Phenotypic expression of the fibroblast growth factor receptor 3 (FGFR3) mutation P250R in a large craniosynostosis family.

Abstract

The craniosynostosis syndromes are a heterogeneous group of sporadic, autosomal dominant disorders with significant clinical overlap. Recently, we described a large family with autosomal dominant craniosynostosis suggestive of SaethreChotzen syndrome, in which linkage to the Saethre-Chotzen syndrome loci on 7p had been excluded.We now report the presence of a mutation in the fibroblast growth factor receptor 3 (FGFR3) in this family. The mutation, P250R, had been previously reported in 10 patients with non-syndromic craniosynostosis. Variable expression of this mutation is evident especially in two additional members of this family, one of whom is severely affected with pancraniosynostosis. The family provides a further example of genetic heterogeneity and variable expression of the craniosynostosis syndromes and broadens the phenotypic spectrum associated with the FGFR3 mutation P250R. In addition, we found a polymorphism (F384L) in the transmembrane domain of FGFR3 which occurs with a frequency of 3% in the Turkish population but is uncommon among Germans.

Mutations within or upstream of the basic helix–loop–helix domain of the TWIST gene are specific to Saethre-Chotzen syndrome

“…16,17 On clinical re-examination, both patients appeared to have a milder phenotype than typical ACS III individuals. Yet the phenotypical overlap of patients with TWIST and P250R FGFR 3 mutations further supports the view that the two factors are involved in a common signalling pathway during craniofacial and limb development, 7,8 especially as a drosophila homolog of FGFRs (DFR-1/heartless) acts as a target for the TWIST protein during Drosophila mesodermal differentiation.…”

“…[11][12][13][14] The putative interactions between TWIST and Fibroblast Growth Factor Receptors (FGFRs) via a common signalling pathway are supported by the recent observation that several familial cases of ACS III-like craniosynostosis syndromes and sporadic cases originally diagnosed as ACS III, harboured the recurrent P250R FGFR 3 mutation in the extracellular region of the receptor. [15][16][17][18] Here we report on 16 additional TWIST mutations (including 11 novel mutations) in typical ACS III patients. All these mutations are expected to truncate or disrupt the b-HLH domain of the protein.…”

FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies

“…OPM-1 and KMS11 cells overexpress FGFR3 mutant with a single activating mutation K650E in the kinase domain and Y373C in the transmembrane domain (Ronchetti et al, 2001), respectively, whereas LP1 cells express FGFR3 wild-type with a polymorphism of F384L in the transmembrane domain (Golla et al, 1997). PKC412 effectively inhibited the growth of OPM-1 and KMS11 cells (Figure 3a).…”

Sudden infant death in a patient with FGFR3 P250R mutation

“…Reported clinical manifestations are coronal craniosynostosis, craniofacial abnormalities, sensorineural deafness, digital abnormalities, and mental retardation [Bellus et al, 1996;Golla et al, 1997;Muenke et al, 1997]. We report a mother and her daughter with this mutation diagnosed following a sudden unexpected death of the daughter.…”