Alternative titles; symbols
HGNC Approved Gene Symbol: MSX2
SNOMEDCT: 720817008, 771338002;
Cytogenetic location: 5q35.2 Genomic coordinates (GRCh38): 5:174,724,582-174,730,896 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.2 | Craniosynostosis 2 | 604757 | Autosomal dominant | 3 |
| Parietal foramina 1 | 168500 | Autosomal dominant | 3 | |
| Parietal foramina with cleidocranial dysplasia | 168550 | Autosomal dominant | 3 |
Li et al. (1993) cloned and sequenced the human MSX2 homeobox gene.
By in situ hybridization, Li et al. (1993) mapped the MSX2 gene to the same region of chromosome 5 to which a form of craniosynostosis (CRS2; 604757) had been mapped.
Jabs et al. (1993) mapped the MSX2 gene to chromosome 5 by study of a human/rodent somatic cell hybrid mapping panel and regionalized it to 5q34-q35 by fluorescence in situ hybridization.
Takahashi et al. (1996) isolated a cDNA (CT124) encoding the C-terminal 58-amino acid region of human MSX2. CT124 was found to induce a low frequency of reversion when expressed in ras (190070)-transformed NIH3T3 cells. Northern hybridization analyses showed that expression of endogenous MSX2 was low in most of the normal adult tissues examined. In contrast, high expression of the MSX2 gene was detected in several cell lines derived from human tumors. In addition, they found that the full-length human MSX2 cDNA induced transformation in chicken myoblast cultures, supporting the view that MSX2 promotes rather than suppresses cell growth under certain conditions (Davidson, 1995). Takahashi et al. (1996) also tested the activities of a near full-length human MSX2 cDNA and of CT124 in fibroblast and myoblast cell systems. They found that in NIH3T3 fibroblasts, both antisense MSX2 cDNA and truncated CT124 interfered with the transforming activities of the v-Ki-ras oncogene. In C2C12 myoblasts, MSX2 suppressed MyoD (159990) gene expression as did activated RAS oncogenes, and CT124 inhibits the activities of both MSX2 and ras. These findings suggested to Takahashi et al. (1996) that CT124 may act as a dominant suppressor of MSX2 and that the MSX2 gene may be an important target for the RAS signaling pathways.
Hassan et al. (2004) found that Msx2, Dlx3 (600525), Dlx5 (600028), and Runx2 (600211) regulated the expression of osteocalcin (OC) (BGLAP; 112260) in mouse embryos and therefore are implicated in the control of bone formation. Msx2 associated with transcriptionally repressed OC chromatin, and Dlx3 and Dlx5 were recruited with Runx2 to initiate OC transcription. In a second regulatory switch, Dlx3 association decreased and Dlx5 recruitment increased coincident with the mineralization stage of osteoblast differentiation. The appearance of Dlx3 followed by Dlx5 in the OC promoter correlated with increased transcription represented by increased occupancy of RNA polymerase II.
Shiihara et al. (2004) described a 2-year-old girl with craniosynostosis with early closure of the sagittal and lambdoid sutures, atrial septal defect, patent ductus arteriosus, and a karyotype showing 46,XX,der(13)t(5;13)(q33.3;q34). FISH analysis demonstrated 3 copies of the MSX2 gene. Shiihara et al. (2004) suggested that the patient's clinical findings were explained by either partial 13q deletion or partial 5q trisomy, or both, and that the overdose of MSX2 was related to her craniosynostosis through the MSX2-mediated pathway of calvarial osteogenic differentiation.
Bernardini et al. (2007) described a 6-month-old female with premature closure of the metopic, sagittal, lambdoid, and squamous sutures, together with peripheral coronal synostosis and multiple areas of defective parietal ossification, suggestive of craniolacunae. The patient also had prenatal-onset growth deficiency, developmental delay, facial dysmorphism, mitral valve stenosis, bicuspid aortic valve, pulmonary hypertension, and inguinal hernia. An integrated approach of standard cytogenetics, mBAND, locus-specific FISH, and 75-kb resolution array CGH disclosed a complex chromosome 5 rearrangement, resulting in 3 paracentric inversions, 2 between-arm insertions, and partial duplication of 5q35. Molecular cytogenetic studies confirmed an extra copy of the MSX2 gene within the duplicated segment. Bernardini et al. (2007) suggested that MSX2 dosage is crucial in the development of craniofacial structures and a distinct form of craniosynostosis.
Craniosynostosis 2
To determine whether MSX2 expression is consistent with its being a candidate gene for craniosynostosis (CRS2; 604757), Li et al. (1993) demonstrated by in situ hybridization that mouse Msx2 transcripts are present in osteoblasts adjacent to calvarial sutures during mouse embryonic and postnatal development. In addition, Li et al. (1993) found that a (CA)n polymorphism within the MSX2 gene segregated with craniosynostosis in the Boston family studied by Warman et al. (1993) and Muller et al. (1993); no recombination was observed, giving a maximum lod score of 4.80. All affected members were found to have substitution of histidine for proline at amino acid position 7 of the homeodomain (P148H; 123101.0001); the mutation was absent in all unaffected members of the family and 68 controls. This proline residue is conserved in all known MSX genes in organisms as diverse as insects and mammals. Li et al. (1993) claimed that this was the first report of a mutation in a homeobox gene associated with a human disorder. See Jabs et al. (1993) for the full report. This is a good example of identification of the defect in a disorder by the candidate gene approach.
Mavrogiannis et al. (2006) did not identify any pathogenic mutations in the MSX2 gene in 181 patients with craniosynostosis, suggesting that it is not a common cause of the disorder.
In affected members of a 4-generation Bosnian family segregating autosomal dominant multiple-suture craniosynostosis, Florisson et al. (2013) identified heterozygosity for a P148L mutation (123101.0009) in the MSX2 gene.
Parietal Foramina
Wilkie et al. (2000) described heterozygous mutations of the MSX2 gene in 3 unrelated families with enlarged parietal foramina (PFM1; 168500). One was a deletion of approximately 206 kb including the entire gene, and the others were intragenic mutations of the DNA-binding homeodomain that predicted disruption of critical intramolecular and DNA contacts. Mouse Msx2 protein with either of the homeodomain mutations exhibited more than 85% reduction in binding to an optimal Msx2 DNA-binding site. These findings contrasted with the previously described MSX2 homeodomain mutation pro148 to his, associated with craniosynostosis, which binds with enhanced affinity to the same target. In the family with a 2-amino acid deletion in MSX2 and enlarged parietal foramina (123101.0002), the 27-year-old mother had completely false upper teeth, suggesting dental abnormalities consistent with the mouse phenotype. Wilkie et al. (2000) concluded that MSX2 dosage is critical for human skull development and suggested that enlarged parietal foramina and craniosynostosis result, respectively, from loss and gain of activity in an MSX2-mediated pathway of calvarial osteogenic differentiation.
In the affected father of a child with parietal foramina, Spruijt et al. (2005) identified an 8-bp deletion in the MSX2 gene (123101.0008). The father and proband both had normal clavicles on examination; DNA analysis was refused for the proband and her grandparents.
Parietal Foramina with Cleidocranial Dysplasia
In a 3-generation family segregating parietal foramina with cleidocranial dysplasia (PFMCCD; 168550), Garcia-Minaur et al. (2003) identified a heterozygous frameshift mutation (123101.0007) in the homeodomain of the MSX2 gene in affected family members. The authors noted that the clavicular involvement was mild and difficult to assess on physical examination, and suggested that this finding may be more commonly associated with PFM than previously believed and may be characteristic of individuals with MSX2 rather than ALX4 (605420) mutations.
To investigate the function of MSX2 in tissue interactions and in vertebrate craniofacial development, and to test further the hypothesis that a mutation of MSX2 is the cause of Boston-type craniosynostosis, Liu et al. (1995) engineered the pro-to-his mutation in the homeodomain of the mouse Msx2 gene and expressed the mutant gene in the developing skulls of transgenic mice. They showed that these mice exhibited precocious fusion of cranial bones and development of ectopic cranial bone. Liu et al. (1995) also showed that overexpression of the wildtype Msx2 gene can also produce craniosynostosis in mice, consistent with the possibility that the mutation enhances the normal activity of Msx2. See also 123101.0001 and Ma et al. (1996).
Winograd et al. (1997) likewise generated transgenic mice with the P148H MSX2 mutation carried by a 34-kb DNA fragment encompassing the human MSH2 gene (609309). Inheritance of either the mutant transgene or a normal transgene resulted in perinatal lethality and multiple craniofacial malformations of varying severity, including mandibular hypoplasia, cleft secondary palate, exencephaly, and median facial cleft, which are among the severe craniofacial malformations observed in humans. Transgenic mice also manifested aplasia of the interparietal bone and decreased ossification of the hyoid. Transgene-induced malformations involved cranial neural-crest derivatives, were characterized by a deficiency of tissue, and were similar to malformations associated with embryonic exposure to ethanol or retinoic acid, teratogens that cause increased cell death. Together with previous observations implicating MSX2 expression in developmentally programmed cell death, these results suggested to the investigators that wildtype levels of MSX2 activity may establish a balance between survival and apoptosis of neural crest-derived cells required for proper craniofacial morphogenesis.
Satokata et al. (2000) generated Msx2-deficient mice by targeted disruption. The mice had defects of skull ossification and persistent calvarial foramen. This phenotype results from defective proliferation of osteoprogenitors at the osteogenic front during calvarial morphogenesis, and closely resembles that associated with human MSX2 haploinsufficiency in parietal foramina. Msx2 -/- mice also have defects in endochondral bone formation. In the axial and appendicular skeleton, postnatal deficits of parathyroid hormone (168450)/parathyroid hormone receptor (see 168468) signaling and in expression of marker genes for bone differentiation indicate that MSX2 is required for both chondrogenesis and osteogenesis. Consistent with phenotypes associated with parietal foramina, Msx2-mutant mice also display defective tooth, hair follicle, and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum. Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 (142983) loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype. Satokata et al. (2000) concluded that their results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites during organogenesis. Msx2 +/- mice were indistinguishable from wildtype mice. Unlike the defect in PFM, the calvarial defect in Msx2 -/- mice was a large, midline foramen spanning the frontal bones, and the interparietal and supraoccipital bones were small and abnormally shaped.
To investigate possible functions of MSX2 in early ocular development, Wu et al. (2003) created transgenic mice overexpressing Msx2. Forced expression of the Msx2 gene resulted in optic nerve aplasia and microphthalmia in all transgenic mice. In the developing retinas of the transgenic mice, proliferation was significantly reduced and increased numbers of retinal cells underwent apoptosis. Marker analysis showed suppression of Bmp4 (112262) and induction of Bmp7 (112267) gene expression in the optic vesicle. Ectopic concurrent expression of the retinal pigment epithelial cell markers Cx43 (121014) and Tyrp2 (191275) in the neural retinal layer suggested cell fate respecification. These results indicated that forced expression of Msx2 perturbed BMP signaling in the developing eye and was accompanied by an increase in retinal cell death and a reduction in cell proliferation.
In affected members of a 3-generation American family from Boston segregating autosomal dominant variable craniosynostosis (CRS2; 604757), originally reported by Warman et al. (1993), Li et al. (1993) identified a substitution of histidine for proline at amino acid position 7 of the homeodomain of the MSX2 homeobox gene (residue 148 of the polypeptide).
Ma et al. (1996) reported that the P148H mutation in MSX2 is found exclusively in individuals with craniosynostosis type 2, and that it alters the DNA-binding properties of the MSX2 homeoprotein. They demonstrated that the enhanced DNA-binding affinity of the P148H form of MSX2 is caused by enhanced stability of the MSX2-DNA complex. This mutation had no discernible effect on the sequence specificity of MSX2 binding. They had previously reported (Liu et al., 1995) that transgenic mice in which either the mutant or the wildtype Msx2 gene is overexpressed exhibited craniosynostosis. Ma et al. (1996) noted that their recent results showing increased DNA-binding affinity of P148H and their studies in transgenic mice are consistent with the possibility that the mutation acts via a dominant-positive mechanism.
In a family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wilkie et al. (2000) identified deletion of 6 nucleotides (475-480) of the MSX2 gene resulting in the deletion of 2 amino acids, arginine and lysine, from codons 159 and 160. This mutation occurs in helix 1. Mouse protein with the same mutation showed DNA-binding affinity reduced to 3% that of wildtype.
In a family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wilkie et al. (2000) identified a G-to-A transition at nucleotide 515 of the MSX2 gene resulting in an arg172-to-his (R172H) substitution. Mouse protein with the same mutation showed DNA-binding affinity reduced to 15% that of wildtype.
In a family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wilkie et al. (2000) identified a 206-kb deletion that included the entire MSX2 gene, indicating that haploinsufficiency for MSX2 results in enlarged parietal foramina.
In a family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wuyts et al. (2000) identified mutations in consecutive nucleotides 265-266 in exon 1 of the MSX2 gene (G265T, C266A), resulting in an ala89-to-ter substitution. The protein product was predicted to lack the entire C terminus, which includes the conserved homeodomain.
In a family with autosomal dominant enlarged parietal foramina (PFM1; 168500), Wuyts et al. (2000) identified a 1-bp deletion at nucleotide 344 or 345 of the MSX2 gene, resulting in a trp115-to-ter substitution. The protein product was predicted to lack the entire C terminus, which includes the conserved homeodomain.
In a 3-generation family segregating parietal foramina with cleidocranial dysplasia (PFMCCD; 168550), Garcia-Minaur et al. (2003) identified a heterozygous duplication of a tetranucleotide (505dupATTG) in exon 2 of the MSX2 gene in affected individuals. The duplication causes a frameshift at residue 29 of the homeodomain, and predicts a termination codon 75 triplets downstream. Affected family members exhibited classic parietal foramina (see 168500) and short abnormal clavicles with tapering lateral ends. They had mild craniofacial dysmorphism with a broad forehead and central bossing, which was more evident in the children. Garcia-Minaur et al. (2003) noted that the mild clavicular involvement was difficult to assess on physical examination, and suggested that this finding may be more commonly associated with PFM than previously believed and may be characteristic of individuals with MSX2 rather than ALX4 (605420) mutations.
In the affected father of a child with parietal foramina (PFM1; 168500), Spruijt et al. (2005) identified an 8-bp deletion in exon 2 of the MSX2 gene, resulting in a frameshift and premature stop codon 59 codons downstream. DNA analysis was refused for the proband and her grandparents.
In 7 affected members of a 4-generation Bosnian family segregating autosomal dominant multiple-suture craniosynostosis (CRS2; 604757), Florisson et al. (2013) identified heterozygosity for a c.443C-T transition (c.443C-T, NM_002449.4) in exon 2 of the MSX2 gene, resulting in a pro148-to-leu (P148L) substitution at a highly conserved residue. The mutation was not found in unaffected family members, in an in-house database, or in the 1000 Genomes Project or Exome Variant Server databases.
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