Abstract

Here we report our study on one of the skeletal diseases, the Apert syndrome, which occurs at one in 65,000 live births in human. We first introduced a Ser252Trp mutation that is found in human Apert patients, to mouse FGFR2 gene. The FGFR2-Ser252Trp mutant mice displayed phenotypes mimicking the human Apert disease. We then use this mouse model to test preventivetherapeutic approaches to see if the disease can be prevented or cured. We show that a small hairpin RNA (shRNA), targeting the FGFR2-S252W mutant form mRNA in this mouse model, completely inhibits Apert-like craniosynostosis and the related defects. We further show that restoration of normal FGFR2 signaling is manifested by an alteration of ERK12 activity, implicating ERK and its downstream genes in disease expressivity. Furthermore, treatment of mutant mice with an ERK inhibitor results in a complete cure of mutant phenotypes. These results illustrate an unknown pathogenic role of ERK activation in the FGFR2-S252W-associated craniosynostosis and represent a new concept of shRNA-mediated therapy for diseases caused by gain of functions associated with activating point mutations in human genome.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIADK056004-03
Application #
7967604
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2009
Total Cost
$581,734
Indirect Cost

  Institution

Name
National Institute of Diabetes and Digestive and Kidney Diseases
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

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Hsiao, Yi-Hsuan; Deng, Chuxia; Mason, Jeffrey T et al. (2011) Hidden malignant cells within leukocyte aggregates: seeds for invasive and metastatic cancer? Cancer Epidemiol 35:475-9
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Su, Nan; Xu, Xiaoling; Li, Cuiling et al. (2010) Generation of Fgfr3 conditional knockout mice. Int J Biol Sci 6:327-32
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Jia, Rong; Li, Cuiling; McCoy, J Philip et al. (2010) SRp20 is a proto-oncogene critical for cell proliferation and tumor induction and maintenance. Int J Biol Sci 6:806-26
Deng, Chuxia; Liu, Hanqin (2010) An unknown piece of early work of nuclear reprogramming in fish eggs. Int J Biol Sci 6:190-1

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