Identification and characterization of an inhibitory Fibroblast growth factor receptor 2 (FGFR2) molecule, upregulated in an Apert Syndrome mouse model

Lee M Wheldon , Naila Khodabukus , Susannah J Patey , Terence G Smith , Jk Heath , Mohammad K Hajihosseini (1)

1 School of Biological Sciences

Apert syndrome (AS) is a congenital disease composed of skeletal, visceral and neural abnormalities, caused by dominant-acting mutations in FGFR2. Multiple FGFR2 splice variants are generated through alternative splicing, including premature termination codon (PTC)-containing transcripts that are normally eliminated via the nonsense mediated decay (NMD) pathway. We have discovered that a soluble truncated FGFR2 molecule encoded by a PTC-containing transcript is upregulated and persists in tissues of an Apert syndrome mouse model. We have termed this IIIa-TM as it arises from aberrant splicing of FGFR2 exon 7 (IIIa) into exon 10 (transmembrane domain). IIIa-TM is glycosylated and can modulate the binding of FGF1 to FGFR2 molecules in BIAcore binding assays. We also show that IIIa-TM can negatively regulate FGF signalling in vitro and in vivo. Apert syndrome phenotypes are thought to result from gain-of-FGFR2 signalling, but our findings suggest that IIIa-TM can contribute to these through a loss-of-FGFR2 function mechanism. Moreover, our findings raise the interesting possibility that FGFR2 signalling may be a regulator of NMD pathway.

Mots clés: Life Sciences

Lee M Wheldon, Naila Khodabukus, Susannah J Patey, Terence G Smith, Jk Heath, et al.. Identification and characterization of an inhibitory Fibroblast growth factor receptor 2 (FGFR2) molecule, upregulated in an Apert Syndrome mouse model. Biochemical Journal, 2011, 436 (1), pp.71-81. ⟨10.1042/BJ20100884⟩. ⟨hal-00591703⟩