一个表现为快速进展的帕金森综合症大家系致病基因研究

A large pedigree with parkinsonism has been followed for 10 years, which is autosomal dominant hereditary, composed of 6 generations and 29 patients, and which manifests itself with bradykinesia, rigidity and tremors. Some patients exhibited sexual dysfunction, urinary incontinence, fecal incontinence or constipation during the early stages of the disease. All patients had no response to L-dopa therapy. The onset age ranged from 23 to 53 years of age (average 40.9±8.80 y). The disease progressed rapidly after onset, with the patients' survival duration ranging from 2 to 10 years (average 4.3±2.40 y). Blood cell counts, chemical analyses, thyroid function, immunology, and brain MRI scan were all normal. Blood samples of 6 patients and 5 normal controls over the responding onset age from 2 generations were collected. The primary whole genome sequencing of 1 patient and 1 control in the pedigree found 1296 gene variants and excluded the known genes' mutations of Parkinson's disease and multiple system atrophy. On these bases, whole genome sequencing and bioinformatics' analysis will be carried out on more samples in the pedigree to find the causative gene. Further functional studies of the causative gene will be carried out by transfected cell, induced pluripotent stem (iPS) cell. This project will be helpful in elucidating the etiology and pathophysiology of parkinsonism in the pedigree, and will be helpful to research and studies in related neurodegenerative diseases.

摘要：一个随访10年的帕金森综合征大家系，呈常染色体隐性遗传，共6代29名患者，临床表现为运动迟缓、肌强直及震颤，部分较早出现性功能障碍、小便和/或大便失禁，患者对多巴类药物无效，疾病早发（发病年龄23-53岁，平均40.9±8.80岁），快速进展至死亡（病后生存时间2-10年，平均4.3±2.40年），常规、生化、甲状腺功能、免疫及颅脑MRI均正常，已经收集了2代6名患者5名超过相应发病年龄的正常对照血样。初步1个患者1个家族正常成员对照的全基因组测序排除了帕金森病、多系统萎缩已知致病基因的突变，发现1296个基因变异位点。本研究拟此基础上，扩大样本进行全基因组测序，通过生物信息学分析等方法确定可能的致病基因，对致病基因进行克隆、转染细胞、建立诱导的多功能干细胞（iPS细胞）等方法，对基因功能进行初步研究，以进一步确定致病基因及其相关功能，对于阐明本病及其发病机制具有重要意义

研究背景：在前期随访的帕金森症大家系基础上，排除了已知的帕金森病致病基因，拟采用全基因组测序等方法目确本家系致病基因，并进行初步功能研究。主要研究内容、重要结果、关键数据：（1）采用全基因组测序技术，检测了本家系病人及家系中健康成员，发现微管相关蛋白tau（Microtubule-associated protein tau, MAPT）基因致病性突变c. 1859 G>T, p. G620V，存在所有病人，正常健康成员为野生型，与疾病共分离，是家系致病基因的致病性突变。已经建立细胞转染模型及转基因小鼠动物模型，进一步功能研究正在进行中。（2）与美国Deng Y等合作，发现一个帕金森病大家系新的致病基因TMEM230，并在中国家族性及散发性帕金森病患者得到验证，发现了新的突变，文章发表于Nat Genet及Mov Disord；进一步基因功能研究正在进行中。（3）其他帕金森病致病基因筛查及相关基因研究，发现致病基因新的突变及增加或减低中国帕金森病发病风险的相关基因位点。这些研究，帕金森症大家系致病基因确定，对于家系遗传咨询具有重要意义；帕金森病新基因发现，对于帕金森病发病机制研究、开发新的诊断及治疗靶点具有一定意义。