发育性青光眼合并眼外肌纤维化家系的分子遗传学研究

Glaucoma is one of the leading causes of irreversible blindness, and the etiology is still unknown. Studies on pedigrees with glaucoma are more likely to identify the disease-causing genes. We investigated a Chinese five-generation family (44 members, 11 patients) with developmental glaucoma associated with congenital fibrosis of the extraocular muscles (CFEOM), with the latter conformed by clinical and pathological examinations. All the family members live in the remote area in Sichuan Province, China. Affected individuals of this family exhibited similar clinical features with an autosome dominant. No studies of such disease were reported. In order to find causative genes of this pedigree, several steps were used as bellows: (1) Linkage analysis, target region capture and exome sequencing (the back-up plan) are used to localize and identify the disease-causing gene. (2) PCR and Sanger sequencing are used to determine whether any of the remaining variants co-segregated with the disease phenotype in this family. (3) the gene identified of the patients of sporatic developmental glaucoma, CFEOM and normal unaffected individuals will be analized to further con?rm that the mutation is responsible for this disease. The study should help us to understand the molecular mechanism of the developmental glaucoma and CFEOM, find out the possisble relationship between them, provide a reliable basis for the molecular diagnosis and gene therapy for this disease in the furture.

青光眼是主要致盲性眼病，发病机制不明，收集有价值的家系进行分子遗传学研究是寻找致病基因的重要途径。课题组采集并随访了一个发育性青光眼合并眼外肌纤维化的家系共5代44人，其中患者11人，经临床及病理检查确诊。该家系居住在川西边远闭塞山区，遗传方式为常染色体显性遗传，表型特殊，目前国内外未见类似报道。课题组在筛查已知致病基因但未发现相关突变的基础上，拟（1）通过连锁分析、目标区域捕获及外显子组全测序（备用方案）确定致病基因；（2）DNA直接测序验证突变是否在该家系中共分离；（3）验证突变是否存在于发育性青光眼及眼外肌纤维化的散发患者和正常人群中。本课题有助于在分子水平上深入理解发育性青光眼和眼外肌纤维化的发病机制及两者之间可能存在的相互关系，既为将来的基因诊断和治疗提供可靠依据，也丰富了相关眼病和/或综合征的疾病和遗传资源库。

青光眼是主要致盲性眼病，发病机制不明，收集有价值的家系进行分子遗传学研究是寻找致病基因的重要途径。课题组采集并随访了一个发育性青光眼合并眼外肌纤维化的家系共5代44人，其中患者11人，经临床及病理检查确诊。该家系居住在川西边远闭塞山区，遗传方式为常染色体显性遗传，表型特殊。通过外显子组全测序、连锁分析、目标区域捕获等方法找到了致病基因为SPTB基因，其第25号外显子的c.5326A>T（p.N1776Y）杂合突变（碱基A>T），导致第1776位的天冬酰胺变成酪氨酸，该基因位于第14号染色体长臂23.3区域。DNA直接测序验证发现了SPTB基因大致符合共分离。据我们查阅文献所知，发育性青光眼合并眼外肌纤维化的致病基因为我们首次报道。

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