Genetic and Molecular Characterization of SCA26

描述（由申请人提供）： 常染色体显性遗传性脊髓小脑共济失调（SCA）是一组临床和遗传异质性的神经退行性疾病。SCA的发生与多种基因和突变机制有关，但浦肯野细胞变性导致SCA的分子过程和机制尚不清楚。SCA发病机制的进一步见解可能来自更多的研究，这些研究表明，并非所有SCA都是由于新基因中的DNA重复序列扩增所致。我们最近发现了一个新的显性共济失调的大家庭，登记为SCA 26，并将疾病位点定位到19p13.3。这项研究的长期目标是扩大我们对遗传性共济失调发病机制的理解，特别是近选择性浦肯野细胞变性的基础。我们假设SCA 26是由一个对小脑神经元存活或特定功能至关重要的基因突变引起的，并确定了一些引人注目的候选基因。本项目的目的是通过招募更多的家庭成员来完善基因座图谱，并通过从无关家庭中寻找不同的创始人单倍型，通过对所有候选基因的编码区进行测序来确定基因和突变基础，并调查SCA 26的患病率。该项目的意义在于：1）为共济失调的诊断和遗传咨询提供了一种新的基因检测方法，将使共济失调患者直接受益; 2）为研究共济失调患者的浦肯野细胞和小脑变性提供了一种新的模型; 3）更广泛地说，它将建立一个新的点，将已知的因素连接在一起，并揭示了新的见解，以描绘参与神经变性或对神经元存活和功能至关重要的共同途径。

DESCRIPTION (provided by applicant): The autosomal dominant spinocerebellar ataxias (SCA) are a clinically and genetically heterogeneous group of neurodegenerative diseases. It is clear that a diverse of genes and mutational mechanisms can cause SCA, but the molecular process and mechanism for Purkinje cell degeneration that leads to SCA is still unknown. Further insights into SCA pathogenesis may come from more studies that have demonstrated that not all SCAs are due to expanded DNA repeats in novel genes. We recently identified a large family with a novel dominant ataxia, register as SCA26, and mapped the disease locus to 19p13.3. The long-range goal of this research is to expand our understanding of the pathogenesis of the hereditary ataxias, and specifically the basis for the nearly selective Purkinje cell degeneration. We hypothesize that SCA26 is caused by a mutation in a gene that is vital to neuron survival or specific function in the cerebellum, and have identified a few compelling candidate genes. The objective of this project is to refine the locus map by recruiting more family members, and by seeking a different founder haplotype from unrelated families, and to identify the gene and mutational basis by sequencing all coding regions of top candidate genes, and to survey the prevalence of SCA26. This project is significant because: 1) it will directly benefit ataxic patients by providing a new genetic test for diagnosis and genetic consulting; 2) it will provide a new model to study Purkinje cell and cerebellar degeneration in ataxia patients; 3) more broadly, it will establish a new point to inter-connect known factors together, and unveil new insights to delineate the common pathways involved in neurodegeneration or vital to neuron survival and function.