Grant: $497,358 - National Institutes of Health - Sep. 20, 2009
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Award Description: Familial episodic ataxia (EA) syndromes are rare and heterogeneous (EA1-EA7 to date) monogenic disorders, the study of which has illuminated previously unrecognized but important roles of ion channels and transporters in neuronal and cerebellar function. Overlapping features between the EA syndromes and the more common but genetically complex vertigo and ataxia syndromes, particularly those associated with migraine, suggest possibly shared disease mechanisms. We have recruited the largest number of patients with EA under the care of any research group worldwide. We have expanded the clinical and genetic spectrum of EA2 and EA1, defined a new syndrome EA6, and mapped EA7. Furthermore, we performed functional studies to find that the type and location of mutations affect the biophysical and biochemical properties of the abnormal proteins, which correlate with phenotypic variability.
Project Description: 1) To develop strategies to rapidly and reliably identify mutations in genes known to cause EA. Background: The number of identified EA phenotypes is rapidly expanding. So far, mutations have been identified in 4 genes, all coding for membrane proteins including ion channels and transporters. Commercial tests for identifying mutations are available on only one EA gene, CACNA1A. Screening of exons and flanking introns of EA genes by conventional methods is expensive, time consuming and incomplete. Hypothesis: The genetic diagnosis of EA can be improved by new technology. Plan: We will search for exonic deletions or amplifications using Multiplex Ligation-dependent Probe Amplification (MLPA). We propose to use array-based Illumina Solexa sequencing to screen the proband and at least one additional family member (when available) for mutations in the EA2 gene CACNA1A, the EA1 gene KCNA1, the EA5 gene CACNB4, and EA6 gene SLC1A3. We have preliminary data demonstrating the feasibility, efficiency, and accuracy of this technology. 2) To identify genetic causes of novel EA syndromes in individuals without mutations in the known EA genes. Background: Of the proband in our database, less than one third was found to have EA1 or EA2. We have characterized several novel phenotypes and established suggestive linkage in three new EA syndromes. Hypothesis: We hypothesize that clinically distinct EA syndromes likely have distinct genetic loci and that mutations in membrane proteins including but not limited to ion channels that regulate cerebellar neuronal excitability are ideal candidate genes for these new EA syndromes. Plan: We will use Illumina 300K Human CytoSNP-12 BeadChip with dense, uniform genome coverage and high throughput for linkage analysis and ancestral identity-by-descent mapping of the disease loci of novel EA syndromes. Candidate genes will be prioritized by genetic location, function, and expression profile.
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 20, 2009. Help expand these official descriptions using the wiki below.