AS (Apert syndrome) is a congenital disease composed of skeletal, visceral and neural abnormalities, caused by dominant-acting mutations in FGFR2 [FGF (fibroblast growth factor) receptor 2]. Multiple FGFR2 splice variants are generated through alternative splicing, including PTC (premature termination codon)-containing transcripts that are normally eliminated via the NMD (nonsense-mediated decay) pathway. We have discovered that a soluble truncated FGFR2 molecule encoded by a PTC-containing transcript is up-regulated and persists in tissues of an AS mouse model. We have termed this IIIa–TM as it arises from aberrant splicing of FGFR2 exon 7 (IIIa) into exon 10 [TM (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. AS 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 the NMD pathway.
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Research Article|
April 27 2011
Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model
Lee M. Wheldon;
Lee M. Wheldon
1
*School of Biosciences, University of Birmingham, Edgbaston B15 2TT, U.K.
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Naila Khodabukus;
Naila Khodabukus
*School of Biosciences, University of Birmingham, Edgbaston B15 2TT, U.K.
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Susannah J. Patey;
Susannah J. Patey
*School of Biosciences, University of Birmingham, Edgbaston B15 2TT, U.K.
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Terence G. Smith;
Terence G. Smith
†School of Biological Sciences, University of East Anglia, Norwich, Norfolk NR4 7TJ, U.K.
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John K. Heath;
John K. Heath
*School of Biosciences, University of Birmingham, Edgbaston B15 2TT, U.K.
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Mohammad K. Hajihosseini
Mohammad K. Hajihosseini
2
†School of Biological Sciences, University of East Anglia, Norwich, Norfolk NR4 7TJ, U.K.
2To whom correspondence should be addressed (email m.k.h@uea.ac.uk).
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Publisher: Portland Press Ltd
Received:
June 18 2010
Revision Received:
February 17 2011
Accepted:
February 28 2011
Accepted Manuscript online:
February 28 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2011 Biochemical Society
2011
Biochem J (2011) 436 (1): 71–81.
Article history
Received:
June 18 2010
Revision Received:
February 17 2011
Accepted:
February 28 2011
Accepted Manuscript online:
February 28 2011
Citation
Lee M. Wheldon, Naila Khodabukus, Susannah J. Patey, Terence G. Smith, John K. Heath, Mohammad K. Hajihosseini; Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model. Biochem J 15 May 2011; 436 (1): 71–81. doi: https://doi.org/10.1042/BJ20100884
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