Identification of the gene causing spinocerebellar ataxia in a Filipino family

主导性脊髓小脑性共济失调(SCA)是一组不断增长的异质性神经变性 疾病。共有26个显性基因座已知，其中10个是致病基因或突变 下定决心。尽管在识别共济失调的基因座和基因方面取得了显著进展，但大约 40%的常染色体显性遗传性共济失调仍下落不明。表型特征和基因分型 到目前为止，新的共济失调基因的识别为每种疾病提供了有价值和独特的见解 突变。SCA的几个病理病因与其他神经退行性疾病相同， 这使得他们的发现和特征变得特别相关。我们已经确定了一个很大的菲律宾血统 分离小脑性共济失调的显性性状与电压门控性钾离子突变 KCNC3频道。具体目标包括：1)通过确定SCA13的表型特征 该共济失调综合征的临床、神经生理学和影像特征，2)确定其性质 R420H突变中描述的显性负面影响，以及3)分析大量SCA集合 患者的基因突变和进行基因-表型分析。这项提议的最终目标是 对申请者进行临床研究方法培训，扩大申请者的实验能力 包括分子生物学、生物信息学和基因组学，并将这种新基因的突变与 申请人所记录的表型。

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, 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.