Human FMR1 Isoform-Specific Regulation of Translation and Behavior
Fragile X syndrome is caused by lack of one protein, FMRP. But this one protein occurs in different variations. Do the different versions of FMRP have different roles in the brain, and if so, is there one that's key? If we could replace FMRP to treat Fragile X syndrome, which version would we use? This team aims to find out.
By Yongjie Yang, PhD and Kathryn Reynolds, PhD
Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene that prevents production of its normal protein product, FMRP. But not all FMRP is alike: at least 11 versions of FMRP resulting from 11 different FMR1 mRNA isoforms (variants) have been found in the human brain.
These isoforms change between fetal development and adulthood. However, the function of the dominant FMR1 isoform at these different developmental stages is unclear.
With this grant from FRAXA, we will study how the different versions of FMRP regulate translation and influence FXS-related behaviors in a mouse model of FXS. Results from these experiments will help us to understand the function of different FMR1 isoforms in brain development, which may inform future therapeutic research. These results will also provide preclinical data indicating whether these FMR1 mRNA isoforms can be further developed as a potential treatment strategy for FXS.