The dominant spinocerebellar ataxias (SCA) are a growing group of heterogeneous neurodegenerative diseases. A total of 26 dominant loci are known, and for 10 the causative gene or mutation has been determined. Despite the remarkable progress in identifying loci and genes for the ataxias, approximately 40% of autosomal dominant ataxias remain unaccounted for. The phenotypic characterization, and genotypic identification of new ataxia genes has thus far provided valuable and unique insights regarding each disease mutation. Several of the pathologic etiologies of SCAs are shared by other neurodegenerative diseases, making their discovery and characterization particularly relevant. We have identified a large Filipino pedigree segregating a dominant trait for cerebellar ataxia with a causative mutation in the voltage-gated potassium channel KCNC3.
Specific aims i nclude: 1) phenotypic characterization of SCA13 through the ascertainment of clinical, neurophyisologic, and imaging characteristics of this ataxia syndrome, 2) determining the nature of the dominant negative effect described in the R420H mutation, and 3) analyzing a large collection of SCA patients for mutations and performing genotype-phenotype analyses. The ultimate goals of this proposal are to train the applicant in methods of clinical research, to expand the experimental repertoire of the candidate including molecular biology, bioinformatics, and genomics, and to correlate mutations in this novel gene with the phenotypes recorded by the applicant.
|Gallego-Iradi, Carolina; Bickford, Justin S; Khare, Swati et al. (2014) KCNC3(R420H), a K(+) channel mutation causative in spinocerebellar ataxia 13 displays aberrant intracellular trafficking. Neurobiol Dis 71:270-9|
|Subramony, S H; Advincula, Joel; Perlman, Susan et al. (2013) Comprehensive phenotype of the p.Arg420his allelic form of spinocerebellar ataxia type 13. Cerebellum 12:932-6|