Effects of Alternative Splicing at FMR1 Exon 15 on Understanding Fragile X Syndrome

With $118,500 in grants from FRAXA Research Foundation from 2007-2008, Dr. Robert Denman and his team at the New York State Institute for Basic Research studied protein splicing, specifically looking at exon 15-encoded residues of of FMPR.

Robert Denman, PhD
$118,500 Grant
Robert Denman, PhD
Principal Investigator

Wen Xie, PhD
FRAXA Postdoctoral Fellow (2008)

New York State Institute for Basic Research
2007-2008 FRAXA Research Grant
$118,500 over 2 Years

by Robert Denman, 9/1/2008

Alternative splicing and post-translational modification are two cellular processes that subtly modify protein function. Alternative splicing modifies the three-dimensional structure of proteins by making small additions or deletions to its primary structure. Post-translational modification marks proteins with unique chemical tags (methyl, phosphate sugar groups etc.) The Fragile X mental retardation protein, FMRP, is affected by both processes; however, the consequence each has on FMRP’s function is not well-known.

The focus of our present studies is the exon 15-encoded residues of FMRP, which are alternatively spliced and multiply modified post-translationally. We have recently found that Fmr1 alternative splicing at both exon 12 and exon 15 are developmentally regulated and change predictably during neuronal differentiation. We have also determined that post-translational methylation of FMRP’s RG-rich region is modulated by exon 15 alternative splicing and are currently investigating the effect a potential “modifier” protein, MSP58, plays in controlling these processes.

As our objective is to relate both alternative splicing and arginine methylation to fundamental processes in neurons we have recently begun to determine whether particular arginine methyltransferases are found in dendritic processes and whether arginine methylation can be locally modulated. Completing these studies will further our understanding of the role FMRP plays in normal cellular metabolism and may lead to new targets for future drug treatments.

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