We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis.
In particular, coronal synostosis evidences a higher tendency to be genetically caused, and TWIST1 and FGFR3 have been identified as major causative genes.
Genetic testing of nonsyndromic cases (at least for FGFR3P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses.
All patients with either bicoronal synostosis or unicoronal synostosis with syndromic features should be screened for TWIST1 mutations, as this confers a greater risk than nonsyndromic synostosis of the same sutures.
Here we present 61 individuals from 20 unrelated families where coronal synostosis is due to an amino acid substitution (Pro250Arg) that results from a single point mutation in the fibroblast growth factor receptor 3 gene on chromosome 4p.
TCF12 molecular testing should be considered in patients with unilateral- or bilateral-coronal synostosis associated or not with syndactyly, after having excluded mutations in the TWIST1 gene and the p.Pro250Arg mutation in FGFR3.
We show that TCF12 and TWIST1 act synergistically in a transactivation assay and that mice doubly heterozygous for loss-of-function mutations in Tcf12 and Twist1 have severe coronal synostosis.
We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function.
Using genetic data obtained from a six-generation Chinese family, we identified a missense variant in GDF6 (NP_001001557.1; p.Y444N) that fully segregates with a novel autosomal dominant synostoses (SYNS) phenotype, which we designate as SYNS4.
Genetic testing of nonsyndromic cases (at least for FGFR3 P250R and FGFR2 exons IIIa/c) should be targeted to patients with coronal or multisuture synostoses.
RESULTS - Animals that received control osteoblasts, sham surgery, or no surgery demonstrated normal skull growth and coronal suture histology, whereas animals transplanted only with FGFR2 mutant osteoblasts showed evidence of bridging synostosis on the calvarial dural surface.
Recently it has been proposed that an extra copy of MSX2 that maps to 5q35.2 causes premature synostosis of the sutures via the MSX2-mediated pathway of calvarial osteogenic differentiation.
Mutations of the NOGGIN (NOG) gene in humans are associated with several autosomal dominant disorders such as proximal symphalangism and multiple synostoses.