Developing a Drosophila Model of Schwannomatosis
Final rept. 15 Jul 2009-14 Jan 2013
MASSACHUSETTS GENERAL HOSPITAL BOSTON
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This project examined mutations found in familial cases of schwannomatosis in the tumor suppressor SMARCB1, a component of the SWISNF chromatin remodeling complex. Drosophila is was used to investigate the nature of the SMARCB1 mutations and the molecular consequences which give rise to schwannomas. Sensitized in vivo assays for SMARCB1 function using RNAi knockdown of Snr1 fly ortholog of SMARCB1 revealed missense mutations from patients have varying degrees of residual function suggesting they are hypomorphic. Drosophila genetics identified novel Snr1 interactions, including a potent interaction between Snr1 and the NF2merlin tumor suppressor gene, which is also involved in schwannomatosis, as well as regulators of Cyclin E and the Hedgehog pathway. The consequences of SMARCB1Snr1 knockdown on gene expression was examined using microarrays. Purification of wild type and mutant SMARCB1 was performed to examine altered protein interactions that may contribute to schwannomatosis.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research