Alternative titles; symbols
HGNC Approved Gene Symbol: MEIS2
Cytogenetic location: 15q14 Genomic coordinates (GRCh38): 15:36,889,204-37,101,311 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q14 | Cleft palate, cardiac defects, and impaired intellectual development | 600987 | Autosomal dominant | 3 |
The MEIS2 gene encodes a homeodomain-containing transcription factor (summary by Louw et al., 2015).
The Meis1 locus (601739) was isolated as a common site of viral integration involved in myeloid leukemia in BXH-2 mice. Steelman et al. (1997) noted that MEIS1 encodes a homeobox protein belonging to the TALE ('three amino acid loop extension') family of homeodomain-containing proteins. The homeodomain of MEIS1 is the only conserved motif in the entire 390-amino acid protein. Steelman et al. (1997) reported that Southern blot analyses using the MEIS1 homeodomain as a probe revealed the existence of a family of Meis1-related genes (MRGs) in several divergent species. In addition, the 3-prime untranslated region (UTR) of MEIS1 is remarkably conserved in evolution. Steelman et al. (1997) cloned Meis1-related genes from the mouse and human genomes. One such gene, which the authors designated Mrg1, shares a similar genomic organization in the mouse with Meis1.
During the course of their studies of the human MEIS1 homeobox gene, Smith et al. (1997) identified a gene closely related but not identical to MEIS1. Sequence analysis showed it to be the human counterpart of the mouse gene Meis2 (Nakamura et al., 1996). Human MEIS2 was found to be expressed in various human tissues. In hematopoietic tissues, the lymphoid organs expressed high levels of MEIS2 as 2 transcripts of 4.0 kb and 3.5 kb. MEIS2 is also expressed in some regions of the brain, such as the putamen.
Nakamura et al. (1996) mapped the mouse Meis2 gene to chromosome 2 in a region syntenic to human chromosome 15q. By fluorescence in situ hybridization with a genomic MEIS2 clone, Smith et al. (1997) mapped the human MEIS2 gene to a position that is 27% of the distance from the chromosome 15 centromere to the telomere, corresponding to chromosome 15q14.
Steelman et al. (1997) found that Mrg1 was located on mouse chromosome 2, not mouse chromosome 11, where Meis1 maps. In humans, Steelman et al. (1997) mapped MRG1 to chromosome 15q22-q25 in a region associated with various cytogenetic abnormalities associated with acute myelocytic leukemia, chronic myeloid leukemia, and astrocytomas. The authors reported data suggesting that another related gene (MRG2) maps to human chromosome 17.
Capdevila et al. (1999) showed that restriction of expression of the chick homeobox gene Meis2 to proximal regions of the limb bud is essential for limb development, since ectopic Meis2 severely disrupted limb outgrowth. They also uncovered an antagonistic relationship between the secreted factor gremlin (GREM1; 603054) and the bone morphogenetic proteins (Bmps; see 112264) that is required to maintain the Sonic hedgehog (600725)/fibroblast growth factor (see 131220) loop that regulates distal outgrowth. These proximal and distal factors were found to have coordinated activities: Meis2 could repress distal genes, and the Bmp and Hoxd (142987) genes restricted Meis2 expression to the proximal limb bud. Moreover, combinations of Bmps and apical ectodermal ridge (AER) factors were sufficient to distalize proximal limb cells. These results unveiled a set of proximal-distal regulatory interactions that establish and maintain outgrowth of the vertebrate limb.
Mercader et al. (1999) described the role of homeobox genes Meis1, Meis2, and Pbx1 (176310) in the development of mouse, chicken, and Drosophila limbs. Mercader et al. (1999) found that Meis1 and Meis2 expression is restricted to the proximal domain, coincident with the previously reported domain in which Pbx1 is localized to the nucleus. Meis1 regulates Pbx1 activity by promoting nuclear import of the Pbx1 protein. Mercader et al. (1999) also demonstrated that ectopic expression of Meis1 in chicken disrupts distal limb development and induces distal-to-proximal transformations. Mercader et al. (1999) concluded that the restriction of Meis1 to proximal regions of the vertebrate limb is essential to specify cell fates and differentiation patterns along the proximodistal axis of the limb.
PAX6 (607108) is required for formation of the lens placode, an ectodermal thickening that precedes lens development. Zhang et al. (2002) found that Meis1 and Meis2 were developmentally expressed in mice in a pattern similar to that of Pax6. Biochemical and transgenic experiments revealed that Meis1 and Meis2 bound a specific 26-bp sequence in the Pax6 lens placode enhancer that was required for its activity. Pax6 and Meis2 exhibited a strong genetic interaction in lens development, and Pax6 expression was elevated in lenses of Meis2-overexpressing transgenic mice. When expressed in embryonic lens ectoderm, dominant-negative forms of Meis downregulated endogenous Pax6.
Using knockdown and overexpression studies, Conte et al. (2010) showed that microRNA-204 (MIR204; 610942) was required for correct lens and optic cup development in medaka fish. They identified a conserved functional MIR204 target site in the 3-prime UTR of medaka and human MEIS2. Most, but not all, consequences of Mir204 knockdown in medaka were due to abnormal Meis2-mediated regulation of the Pax6 transcriptional network.
Using an unbiased screen, Fischer et al. (2014) identified the homeobox transcription factor MEIS2 as an endogenous substrate of the E3 ubiquitin ligase complex CRL4(CRBN) (see 609262). Analysis of crystal structures showed that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds immunomodulatory drugs, including thalidomide, lenalidomide, and pomalidomide. Fischer et al. (2014) concluded that their studies suggested that immunomodulatory drugs block endogenous substrates like MEIS2 from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 (603023) or IKZF3 (606221) for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase.
Crowley et al. (2010) reported a male infant with cleft soft palate, ventricular septal defect, and moderate hearing loss associated with a mosaic 123-kb deletion of 15q14 in approximately 40% of cells that disrupted only the MEIS2 gene. The deletion removed 77-bp (exon 9) of the gene. The deletion was presumed to cause a frameshift and a truncated protein.
In a 5-year-old girl with cleft palate, congenital heart defects, and moderately impaired intellectual development (CPCMR; 600987), Louw et al. (2015) identified a de novo heterozygous 3-bp in-frame deletion in the MEIS2 gene (601740.0001).
In a mother and 3 children with cleft palate and mildly delayed motor development and/or mildly impaired intellectual development, Johansson et al. (2014) performed array-based genomic copy number analysis and identified heterozygosity for a 58-kb intragenic duplication in the MEIS2 gene (601740.0002).
In a 2.75-year-old French girl with cleft palate, atrial and ventricular septal defects, delayed motor development, and severely impaired intellectual development, Fujita et al. (2016) performed whole-exome sequencing and identified heterozygosity for a de novo nonsense mutation in the MEIS2 gene (S204X; 601740.0003).
By whole-exome sequencing in 4 patients with CPCMR, Douglas et al. (2018) identified de novo heterozygous MEIS2 missense variants (see, e.g., 601740.0004). All 4 variants occurred in the functionally important MEIS2 homeodomain. Given that the phenotypes associated with missense variants appeared to be more severe than those with gross deletions, the authors noted that dominant-negative effects of the gene need to be considered.
In 9 patients with CPCMR, Verheije et al. (2019) identified de novo heterozygous mutations in the MEIS2 gene, including frameshift, splice site, nonsense, and missense mutations (see, e.g., 601740.0005 and 601740.0006). The mutations were identified by whole-exome or Sanger sequencing, except for one where targeted sequencing was done because the diagnosis was suspected clinically. The authors compared the features of their patients and reported CPCMR patients with those in patients with 15q14 deletion syndrome and found that patients with 15q14 deletions appeared to have a higher prevalence of moderate to severe intellectual disability, although these differences were not statistically significant. The results suggested the possibility of a separate locus affecting brain growth and neurocognitive development located in the region close to MEIS2.
Machon et al. (2015) generated conditional Meis2-knockout mice. Meis2-null mice displayed lethality between embryonic day (E) 13.5 and E14.5 and displayed hemorrhaging and a small liver. Further study showed no differences in the growth and differentiation of liver erythroid progenitors between Meis2-null mice and controls. At E12.5, Meis2-null mice showed various structural cardiac anomalies, including absent aortic valve and persistent truncus arteriosus. Machon et al. (2015) showed that neural crest cells express Meis2. Conditional knockout of Meis2 in neural crest cells led to a defective heart outflow tract and abnormal cranial nerves as well as severe defects in craniofacial development, including absent interparietal bone, short mandible, and abnormal palate and tongue.
In a 5-year-old girl with cleft palate, congenital heart defects, and moderate intellectual disability (CPCMR; 600987), Louw et al. (2015) identified a de novo heterozygous 3-bp in-frame deletion (c.998_1000del, NM_170674.2) in the MEIS2 gene, resulting in deletion of the highly conserved Arg333 residue in the homeodomain. The variant was found by exome sequencing and confirmed by Sanger sequencing. Functional studies and studies of patient cells were not performed, but the deletion was predicted to interfere with DNA binding and possibly to exert a dominant-negative effect rather than haploinsufficiency.
In a mother and 3 children with cleft palate and mildly delayed motor development and/or mild intellectual disability (CPCMR; 600987), Johansson et al. (2014) identified heterozygosity for a 58-kb duplication within the MEIS2 gene, consisting of a direct duplication of the 77-bp exon 9 and flanking intronic sequences, with 4-base microhomology at the duplication junction. The mutation occurred de novo in the mother. The authors noted that if the tandemly duplicated exons 9 were both transcribed, spliced, and translated, the duplication would cause a frameshift resulting in protein truncation.
In a 2.75-year-old French girl with cleft palate, atrial and ventricular septal defects, and severe intellectual disability (CPCMR; 600987), Fujita et al. (2016) identified heterozygosity for a de novo c.611C-G transversion in the MEIS2 gene, resulting in a ser204-to-ter (S204X) substitution. The mutation was not found in the dbSNP (build137) and Exome Sequencing Project databases or in an in-house exome database of 575 Japanese individuals.
By whole-exome sequencing in a 9-month-old boy (patient 1) with cleft palate, cardiac defects, and impaired intellectual development (CPCMR; 600987), Douglas et al. (2018) identified a de novo heterozygous c.905C-T transition in exon 9 of the MEIS2 gene, resulting in a pro302-to-leu (P302L) substitution in the region between helix 1 and 2 in the functionally important MEIS2 homeodomain. The variant was not present in the EXAC, 1000 Genomes Project, or EVS databases.
By targeted sequencing of the MEIS2 gene in an 11-year-old girl (patient 8) with cleft palate, cardiac defects, and impaired intellectual development (CPCMR; 600987), Verheije et al. (2019) identified a 4-bp deletion (c.934_937del, NM_170674.4) that resulted in a frameshift and a premature stop codon (Leu312argfsTer11).
By whole-exome sequencing in a 10-year-old boy (patient 2) with cleft palate, cardiac defects, and impaired intellectual development (CPCMR; 600987), Verheije et al. (2019) identified a de novo heterozygous splice site mutation (c.639+1G-A, NM_170674.4) in the MEIS2 gene, predicted to result in abnormal splicing of the protein.
Capdevila, J., Tsukui, T., Esteban, C. R., Zappavigna, V., Belmonte, J. C. I. Control of vertebrate limb outgrowth by the proximal factor Meis2 and distal antagonism of BMPs by Gremlin. Molec. Cell 4: 839-849, 1999. [PubMed: 10619030] [Full Text: https://doi.org/10.1016/s1097-2765(00)80393-7]
Conte, I., Carrella, S., Avellino, R., Karali, M., Marco-Ferreres, R., Bovolenta, P., Banfi, S. miR-204 is required by lens and retinal development via Meis2 targeting. Proc. Nat. Acad. Sci. 107: 15491-15496, 2010. [PubMed: 20713703] [Full Text: https://doi.org/10.1073/pnas.0914785107]
Crowley, M. A., Conlin, L. K., Zackai, E. H., Deardorff, M. A., Thiel, B. D., Spinner, N. B. Further evidence for the possible role of MEIS2 in the development of cleft palate and cardiac septum. (Letter) Am. J. Med. Genet. 152A: 1326-1327, 2010. [PubMed: 20425846] [Full Text: https://doi.org/10.1002/ajmg.a.33375]
Douglas, G., Cho, M. T., Telegrafi, A., Winter, S., Carmichael, J., Zackai, E. H., Deardorff, M. A., Harr, M., Williams, L., Psychogios, A., Erwin, A. L., Grebe, T., Retterer, K., Juusola, J. De novo missense variants in MEIS2 recapitulate the microdeletion phenotype of cardiac and palate abnormalities, developmental delay, intellectual disability and dysmorphic features. Am. J. Med. Genet. 176A: 1845-1851, 2018. [PubMed: 30055086] [Full Text: https://doi.org/10.1002/ajmg.a.40368]
Fischer, E. S., Bohm, K., Lydeard, J. R., Yang, H., Stadler, M. B., Cavadini, S., Nagel, J., Serluca, F., Acker, V., Lingaraju, G. M., Tichkule, R. B., Schebesta, M., and 9 others. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512: 49-53, 2014. [PubMed: 25043012] [Full Text: https://doi.org/10.1038/nature13527]
Fujita, A., Isidor, B., Piloquet, H., Corre, P., Okamoto, N., Nakashima, M., Tsurusaki, Y., Saitsu, H., Miyake, N., Matsumoto, N. De novo MEIS2 mutation causes syndromic developmental delay with persistent gastro-esophageal reflux. J. Hum. Genet. 61: 835-838, 2016. [PubMed: 27225850] [Full Text: https://doi.org/10.1038/jhg.2016.54]
Johansson, S., Berland, S., Gradek, G. A., Bongers, E., de Leeuw, N., Pfundt, R., Fannemel, M., Rodningen, O., Brendehaug, A., Haukanes, B. I., Hovland, R., Helland, G., Houge, G. Haploinsufficiency of MEIS2 is associated with orofacial clefting and learning disability. Am. J. Med. Genet. 164A: 1622-1626, 2014. [PubMed: 24678003] [Full Text: https://doi.org/10.1002/ajmg.a.36498]
Louw, J. J., Corveleyn, A., Jia, Y., Hens, G., Gewillig, M., Devriendt, K. MEIS2 involvement in cardiac development, cleft palate, and intellectual disability. Am. J. Med. Genet. 167A: 1142-1146, 2015. [PubMed: 25712757] [Full Text: https://doi.org/10.1002/ajmg.a.36989]
Machon, O., Masek, J., Machonova, O., Krauss, S., Kozmik, Z. Meis2 is essential for cranial and cardiac neural crest development. BMC Dev. Biol. 15: 40, 2015. Note: Electronic Article. [PubMed: 26545946] [Full Text: https://doi.org/10.1186/s12861-015-0093-6]
Mercader, N., Leonardo, E., Azpiazu, N., Serrano, A., Morata, G., Martinez-A, C., Torres, M. Conserved regulation of proximodistal limb axis development by Meis1/Hth. Nature 402: 425-429, 1999. [PubMed: 10586884] [Full Text: https://doi.org/10.1038/46580]
Nakamura, T., Jenkins, N. A., Copeland, N. G. Identification of a new family of Pbx-related homeobox genes. Oncogene 13: 2235-2242, 1996. [PubMed: 8950991]
Smith, J. E., Afonja, O., Yee, H. T., Inghirami, G., Takeshita, K. Chromosomal mapping to 15q14 and expression analysis of the human MEIS2 homeobox gene. Mammalian Genome 8: 951-952, 1997. [PubMed: 9383298] [Full Text: https://doi.org/10.1007/s003359900621]
Smith, J. E., Jr., Bollekens, J. A., Inghirami, G., Takeshita, K. Cloning and mapping of the MEIS1 gene, the human homolog of a murine leukemogenic gene. Genomics 43: 99-103, 1997. [PubMed: 9226379] [Full Text: https://doi.org/10.1006/geno.1997.4766]
Steelman, S., Moskow, J. J., Muzynski, K., North, C., Druck, T., Montgomery, J. C., Huebner, K., Daar, I. O., Buchberg, A. M. Identification of a conserved family of Meis1-related homeobox genes. Genome Res. 7: 142-156, 1997. [PubMed: 9049632] [Full Text: https://doi.org/10.1101/gr.7.2.142]
Verheije, R., Kupchik, G. S., Isidor, B., Kroes, H. Y., Lynch, S. A., Hawkes, L., Hempel, M., Gelb, B. D., Ghoumid, J., D'Amours, G., Chandler, K., Dubourg, C., and 33 others. Heterozygous loss-of-function variants of MEIS2 cause a triad of palatal defects, congenital heart defects, and intellectual disability. Europ. J. Hum. Genet. 27: 278-290, 2019. [PubMed: 30291340] [Full Text: https://doi.org/10.1038/s41431-018-0281-5]
Zhang, X., Friedman, A., Heaney, S., Purcell, P., Maas, R. L. Meis homeoproteins directly regulate Pax6 during vertebrate lens morphogenesis. Genes Dev. 16: 2097-2107, 2002. [PubMed: 12183364] [Full Text: https://doi.org/10.1101/gad.1007602]