Genes and susceptibility factors in primary torsion dystonia

总结 原发性扭转性肌张力障碍（PTD）是一组以扭转为特征的运动障碍 肌肉挛缩，其中肌张力障碍是唯一的临床体征（震颤除外）， 神经元变性或后天原因的证据。已经绘制了11个基因， 原发性肌张力障碍包括DYT 1（TOR 1A）、2、4（TUBB 4A）、6（THAP 1）、7、13、17、21、23（CIZ 1）， 24（ANO 3）和25（GNAL），然而只有3个在早发性肌张力障碍患者中具有突变， TOR 1A、THAP 1和GNAL。每一种都是以常染色体显性遗传的， 突变，这意味着个体可以携带突变，但不显示临床症状。 PTD最常见的形式是成人发病局灶性，占所有PTD病例的约90%。 肌张力障碍，在一般人群中的患病率估计为30/100，000。一个小 局灶性病例的百分比是由于CIZ 1，ANO 3，THAP 1，TUBB 4A和GNAL的突变， 绝大多数是无法解释的，很可能是多基因或多因素的。在这份补助金中， 关注于早发性PTD，我们将揭示影响DYT 1表达的基因 肌张力障碍通过GWAS和外显子组测序研究。我们将鉴定其他基因， 使用外显子组测序确定PTD的发病，并确定是否在确定的早期 发病PTD基因或与这些基因相关的途径有助于易感性， 最普遍的PTD形式，局灶性肌张力障碍，使用病例：对照关联研究。的 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 共享和交叉的途径，从而更好地了解分子基础， PTD并为开发新的治疗方法提供基础。此外，深入了解 调节疾病发病率的因素将是确定这些因素是否可以 可以改变，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.