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FGF9 mutation causes craniosynostosis along with multiple synostoses
Author(s) -
RodriguezZabala Maria,
AzaCarmona Miriam,
RiveraPedroza Carlos I.,
Belinchón Alberta,
GuerreroZapata Isabel,
BarrazaGarcía Jimena,
Vallespin Elena,
Lu Min,
del Pozo Angela,
Glucksman Marc J.,
SantosSimarro Fernando,
Heath Karen E.
Publication year - 2017
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23292
Subject(s) - craniosynostosis , biology , synostosis , fgf9 , genetics , missense mutation , mutant , mutation , phenotype , fibroblast growth factor , gene , receptor
Craniosynostosis is commonly caused by mutations in fibroblast growth factor receptors (FGFRs), highlighting the essential role of FGF‐mediated signaling in skeletal development. We set out to identify the molecular defect in a family referred for craniosynostosis and in whom no mutation was previously detected. Using next‐generation sequencing, we identified a novel missense mutation in FGF9 . Modeling based upon the crystal structure and functional studies confirmed its pathogenicity showing that it impaired homodimerization and FGFR3 binding. Only one FGF9 mutation has been previously reported in a multigeneration family with multiple synostoses (SYNS3) but no signs of craniosynostosis. In contrast, our family has a greater phenotypic resemblance to that observed in the Fgf9 spontaneous mouse mutant, elbow‐knee‐synostosis, Eks , with both multiple synostoses and craniosynostosis. We have demonstrated for the first time that mutations in FGF9 cause craniosynostosis in humans and confirm that FGF9 mutations cause multiple synostoses.