遗传性原发性自发性气胸新候选致病基因的确定及分子致病机制

A primary spontaneous pneumothorax (PSP) occurs when air collects in the pleural space without obvious underlying lung disease, and subsequently the condition result in dyspnea. The incidence of PSP is estimated to be approximately 7.4–18 per 100 000 per year for men and approximately 1.2–6 per 100 000 per year for women. About 10% of patients have a positive family history, suggesting that the disease is associated with genetic defects. The mutation of FLCN, a known dominant gene, can account for the pathogenesis of the disorder in a part of patients. PSP occurs with bulla formation and the fracture of alveolar septa. Several syndromes with the mutations of genes coding connective tissue proteins have similar phenotypes indicating the association between the genes and the development and remodeling in pulmonary extracellular matrix.The results of our previous clinical investigation and genetic analysis in a large scale showed that the clinical characteristics of patients with FLCN mutations were significantly different from the other 60 percent of patients, especially lung cysts. Several different modes of inheritance of familial PSP might exist, including recessive and X-linkage. Exome sequencing was performed in the patients from 18 families excluding known genes, and new potential disease-caused genes were found. One of them, COL6A5, is a strong candidate because of its spectrum of expression and potential function. Next, we are going to investigate the relation between genotype and phenotype on a larger sample. Our experiment results will clarify its relationship with abnormalities of extracellular matrix and formation of lung cysts by mutant cell lines and injury tissues. The study will open up a new pathway towards revealing the pathogenesis of PSP.

原发性自发性气胸（PSP）是一种无明确病因的胸外科急症，气体进入胸膜腔因而肺组织塌陷，估计人群中年发生率10/10万左右。约10％患者有家族史，提示该疾病与基因缺陷有关，已知FLCN 基因显性突变可以解释部分病人的病因。PSP发生与肺大泡形成及其间隔断裂有关，一些编码结缔组织蛋白的遗传综合征可有类似表型，表明该疾病与肺间质结缔组织发育及重塑有关。我们前期大样本临床调查和遗传分析发现，FLCN突变患者的临床特征，特别是肺大泡与其它约60%的PSP患者有明显不同;家族性PSP的遗传方式可能多样化，包括隐性和X连锁。从18个排除了已知基因的家系入手，全基因外显子遗传分析发现潜在新致病基因，包括COL6A5等。功能及表达谱分析提示该基因为候选致病基因。我们拟在更大样本中扩大基因型和表型调查，通过突变体细胞系和病变组织病理学研究，明确其与肺间质异常及肺大泡形成的关系，为揭示PSP发病机制开辟新路径。

原发性自发性气胸（PSP）是一种罕见的疾病，但在年轻人中仍然是一个严重的健康问题。在大多数病例中，PSP的病因仍然不清楚，尽管有一些证据表明遗传因素导致了气胸，包括家族性聚集和一些孟德尔疾病。为了阐明PSP的遗传分子病理，我们通过全外显子测序（WES）和全基因组关联分析（GWAS）两个研究路径，分别对家族和散发病例进行了研究。1）通过WES，在两个原发性自发性气胸家系发现新的候选致病基因-INSSR。两个家族的病人在该基因不同位置携带病理性突变。我们对其中一个突变进行了功能分析，该突变可影响INSRR的自身磷酸化。INSSR是一个孤儿受体，碱性环境（PH=9）可激活其表达。从目前已发表的文献查阅，提供该基因如何影响肺细胞或间质发育的线索很少，我们正在通过转染突变体至体外细胞株进行可能的分子通路研究。2）通过GWAS发现四个原发性自发性气胸易感基因位点。我们已确定一个关联位点在CBX7（与染色质结合的转录抑制因子)启动子上，对CBX7的表达有影响，且在该疾病人群占优势的易感等位基因因其降低了CREB1(转录因子)在该基因启动子上的结合度，表现为该基因的低表达。CBX7低表达上调了其下位基因基质金属蛋白酶MMP16 和MMP9 的表达, 后者的高表达可能是肺损伤及肺大泡形成的原因 。该研究所发现的新的致病和易感基因有利于我们对该疾病的分子遗传病理机制的阐明提供线索。