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NM_002449.5(MSX2):c.443C>A (p.Pro148His) AND Craniosynostosis 2

Significance: Pathogenic
ClinVar: RCV000018474

Variant: NM_002449.5(MSX2):c.443C>A (p.Pro148His)

Type: Variant
Allele: NM_002449.5(MSX2):c.443C>A (p.Pro148His) 32000
Gene:
Type: single nucleotide variant
Location: Chr5: 174156225 - assembly GRCh37
Chr5: 174729222 - assembly GRCh38
References: dbSNP: 104893895
OMIM: 123101.0001
UniProtKB: P35548#VAR_003755

Condition

Disease: Craniosynostosis 2

Citations

    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).
PMID:
    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.
PMID:7597092
    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).
PMID:8357019
    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.
PMID:8968743