Genes and susceptibility factors in primary torsion dystonia

摘要 摘要原发性肌张力障碍(PTD)是一组以扭转为特征的运动障碍。 肌肉痉挛，其中肌张力障碍是唯一的临床症状(震颤除外)，没有 神经元变性或后天原因的证据。已经绘制了11个基因的图谱 原发性肌张力障碍包括DYT1(TOR1A)、2、4(TUBB4A)、6(THAP1)、7、13、17、21、23(CIZ1)、 24(ANO_3)和25(GNAL)，但在早发性肌张力障碍患者中只有3人有突变， TOR1A、THAP1和GNAL。每一个都是遗传的常染色体显性性状，但减少了 外显性，这意味着个体可以携带突变，但不会出现临床症状。 PTD最常见的形式是成人起病，约占所有PTD病例的90% 肌张力障碍，在普通人群中的流行率估计为30/100,000。一小块 局部病例的百分比是由CIZ1、AN03、THAP1、TUBB4A和GNAL突变引起的，但 绝大多数原因不明，很可能是多基因或多因素的。在这笔赠款中， 聚焦于早发性PTD，我们将发现影响DYT1外显性的基因 通过GWAS和外显子组测序研究肌张力障碍。我们将在早期发现其他基因 使用外显子组测序来确定PTD的发病情况，并确定是否存在已识别的早期变异体 发病的PTD基因或与这些基因相关的通路有助于 最常见的PTD，局灶性肌张力障碍，使用病例：对照关联研究。这个 拟议的研究将确定新的PTD风险因素和基因，这反过来应该揭示 共享和相交的途径导致更好地理解 并为开发新的治疗方法提供了基础。此外，深入了解 调节疾病外显性的因素将是决定这些因素是否可以 被修改，从而降低疾病的发病率。

Summary Primary torsin dystonias (PTD) are a group of movement disorders characterized by twisting muscle contractures, where dystonia is the only clinical sign (except for tremor) and there is no evidence of neuronal degeneration or an acquired cause. Eleven genes have been mapped for primary dystonia including DYT1 (TOR1A), 2, 4 (TUBB4A), 6 (THAP1), 7, 13, 17, 21, 23 (CIZ1), 24 (ANO3) and 25 (GNAL), however only 3 have mutations in early onset dystonia patients, TOR1A, THAP1 and GNAL. Each is inherited as an autosomal dominant trait but with reduced penetrance, meaning that individuals can carry the mutation but do not show clinical symptoms. The most common form of PTD is adult onset focal accounting for about 90% of all cases of dystonia with a prevalence estimated at 30/100,000 in the general population. A small percentage of focal cases are due to mutations in CIZ1, ANO3, THAP1, TUBB4A and GNAL but the vast majority is unaccounted for and is most likely multigenic or multifactorial. In this grant, focusing on early onset PTD, we will uncover genes that influence the penetrance of DYT1 dystonia through GWAS and exome sequencing studies. We will identify other genes for early onset PTD using exome sequencing and determine whether variants within the identified early onset PTD genes or the pathways associated with these genes contribute to susceptibility in the most prevalent form of PTD, focal dystonia, using a case:control association study. The proposed research will identify novel PTD risk factors and genes, which in turn should reveal shared and intersecting pathways leading to a better understanding of the molecular basis of PTD and provide the underpinnings for developing new treatments. Additionally, insight into the factors that modulate disease penetrance would be a first step in determine whether these could be modified leading to a reduced incidence of the disease.