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Research Report :Dr. Gil Ast June 2010

Genes are the basic units of heredity. Genes are made up of DNA and are located on chromosomes like chains of beads on a string. They act like templates for synthesis of proteins, the molecules which carry out much of the work in cells. When a gene is activated, the information stored in its DNA is transferred to a molecule called pre-mRNA. Some of the sequence of the pre- mRNA encodes protein sequence (exons) and other regions (introns) are removed during the process of creating the mature mRNA. This process is called splicing. Familial Dysautonomia (FD) is a splicing disease due to a single point mutation (change of one letter) in a gene called IKBKAP. The exact function of the IKBKAP gene is unclear, but it is believed to be part of a complex that assists in the elongation of genes. The most common mutation in FD is found in an intron segment of IKBKAP called a donor splice site (5' ss). This 5’ss has direct control over the removal of a particular intron and pasting together of two exons. Because of the mutation, exon 20 is not included in the mature mRNA in FD patients; the result is lower production of the normal protein.

Our ultimate goal is to restore the normal splicing of the IKBKAP gene in order to restore normal protein activity in FD patients. We have investigated various therapeutic agents that could be used as possible treatments. We first tested these substances on cells derived from FD patients; these cells were generated in our lab. One of the substances that elevates expression of normal IKBKAP is a food supplement already approved for use by the FDA for improving cognitive function and reducing dementia in the elderly, called phosphatidylserine. This supplement, as well as some of its derivatives, raised levels of both the normal IKBKAP mRNA and the functional protein in FD- derived cells. The supplement enhanced cell viability as it also increased the expression levels of certain genes involved in cell cycle regulation and DNA metabolic processes. In addition, we found that etorphine, a δ-opioid agonist, and L-glutamic acid, an amino acid, the most abundant excitatory neurotransmitter in the nervous system, increased IKBKAP mRNA levels in FD- derived cells. These substances acted through a signaling pathway called the MAPK/ERK.

In order to test these drugs for their effect on FD disease symptoms, we and our collaborators have generated an animal system model for the FD disease. This mouse model is based on our scientific achievements in the understanding of the molecular mechanism of FD and it is the first transgenic mouse that recapitulates a human alternative splicing disease. The mice were created by generating embryonic mice cells that contain the human gene with or without the mutation causing FD. These cells were inserted into mice that were mated to produce heterozygous mice, carriers of the FD mutation and finally homozygous mice which have the mutated FD gene. The FD mice will be used to study the etiology the FD disease and for testing agents we identified in cell culture and other therapeutic approaches for treatment of this devastating phenotype.