease
- DISEASE: Cleft palate, cardiac defects, and mental retardation (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. {ECO:0000269|PubMed:24678003, ECO:0000269|PubMed:25712757, ECO:0000269|PubMed:27225850}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.163
Intolerance Scores
- LoFtool
- 0.0910
- RVIS EVS
- -0.4
- RVIS percentile EVS
- 26.53
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.977
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |