A novel mutation, Ala315Ser, in FGFR2: a gene–environment interaction leading to craniosynostosis?

Abstract

Mutations in the fibroblast growth factor receptor 1, 2 and 3 (FGFR1, -2 and -3) and TWIST genes have been identified in several syndromic forms of craniosynostosis. There remains, however, a significant number of patients with non-syndromic craniosynostosis in whom no genetic cause can be identified. We describe a novel heterozygous mutation of FGFR2 (943G ® T, encoding the amino acid substitution Ala315Ser) in a girl with non-syndromic unicoronal craniosynostosis. The mutation is also present in her mother and her maternal grandfather who have mild facial asymmetry but do not have craniosynostosis. None of these individuals has the Crouzonoid appearance typically associated with FGFR2 mutations. However, the obstetric history revealed that the proband was in persistent breech presentation in utero and was delivered by Caesarean section, at which time compression of the skull was apparent. We propose that this particular FGFR2 mutation only confers a predisposition to craniosynostosis and that an additional environmental insult (in this case foetal head constraint associated with breech position) is necessary for craniosynostosis to occur. To our knowledge, this is the first report of an interaction between a weakly pathogenic mutation and intrauterine constraint, leading to craniosynostosis.

Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia

“…An asymptomatic 49-year-old male (individual II-2 in ref. 31), heterozygous for both the 943GϾT (Ala315Ser) mutation and 749-112G͞A SNP in FGFR2, provided two semen samples at 1-week intervals. His carrier daughter was homozygous (GG) at the SNP, establishing that the 943T allele was in cis with the G allele of the SNP.…”

“…These two changes are pathologically synergistic from both the phenotypic and functional viewpoints. The heterozygous state of either single substitution is clinically mild (26,31); but, when both substitutions exist on the same FGFR2 allele, syndactyly of severity comparable to Apert syndrome is evident (29). The functional corollary is that illegitimate binding by FGF10, a ligand that is normally selective for the FGFR2b isoform, occurs to mutant FGFR2c when both substitutions are present (21).…”

“…To assess whether the 755CϾT and 943GϾT mutations synergize in the testis, we analyzed the levels of FGFR2 755C substitutions in two sperm samples from a 49-year-old man heterozygous both for 943GϾT (31) and the 749-112G͞A SNP. Whereas the levels of 755CϾG were within the normal range, 755CϾT was present at the highest level yet recorded (an average of 1 in 5,147) (Fig.…”

Grb2 controls phosphorylation of FGFR2 by inhibiting receptor kinase and Shp2 phosphatase activity

“…Somatic mutations in FGFR2 have been associated with a number of human cancers (Jang et al, 2001;Pollock et al, 2007;Dutt et al, 2008;Byron et al, 2010), whereas missense germline mutations of the fgfr2 gene are seen in congenital skeletal disorders (Wilkie et al, 1995;Johnson et al, 2000;Yu et al, 2000;Goriely et al, 2010;Turner and Grose, 2010). Alternative gene-splicing events provide numerous structural variants of FGFR2.…”

A further mutation of the FGFR2 tyrosine kinase domain in mild Crouzon syndrome

“…15 A different subset of FGFR2 mutations seems to be associated with nonsyndromic craniosynostosis (without the facial features of Crouzon syndrome) in some individuals and nonpenetrance in others. These mutations include Ala315Ser 16 and Ala337Thr (AOMW, SA Wall, unpublished data).…”