Disease relevance of MSX1

• With transmission disequilibrium test analysis, cleft lip with/without cleft palate, cleft lip with palate plus cleft palate only, and all datasets combined showed evidence of association with MSX1 (p = 0.004, p = 0.037, and p = 0.001, respectively) [1].
• Mutations in the MSX1 homeobox gene are associated with non-syndromic cleft palate and tooth agenesis in humans [2].
• In this study of 516 Caucasians with isolated birth defects registered in the Maryland Birth Defects Reporting and Information System (BDRIS), we report an association between a dinucleotide repeat polymorphism in MSX1 and isolated limb deficiency [3].
• Frequencies of rare alleles at the MSX1 locus are significantly higher among 34 infants with limb deficiency compared to 482 infants with other isolated birth defects (oral clefts, dislocation of hip, clubfoot, hypospadias, polydactyly, or syndactyly) (chi2 = 11.0, df = 3, P = 0.012) [3].
• Somatic mutations and altered expression of the candidate tumor suppressors CSNK1 epsilon, DLG1, and EDD/hHYD in mammary ductal carcinoma [4].

Psychiatry related information on MSX1

• However, there is no evidence that the risk of CL+/-P or CP is influenced by gene-environment interactions involving MSX1 or TGFB3 and either first trimester exposure to maternal cigarette smoke or alcohol consumption [5].

High impact information on MSX1

• Genetic linkage analyses in a family with autosomal dominant agenesis of second premolars and third molars identified a locus on chromosome 4p, where the MSX1 gene resides [6].
• A human MSX1 homeodomain missense mutation causes selective tooth agenesis [6].
• We demonstrate that a mutation in the homeobox gene, MSX1, causes a common developmental anomaly, familial tooth agenesis [6].
• MSX1 inhibits myoD expression in fibroblast x 10T1/2 cell hybrids [7].
• We show that PIAS1 is required for the appropriate localization and retention of Msx1 at the nuclear periphery in myoblast cells [8].

Chemical compound and disease context of MSX1

• Alanine substitution analysis and a peptide deletion strategy were used to determine the minimal element of HYD1 necessary for bioactivity in a prostate cancer cell line called PC3N [9].

Biological context of MSX1

• MSX1 showed evidence of linkage disequilibrium in both case-control and case-parent trio analysis [10].
• Only MSX1 showed significant differences in allele frequencies between CP cases and controls [10].
• There was a positive association between subjects with cleft lip or cleft lip and palate who had hypodontia outside the cleft region (compared with noncleft controls) and both muscle segment homeo box homolog 1 (MSX1) (p =.029) and transforming growth factor beta 3 (TGFB3) (p =.024) [11].
• Direct sequencing and restriction-enzyme analysis revealed that a heterozygous stop mutation in the homeodomain of MSX1 cosegregated with the phenotype [12].
• Individuals with MSX1 genotype 3/3 tended to have younger AO [13].

Anatomical context of MSX1

• Molecular basis of non-syndromic tooth agenesis: mutations of MSX1 and PAX9 reflect their role in patterning human dentition [14].
• Since a missense mutation in the homeobox gene, MSX1, was previously linked to tooth agenesis in a single family lacking second premolars and third molars, we performed a mutational analysis of MSX1 by PCR [15].
• For example, tarsiers are the only extant primates without deciduous incisors, and MSX1 is expressed exclusively in the incisor regions during the earliest stages of dental development [16].
• In addition, histological analysis of Msx1-knockout mice, combined with a finding of Msx1 expression in mesenchyme of developing nail beds, revealed that not only was tooth development disrupted in these mice, but nail development was affected as well [12].
• Secondly, the same factors (Wnt1 and Lmx1a/Msx1) appear to regulate midbrain dopaminergic and/or neuronal fate specification in the postmitotic progeny of these precursors by controlling the expression of midbrain dopaminergic-specific and/or general proneural factors at later stages of neural development [17].

Associations of MSX1 with chemical compounds

• Previously, we found that the cause of autosomal dominant selective tooth agenesis in one family is a missense mutation resulting in an arginine-to-proline substitution in the homeodomain of MSX1 [18].
• DETA-NONOate evoked a wave of expression changes (maximum at 4 h), with a remarkable downregulation of the transcription factors MSX1, RELB, and Egr-1 [19].
• 3. Sequence analysis of candidate gene MSX1 revealed a novel recessive missense mutation resulting in substitution of alanine to threonine amino acid (p. A219T), located in the MSX1 homeodomain, which is important for DNA binding and protein-protein interaction [20].
• Msx1 is present in thyrotropic cells and binds to a consensus site on the glycoprotein hormone alpha-subunit promoter [21].
• Furthermore, the repression of Msx1 promoter by Msx3 could be relieved by treating transfected cells with trichostatin A, an inhibitor of HDAC(s) [22].

Physical interactions of MSX1

• There were statistically significant data suggesting that MSX1 interacts with PAX9 [23].
• 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 [24].

Enzymatic interactions of MSX1

• MSX1 gene is deleted in Wolf-Hirschhorn syndrome patients with oligodontia [25].

Regulatory relationships of MSX1

• We conclude that MSX1 inhibits transcription of myoD and that myoD is a target for homeobox gene regulation [7].
• The IC(50) of the HYD-1 peptide for blocking adhesion to fibronectin, laminin 1, laminin 5, and collagen IV was 6.9 microg, 5.7 microg, >10 microg, and 6.2 microg/well, respectively [26].

Other interactions of MSX1

• Association of MSX1 and TGFB3 with nonsyndromic clefting in humans [27].
• To date, the only genes associated with the non-syndromic form of tooth agenesis are MSX1 and PAX9, which encode transcription factors that play a critical role during tooth development [14].
• We further investigated interactions between Msx1 and myocardin/serum response factor (SRF)/CArG-box motif (cis element for SRF) using coimmunoprecipitation, gel-shift, and chromatin immunoprecipitation assays [28].
• Cleft lip and/or palate with hypodontia outside the cleft region was positively associated with both TGFB3 and MSX1, compared with noncleft controls [11].
• Gene defect in hypodontia: exclusion of MSX1 and MSX2 as candidate genes [29].

Analytical, diagnostic and therapeutic context of MSX1

• Sequence analyses demonstrated an Arg31Pro missense mutation in the homeodomain of MSX1 in all affected family members [6].
• The present study evaluated potential associations between CL+/-P and CP and two putative clefting susceptibility loci, MSX1 and TGFB3, using data from a nationwide case-control study conducted in Denmark from 1991 to 1994 [5].
• The extent of each individual deletion was established by fluorescence in situ hybridization, with a cosmid contig spanning the genomic region from MSX1 (distal half of 4p16.1) to the subtelomeric locus D4S3359 [30].
• cDNA clones for a human HOX 7 gene obtained with homologous clones of Drosophila were used in human gene mapping studies [31].
• To demonstrate that Pax9 interacts with Msx1 physiologically in vivo and in vitro, we performed co-immunoprecipitation and GST interaction assays [32].

References