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Gene Review

MSX2  -  msh homeobox 2

Homo sapiens

Synonyms: CRS2, FPP, HOX8, Homeobox protein Hox-8, Homeobox protein MSX-2, ...
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Disease relevance of MSX2


Psychiatry related information on MSX2

  • The planar rigidized molecule fluorazene (FPP) undergoes fast reversible intramolecular charge transfer (ICT) in the excited state, with a reaction time of 12 ps in the polar solvent ethyl cyanide at -45 degrees C. The ICT state of FPP has a dipole moment mu(e)(ICT) of 13 D, much larger than that of the locally excited state LE (1 D) [7].
  • Recognised clinical signs include EXT, FPP, mental retardation, facial asymmetry, asymmetric calcification of coronary sutures, defective vision (severe myopia, nystagmus, strabismus), skeletal anomalies (small hands and feet, tapering fingers), heart defect, and anal stenosis [8].
  • The study variables were PFM exercise adherence, pelvic muscle strength, Continence self-efficacy, geriatric depression and incontinence stress [9].

High impact information on MSX2

  • We previously identified mutations of MSX2 in non-syndromic PFM and demonstrated genetic heterogeneity [10].
  • Our findings contrast with the only described MSX2 homeodomain mutation (P148H), associated with craniosynostosis, that binds with enhanced affinity to the same target [11].
  • Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification [11].
  • The human MSX2 gene localizes to chromosome 5, and a polymorphic marker in the MSX2 intron segregates in a kindred with the disorder with no recombination [12].
  • Moreover, a histidine substitutes for a highly conserved proline at position 7 of the MSX2 homeodomain exclusively in affected members [12].

Chemical compound and disease context of MSX2


Biological context of MSX2


Anatomical context of MSX2


Associations of MSX2 with chemical compounds

  • MSX2 promotes vaginal epithelial differentiation and wolffian duct regression and dampens the vaginal response to diethylstilbestrol [22].
  • 3. Each of these three loci was co-amplified with the autosomal gene MSX2 using Cy5-labelled primers and the products separated by electrophoresis in polyacrylamide gels [23].
  • GGTase-I discriminates against farnesyl diphosphate (FPP) at the product turnover step through the inability of a 15-C FPP to displace the 20-C prenyl-peptide product [24].
  • CRS2 co-sediments with group II intron RNA during centrifugation of stroma through sucrose gradients, suggesting that CRS2 facilitates splicing via direct interaction with intron RNA [25].
  • Green fluorescent protein localization experiments suggest that a change in subcellular localization led to the FaNES1 enzyme encountering both GPP and FPP, allowing it to produce linalool and nerolidol [13].

Physical interactions of MSX2

  • In this study, both wild-type and mutant Msx2 were shown to specifically bind to a DNA sequence previously identified as a high-affinity binding site for the related homeodomain protein Msx1 [26].

Regulatory relationships of MSX2

  • Our data support a model by which BMP4 induces programmed cell death via an Msx2-mediated pathway and provide direct functional evidence that Msx2 expression is a regulator of this process [27].
  • Dlx2 activates the Msx2 promoter in several cell lines and binds DNA as a monomer and dimer [28].
  • Msx2 is a mammalian homeodomain protein that is expressed during craniofacial development [26].
  • The role of BMP-2 may be through inducing osteoblastic differentiation of VSMCs through induction of MSX-2, or by inducing apoptosis of VSMCs, a process thought critical in the initiation of vascular calcification [29].

Other interactions of MSX2

  • Homeobox genes MSX1 and MSX2 are expressed in presumptive dental tissues at the stage of initiation of tooth development [30].
  • PFMCCD is indeed aetiologically distinct from CCD, which is caused by mutations in the RUNX2 gene, but allelic with isolated PFM, in which MSX2 mutations were previously identified [1].
  • Craniosynostosis associated with ocular and distal limb defects is very likely caused by mutations in a gene different from FGFR, TWIST, and MSX2 [31].
  • A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis [12].
  • Mutation analysis of the ALX4 gene in three unrelated FPP families without the MSX2 mutation identified mutations in two families, indicating that mutations in ALX4 could be responsible for these skull defects and suggesting further genetic heterogeneity of FPP [4].

Analytical, diagnostic and therapeutic context of MSX2


  1. Parietal foramina with cleidocranial dysplasia is caused by mutation in MSX2. Garcia-Miñaur, S., Mavrogiannis, L.A., Rannan-Eliya, S.V., Hendry, M.A., Liston, W.A., Porteous, M.E., Wilkie, A.O. Eur. J. Hum. Genet. (2003) [Pubmed]
  2. MSX2 overexpression inhibits gemcitabine-induced caspase-3 activity in pancreatic cancer cells. Hamada, S., Satoh, K., Kimura, K., Kanno, A., Masamune, A., Shimosegawa, T. World J. Gastroenterol. (2005) [Pubmed]
  3. The homeobox protein MSX2 interacts with tax oncoproteins and represses their transactivation activity. Twizere, J.C., Lefèbvre, L., Collete, D., Debacq, C., Urbain, P., Heremans, H., Jauniaux, J.C., Burny, A., Willems, L., Kettmann, R. J. Biol. Chem. (2005) [Pubmed]
  4. The ALX4 homeobox gene is mutated in patients with ossification defects of the skull (foramina parietalia permagna, OMIM 168500). Wuyts, W., Cleiren, E., Homfray, T., Rasore-Quartino, A., Vanhoenacker, F., Van Hul, W. J. Med. Genet. (2000) [Pubmed]
  5. Cell mixing at a neural crest-mesoderm boundary and deficient ephrin-Eph signaling in the pathogenesis of craniosynostosis. Merrill, A.E., Bochukova, E.G., Brugger, S.M., Ishii, M., Pilz, D.T., Wall, S.A., Lyons, K.M., Wilkie, A.O., Maxson, R.E. Hum. Mol. Genet. (2006) [Pubmed]
  6. Up-regulation of MSX2 enhances the malignant phenotype and is associated with twist 1 expression in human pancreatic cancer cells. Satoh, K., Hamada, S., Kimura, K., Kanno, A., Hirota, M., Umino, J., Fujibuchi, W., Masamune, A., Tanaka, N., Miura, K., Egawa, S., Motoi, F., Unno, M., Vonderhaar, B.K., Shimosegawa, T. Am. J. Pathol. (2008) [Pubmed]
  7. Fast intramolecular charge transfer with a planar rigidized electron donor/acceptor molecule. Yoshihara, T., Druzhinin, S.I., Zachariasse, K.A. J. Am. Chem. Soc. (2004) [Pubmed]
  8. Proximal 11p deletion syndrome (P11pDS): additional evaluation of the clinical and molecular aspects. Wuyts, W., Waeber, G., Meinecke, P., Schüler, H., Goecke, T.O., Van Hul, W., Bartsch, O. Eur. J. Hum. Genet. (2004) [Pubmed]
  9. The development and evaluation of an incontinence intervention program for the elderly women at elderly welfare center. Kim, J. Taehan Kanho Hakhoe chi (2004) [Pubmed]
  10. Haploinsufficiency of the human homeobox gene ALX4 causes skull ossification defects. Mavrogiannis, L.A., Antonopoulou, I., Baxová, A., Kutílek, S., Kim, C.A., Sugayama, S.M., Salamanca, A., Wall, S.A., Morriss-Kay, G.M., Wilkie, A.O. Nat. Genet. (2001) [Pubmed]
  11. Functional haploinsufficiency of the human homeobox gene MSX2 causes defects in skull ossification. Wilkie, A.O., Tang, Z., Elanko, N., Walsh, S., Twigg, S.R., Hurst, J.A., Wall, S.A., Chrzanowska, K.H., Maxson, R.E. Nat. Genet. (2000) [Pubmed]
  12. A mutation in the homeodomain of the human MSX2 gene in a family affected with autosomal dominant craniosynostosis. Jabs, E.W., Müller, U., Li, X., Ma, L., Luo, W., Haworth, I.S., Klisak, I., Sparkes, R., Warman, M.L., Mulliken, J.B. Cell (1993) [Pubmed]
  13. Gain and loss of fruit flavor compounds produced by wild and cultivated strawberry species. Aharoni, A., Giri, A.P., Verstappen, F.W., Bertea, C.M., Sevenier, R., Sun, Z., Jongsma, M.A., Schwab, W., Bouwmeester, H.J. Plant Cell (2004) [Pubmed]
  14. Human geranylgeranyl diphosphate synthase. cDNA cloning and expression. Kuzuguchi, T., Morita, Y., Sagami, I., Sagami, H., Ogura, K. J. Biol. Chem. (1999) [Pubmed]
  15. Continuous-infusion cisplatin, 5-fluorouracil, and bolus methotrexate in the treatment of advanced non-small cell lung cancer. Lynch, T.J., Clark, J.R., Kalish, L.A., Fallon, B.G., Elias, A.D., Skarin, A., Frei, E. Cancer (1992) [Pubmed]
  16. Regulation of Msx2 gene expression by steroid hormones in human nonmalignant and malignant breast cancer explants cultured in vitro. Malewski, T., Milewicz, T., Krzysiek, J., Gregoraszczuk, E.L., Augustowska, K. Cancer Invest. (2005) [Pubmed]
  17. Identification of mutations in the MSX2 homeobox gene in families affected with foramina parietalia permagna. Wuyts, W., Reardon, W., Preis, S., Homfray, T., Rasore-Quartino, A., Christians, H., Willems, P.J., Van Hul, W. Hum. Mol. Genet. (2000) [Pubmed]
  18. The molecular basis of Boston-type craniosynostosis: the Pro148-->His mutation in the N-terminal arm of the MSX2 homeodomain stabilizes DNA binding without altering nucleotide sequence preferences. Ma, L., Golden, S., Wu, L., Maxson, R. Hum. Mol. Genet. (1996) [Pubmed]
  19. The homeobox genes MSX2 and MOX2 are candidates for regulating epithelial-mesenchymal cell interactions in the human placenta. Quinn, L.M., Latham, S.E., Kalionis, B. Placenta (2000) [Pubmed]
  20. Dysregulation of the BMP-p38 MAPK signaling pathway in cells from patients with fibrodysplasia ossificans progressiva (FOP). Fiori, J.L., Billings, P.C., de la Peña, L.S., Kaplan, F.S., Shore, E.M. J. Bone Miner. Res. (2006) [Pubmed]
  21. Characterization of a human MSX-2 cDNA and its fragment isolated as a transformation suppressor gene against v-Ki-ras oncogene. Takahashi, C., Akiyama, N., Matsuzaki, T., Takai, S., Kitayama, H., Noda, M. Oncogene (1996) [Pubmed]
  22. MSX2 promotes vaginal epithelial differentiation and wolffian duct regression and dampens the vaginal response to diethylstilbestrol. Yin, Y., Lin, C., Ma, L. Mol. Endocrinol. (2006) [Pubmed]
  23. Quantitation of X-Y homologous genes in patients with schizophrenia by multiplex polymerase chain reaction. Ross, N.L., Mavrogiannis, L.A., Sargent, C.A., Knight, S.J., Wadekar, R., DeLisi, L.E., Crow, T.J. Psychiatr. Genet. (2003) [Pubmed]
  24. Structure of mammalian protein geranylgeranyltransferase type-I. Taylor, J.S., Reid, T.S., Terry, K.L., Casey, P.J., Beese, L.S. EMBO J. (2003) [Pubmed]
  25. Recruitment of a peptidyl-tRNA hydrolase as a facilitator of group II intron splicing in chloroplasts. Jenkins, B.D., Barkan, A. EMBO J. (2001) [Pubmed]
  26. DNA binding and transcriptional properties of wild-type and mutant forms of the homeodomain protein Msx2. Semenza, G.L., Wang, G.L., Kundu, R. Biochem. Biophys. Res. Commun. (1995) [Pubmed]
  27. Msx2 is a transcriptional regulator in the BMP4-mediated programmed cell death pathway. Marazzi, G., Wang, Y., Sassoon, D. Dev. Biol. (1997) [Pubmed]
  28. Functional interactions between Dlx2 and lymphoid enhancer factor regulate Msx2. Diamond, E., Amen, M., Hu, Q., Espinoza, H.M., Amendt, B.A. Nucleic Acids Res. (2006) [Pubmed]
  29. Bone morphogenetic proteins in vascular calcification. Hruska, K.A., Mathew, S., Saab, G. Circ. Res. (2005) [Pubmed]
  30. Gene defect in hypodontia: exclusion of MSX1 and MSX2 as candidate genes. Nieminen, P., Arte, S., Pirinen, S., Peltonen, L., Thesleff, I. Hum. Genet. (1995) [Pubmed]
  31. Craniosynostosis associated with ocular and distal limb defects is very likely caused by mutations in a gene different from FGFR, TWIST, and MSX2. Passos-Bueno, M.R., Armelin, L.M., Alonso, L.G., Neustein, I., Sertié, A.L., Abe, K., Pavanello, R.d.e. .C., Elkis, L.C., Koiffmann, C.P. Am. J. Med. Genet. (2002) [Pubmed]
  32. Expression and localization of homeodomain proteins DLX4, HB9 and HB24 in malignant and benign human colorectal tissues. Hollington, P., Neufing, P., Kalionis, B., Waring, P., Bentel, J., Wattchow, D., Tilley, W.D. Anticancer Res. (2004) [Pubmed]
  33. Farnesyl-diphosphate synthase is localized in peroxisomes. Krisans, S.K., Ericsson, J., Edwards, P.A., Keller, G.A. J. Biol. Chem. (1994) [Pubmed]
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