Molecular characterization of congenital cataract

先天性白内障的分子特征

基本信息

批准号：
8720006
负责人：
Elena V Semina
金额：
$ 18.38万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2016-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Pediatric cataracts are observed in 1-15 per 10,000 births. Congenital cataract represents the most severe end of the spectrum due to interference with normal visual development and the possibility of permanent blindness. Genetic studies have identified mutations in numerous genes associated with various forms of cataracts. The exact frequencies of mutations in these known genes in patients with congenital/juvenile cataract are not known and many cases are still awaiting molecular diagnosis. Whole exome sequencing (WES) is a novel technology that can be utilized for identification of causative mutations in both known and novel genes and thus could significantly facilitate characterization/classification of pediatric cataracts at a molecular level. In preliminary experiments, WES was used to screen probands from 22 pedigrees affected with familial dominant congenital/juvenile cataract and identified causative mutations in known cataract genes and one novel crystallin gene in 45% (10/22) of families. In this proposal, we focus on the identification of novel genetic factors involved in human congenital/juvenile cataract through analysis of familial cases. The first aim is to identify genetic mutations associated with cataract in the twelve previously identified families without mutations in known cataract genes and twelve additional affected pedigrees. The first step will be whole exome sequencing/known cataract gene analysis of the additional probands, which is likely to identify causative mutations in 40-50% of the families. Discovery of novel genetic factors in families without mutations will initiall be approached by evaluation of genes which have a known role in vertebrate lens development/function or are located within a previously reported cataract loci. Next, WES of additional family members in mutation-negative pedigrees and combined analysis of their exome variation will be undertaken to identify deleterious variants in novel factors. The second aim is to verify the involvement of novel factors in congenital/juvenile cataract by functional analysis of the new candidate cataract factors in zebrafish and examination of a larger group of human patients affected with cataract and related ocular conditions for mutations in these genes. Identification of the genes/mutant alleles associated with pediatric cataract and determination of their specific contributions to disease will guide development and utilization of genetic tests for accurate diagnosis and predictions of phenotypic severity and recurrence risks, thus offering superior counseling to affected families. In addition to this, understanding of the genetic mechanisms of cataracts will improve our knowledge about lens biology and lead to better treatment and management of lens opacities at all ages.

描述（由申请人提供）：每10,000个出生1-15个小儿白内障。先天性白内障是由于干扰正常视觉发展和永久性失明的可能性而代表了频谱中最严重的端。遗传研究已经确定了与各种形式白内障相关的许多基因中的突变。这些已知基因中的突变的确切频率尚不清楚，许多病例仍在等待分子诊断。整个外显子组测序（WES）是一种新技术，可用于鉴定已知和新基因的致病突变，因此可以显着促进分子水平上小儿白内障的表征/分类。 In preliminary experiments, WES was used to screen probands from 22 pedigrees affected with familial dominant congenital/juvenile cataract and identified causative mutations in known cataract genes and one novel crystallin gene in 45% (10/22) of families.在该提案中，我们专注于通过分析家族病例来鉴定人类先天/少年白内障涉及的新遗传因素。第一个目的是识别与白内障相关的基因突变在十二个先前鉴定的家庭中，已知白内障基因中没有突变和十二个受影响的家族。第一步将是对其他概率的整个外显子组测序/已知的白内障基因分析，这很可能鉴定出40-50％的家族的病因突变。通过评估在脊椎动物晶状体发育/功能中具有已知作用的基因或位于先前报道的白内障基因座中，将发现无突变的家族中新型遗传因素的发现。接下来，将进行突变阴性血统中的其他家庭成员以及对外显子体变异的结合分析，以确定新因素中的有害变体。第二个目的是通过对斑马鱼中的新候选白内障因子的功能分析以及对这些基因突变的相关眼疾病的较大人类患者的检查，并检查新候选白内障因子的功能分析，以验证新的因素参与先天/少年白内障。鉴定与小儿白内障相关的基因/突变等位基因，并确定其对疾病的具体贡献将指导和利用基因检测，以准确诊断和预测表型严重程度和复发风险，从而为受影响的家庭提供出色的咨询。除此之外，对白内障的遗传机制的理解将提高我们对晶状体生物学的了解，并在所有年龄段的晶状体息肉中得到更好的治疗和管理。