Genetics of Familial Episodic Ataxia

家族性阵发性共济失调（EA）综合征是一种罕见的异质性单基因疾病（EA 1-EA 7至今），对它的研究已经阐明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综合征与更常见但遗传复杂的眩晕和共济失调综合征（特别是与偏头痛相关的综合征）之间的重叠特征表明可能存在共同的疾病机制。我们在全球任何研究小组的护理下招募了最多的EA患者。我们扩大了EA 2和EA 1的临床和遗传谱，定义了一种新的综合征EA 6，并绘制了EA 7。此外，我们进行了功能研究，发现突变的类型和位置会影响异常蛋白的生物物理和生化特性，这些特性与表型变异相关。这项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。具体目标是：1）提高EA的基因诊断水平。尽管进行了广泛的筛查，但我们数据库中的大多数受试者尚未进行基因诊断。我们将使用多重连接依赖性探针扩增（MLPA）搜索外显子拷贝数变异。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基因中的突变和其他核苷酸变异，这一点已通过我们的初步分析进行了验证。2)鉴定新的EA位点和基因。我们将通过大家族中的连锁分析和不适合连锁分析和散发病例的小家族中的血统定位（使用IIlumina 300 K HumanCyloSNP-12 BeadChip）来寻找新的疾病位点。我们将选择候选基因的基础上的功能和表达谱，也通过位置，包括那些在连接的区域有或没有充分表征的功能。我们将检验这一假设，即膜蛋白（包括但不限于调节神经元兴奋性的离子通道）的突变会引起发作性共济失调。从这项研究中获得的见解将有助于改善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.