Identical mutations in three different fibroblast growth factor receptor genes in autosomal dominant craniosynostosis syndromes

Abstract

Pfeiffer syndrome (PS; McKusick MIM 101,600) is an autosomal dominant craniosynostosis syndrome with characteristic craniofacial anomalies and broad thumbs and big toes. We have previously demonstrated genetic heterogeneity in PS and mapped a gene to chromosome 8 (ref. 3) and a second to chromosome 10 (ref. 4). The gene on chromosome 8 is the fibroblast growth factor receptor 1 (FGFR1) with a common mutation (C755G) predicting a Pro252Arg substitution. The gene on chromosome 10 is FGFR2 with several different mutations causing sporadic and familial PS (Table 1). We report a recurrent single point mutation in the FGFR3 gene, located on chromosome 4p, in ten unrelated families with craniosynostosis syndromes. This mutation (C749G) predicts a Pro250Arg amino acid substitution in the extracellular domain of the FGFR3 protein. Interestingly, this common mutation occurs precisely at the analogous position within the FGFR3 protein as the mutations in FGFR1 (Pro252Arg) and FGFR2 (Pro253Arg) previously reported in Pfeiffer and Apert syndromes, respectively.

Craniosynostosis in Alagille syndrome

“…Exons 8 and 10 of the FGFR 2 gene were amplified using primers and conditions described by [Meyers et al, 1996]. Exon 7 of the FGFR 3 gene was amplified and using primers and conditions described by [Bellus et al, 1996], the C to G mutation that results in the Pro250Arg amino acid substitution was sought. Sequencing of amplified DNA was performed using the Perkin Elmer Applied Biosystems cycle sequencing kit (Foster City, CA) according to manufacturer's instructions.…”

Saethre–Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome

“…15,16 Group 3: Patients without detectable mutations within FGFR1 -3 and TWIST 1. As mentioned above, patients with mutations in FGFR1 and FGFR2 had been excluded before.…”

“…18 Exon 7 of the FGFR3 gene was amplified and digested with the restriction enzyme NciI to detect mutation Pro250Arg. 15 Exon 1 of the TWIST 1 gene was amplified in two parts 6 and sequenced directly on both strands (Beckman sequencer CEQ 8000).…”

Erk1/2 signaling is required for Tgf‐β2–induced suture closure

“…6). Up-regulation of Erk1/2 protein also provided increased substrate for signaling by means of Fgfr, a known pathway for inducing premature suture closure (Muenke et al, 1994;Wilkie et al, 1995;Bellus et al, 1996;Kim et al, 2003). This increase in Erk1/2 protein expression was demonstrated in calvarial tissues pretreated with Tgf-␤2, and these tissues had greater and more sustained Erk1/2 phosphorylation in response to Fgf2 than tissues not treated with Tgf-␤2.…”

“…The first identified mutations were in genes for transcription factors MSX2 and TWIST (Jabs et al, 1993(Jabs et al, , 1994Liu et al, 1994Liu et al, , 1995el Ghouzzi et al, 1997;Howard et al, 1997). Mutations in genes for fibroblast growth factor receptor (FGFR) and transforming growth factor ␤ (TGF-␤) receptor II (T␤R-II) have also been associated with craniosynostotic disorders (Muenke et al, 1994;Wilkie et al, 1995;Bellus et al, 1996;Loeys et al, 2005).…”