Identification of the gene causing spinocerebellar ataxia in a Filipino family

描述（由申请人提供）：显性脊髓小脑共济失调（SCA）是一种日益增长的异质性神经退行性疾病。已知共有26个显性基因座，其中10个已确定致病基因或突变。尽管在识别共济失调的位点和基因方面取得了显著进展，但大约40%的常染色体显性共济失调仍未得到解释。迄今为止，新的共济失调基因的表型表征和基因型鉴定为每种疾病突变提供了有价值和独特的见解。SCAs的一些病理病因与其他神经退行性疾病相同，使其发现和表征特别相关。我们已经确定了一个大型菲律宾家系分离小脑性共济失调的显性性状与电压门控钾通道KCNC3的致病突变。具体目的包括：1)通过确定这种共济失调综合征的临床、神经生理和影像学特征来确定SCA13的表型特征，2)确定R420H突变中描述的显性负效应的性质，以及3)分析大量SCA患者的突变并进行基因型-表型分析。本申请的最终目标是培训申请人临床研究方法，扩展候选人的实验库，包括分子生物学，生物信息学和基因组学，并将该新基因的突变与申请人记录的表型联系起来。

DESCRIPTION (provided by applicant): 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 include: 1) phenotypic characterization of SCA13 through the ascertainment of clinical, neurophysiologic, 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.