Genetics of Familial Episodic Ataxia

家族性发作性共济失调(EA)综合征是一种罕见的异质性(EA1-EA7)单基因疾病，其研究揭示了离子通道和转运蛋白在神经元和小脑功能中的重要作用。EA综合征和更常见但基因复杂的眩晕和共济失调综合征之间的重叠特征，特别是与偏头痛相关的症状，表明可能有共同的疾病机制。我们招募了世界上最多的EA患者，由世界上任何一个研究小组照顾。我们扩大了EA2和EA1的临床和遗传谱，定义了一个新的综合征EA6，并定位了EA7。此外，我们还进行了功能研究，发现突变的类型和位置影响异常蛋白质的生物物理和生化特性，这些特性与表型变异相关。拟议研究的总体目标是在我们现有的数据库中确定发作性共济失调综合征的遗传原因，以提高识别和诊断。这一建议的具体目的是：1)提高电针的基因诊断水平。尽管进行了广泛的筛查，我们数据库中的大多数受试者都没有被基因诊断。我们将使用多重连接依赖的探针扩增(MLPA)来搜索外显子拷贝数变体。我们将使用基于阵列的IILumina基因组分析仪(Solexa测序技术)来识别已知EA基因的突变和其他核苷酸变异，这一点得到了我们的初步分析的验证。2)寻找新的EA基因座和基因。我们将在不适合连锁分析和散发性病例的小家系中，通过连锁分析和下降定位(使用IILumina 300K HumanCyloSNP-12珠芯片)寻找新的疾病基因座。我们将根据功能和表达谱选择候选基因，并根据位置选择候选基因，包括具有或不具有良好功能的连接区中的基因。我们将测试这一假设，即膜蛋白的突变，包括但不限于调节神经元兴奋性的离子通道，会导致发作性共济失调。从这项研究中获得的见解将有助于改善对家族性发作性共济失调和更常见的发作性眩晕综合征的诊断和治疗。

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. The overall goal of the proposed research is to define the genetic causes of episodic ataxia syndromes in our existing database to improve recognition and diagnosis. The specific aims for this proposal are: 1) To improve the genetic diagnosis in EA. The majority of the subjects in our database has not been genetically diagnosed despite extensive screening. We will search for exonic copy number variants using Multiplex Ligationdependent Probe Amplification (MLPA). We will use array-based IIlumina Genome Analyzers (Solexa sequencing technology) to identify mutations and other nucleotide variations in the known EA genes, as validated by our preliminary analysis. 2) To identify new EA loci and genes. We will search for new disease loci by linkage analysis in large families and identify-by-descent mapping (using IIlumina 300K HumanCyloSNP-12 BeadChip) in small families that are not suitable for linkage analysis and sporadic cases. We will select candidate genes based on function and expression profile and also by position including those in the linked regions with or without well-characterized function. We will test the hypotheSiS that mutations in membrane proteins including but not limited to ion channels that regulate neuronal excitability cause episodic ataxia. Insights gained from the study will lead to improved diagnosis and treatment of familial episodic ataxia and the more common episodic vertigo syndromes.