全基因组外显子测序搜寻多汗症致病基因研究

Primary hyperhidrosis is a psychosocially devastating condition that is characterized by uncontrollable sweating in hands,?feet and the underarms. With a prevalence of 2.8% worldwide, primary hyperhidrosis can be devided into four subtypes. The most severe subtype is palmoplantar hyperhidrosis (PPH, MIM ID 144110), which is an autosomal dominant disease. It is the most common type in Chinese patients, and the prevalence in Chinese is higher than in any other population worldwide. However, the gene mutations are unknown. Our goal is to identify the genetic causes of PPH in Chinese patients, and to characterize the functional consequences of these mutations, thus prepare for future therapeutic development for this incurable disease. In order to facilitate this research, we have established the world's largest clinical database for hyperhydrosis, and have already established a large scale DNA bank of familial as well as sporadic cases of PPH.. There are three specific aims: (1) We will perform whole genome linkage analysis on the three large families affected with this condition to determine the most likely regions in the genome for the presence of gene mutations linked with the development of this disease in the three families;(2)We will perform exome sequencing to identify heterozygous gene mutations within the target regions identified in the linkage analysis, and select the candidate gene mutations to perform confirmation analysis in additional familial as well as sporadic cases of PPH using healthy volunteers as the controls; and (3)We will perform gene expression and functional investigations on the confirmed genes with mutations using cultured cells, and establish animal models if needed to characterize the molecular basis for the development of the disease phenotype. The exact experimental approaches for the functional characterization of the gene mutations will be customized depending on the predicted gene functions. These approaches will include retroviral mediated gene silencing and gene expression in cultured cells.In vivo experiments such as transgenic mouse models will also be used. These methods have been well established in our lab previously. . Our team has access to the most sophisticated research facility and expertise in all experiments proposed, and has already collected most of the samples required for this investigation. Additional samples for confirmation will be recruited over the proposed study period from the dermatology and thoracic surgery clinics of Anhui Medical University teaching hospitals.. Our study will generate ground-breaking knowledge on hyperhidrosis pathogenesis and will facilitate the development of better therapies for this disease in the future.

原发性多汗症是一常见的单基因常染色体显性遗传性疾病。最近研究发现其发病率达2.8%。患者常在掌跖、腋窝及头面部对称性无节制地大量出汗，并因此在日常生活及社会关系方面遭受常人无法想象的困扰。本课题组前期研究表明：原发性多汗症可分为4个亚型，其中以掌跖型对患者的影响最为严重，且在汉人中发病率显著高于其他人群。掌跖亚型的遗传模式为常染色体显性孟德尔遗传，其致病基因不明。本研究的目的是在前期研究的基础上，利用新一代全基因组外显子测序技术，搜寻掌跖型多汗症致病的突变基因。具体内容为：（1）在三大家系中进行全基因组连锁分析，对该多汗症家系的致病基因进行定位；（2）通过全基因组外显子测序在定位区内找到突变的候选基因，并在更多的家族性和散发性病例中及健康对照人群中进行验证；（3）对确认的基因进行功能研究。总之，本课题希望通过多汗症致病基因的研究来达到阐明其发病机制的目的，为将来开发新的诊疗方法提供依据。

原发性多汗症是一常见的单基因常染色体显性遗传性疾病。最经研究表明发现其流行率达到2.8%。患者常在掌跖部，腋窝部及头面部对称性地无节制地大量出汗，并因此在日常生活及社会关系方面遭受常人无法想象的困扰。本课题组前期研究表明，原发性多汗症可分为4个亚型，其中又以掌跖亚型症状和对患者的影响最为严重，且在汉人中发病率显著高于其他人群。掌跖亚型的遗传模式为常染色体显性孟德尔遗传， 其致病基因不明。本研究的目的是在前期准备工作的基础上搜寻掌跖性多汗症的致病基因突变。具体内容为：（1）在三个大家系中，采取全基因组连锁分析，对该多汗症家系的致病基因进行定位；（2）采取全基因组外显子测序，在定位区内找到候选基因突变， 并在更多的家族性的和散发性的病例和健康对照人群中进行验证；（3）对确认的基因进行功能研究。总之，本项研究希望通过致病基因突变的研究来达到阐明多汗症发病机制的目的，为以后开发新的疗法提供依据。在完成研究计划中发现，此病症在华人和欧美人群中的流行率远远超出以前文献的记录。因此把遗传流行病调查作为这个课题的重中之重，为基因鉴定提供关键基数。