Familial dysautonomia (FD; Riley-Day syndrome) is the best known and most frequent of a group of congenital sensory neuropathies characterized by widespread sensory and variable autonomic dysfunction. First described in 1949, FD is a devastating disorder that involves progressive neuronal degeneration with a broad impact on the operation of many of the body's systems leading to a vastly reduced quality of life and premature death. Affected individuals demonstrate lack of overflow tears, impaired temperature and pain sensation and autonomic dysfunction. Despite recent advances in its management, FD is inevitably fatal, with only 50% of patients reaching 30 years of age. FD is due to a recessive genetic defect with a remarkably high carrier frequency in Ashkenazi Jews of 1 in 32, rivaling the gene frequencies of more widely recognized disorders such as Tay-Sachs disease and cystic fibrosis. Recently we reported that a single non-coding mutation in the gene IKBKAP causes 99.5% of all FD cases. IKAP, the protein product of the gene IKBKAP, is a member of the recently identified human Elongator complex, thought to play a role in transcriptional elongation. Interestingly, IKAP has also been implicated in the mammalian stress response pathway through an interaction with c-Jun N-terminal kinase (JNK). The major FD mutation is a single-base change in the donor splice site of intron 20 that results in an apparent decrease in splicing efficiency and variable skipping of exon 20 in the IKBKAP mRNA. Interestingly, despite the fact that FD is a recessive disease, homozygous mutant cells are capable of expressing normal mRNA and protein. In this grant, we aim to further characterize mutations in IKBKAP and functionally related proteins that can cause sensory and autonomic neuropathy, to investigate the nature of the splicing defect, to develop a transgenic mouse model using an FD BAC in order to examine the tissue specific splicing of IKBKAP, and to identify drugs that increase the efficiency of accurate splicing from the FD mutant alleles as a promising route to an effective therapy for this devastating disorder.
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