Molecular characterization of congenital cataract

先天性白内障的分子特征

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8720006
• 关键词: Adolescent; Affect; Age; Alleles; Biology; Birth; Blindness; Candidate Disease Gene; Cataract; Childhood; Classification; Counseling; Crystallins; Cytoskeletal Proteins; Data; Development; Diagnosis; Differentiation and Growth; Disease; Evaluation; Eye Development; Family; Family member; Frequencies; Gene Mutation; Genes; Genetic; Genetic screening method; Human; Knowledge; Lead; Lens Opacities; Membrane Proteins; Molecular; Molecular Diagnosis; Mutation; Patients; Phenotype; Recurrence; Reporting; Risk; Role; Sequence Analysis; Severities; Testing; Variant; Zebrafish; cohort; congenital cataract; exome; exome sequencing; genetic pedigree; improved; lens; mutant; new technology; novel; novel diagnostics; patient population; proband; public health relevance; research study; vision development

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名新生儿中观察到1-15例儿童白内障。先天性白内障是最严重的一种，因为它干扰了正常的视觉发育，并可能导致永久性失明。遗传学研究已经确定了与各种形式的白内障相关的许多基因的突变。先天性/青少年白内障患者中这些已知基因突变的确切频率尚不清楚，许多病例仍在等待分子诊断。全外显子组测序（WES）是一种新技术，可用于鉴定已知和新基因中的致病突变，因此可以在分子水平上显著促进儿科白内障的表征/分类。在初步实验中，WES被用来筛选22个家族性显性先天性/青少年性白内障家系的先证者，并在45%（10/22）的家族中鉴定出已知白内障基因的致病突变和一个新的晶状体蛋白基因。在这个建议中，我们专注于识别新的遗传因素参与人类先天性/青少年白内障通过分析家族性病例。第一个目标是确定与白内障相关的基因突变 在12个先前确定的已知白内障基因没有突变的家族和12个额外的受影响的家系中。第一步将是对其他先证者进行全外显子组测序/已知白内障基因分析，这可能会在40-50%的家族中识别致病突变。在没有突变的家族中发现新的遗传因子，首先将通过评价在脊椎动物透镜发育/功能中具有已知作用或位于先前报道的白内障基因座内的基因来进行。接下来，将对突变阴性家系中的其他家族成员进行WES，并对其外显子组变异进行联合分析，以鉴定新因子中的有害变异。第二个目的是通过对斑马鱼中新的候选白内障因子进行功能分析，并对更大一组受白内障和相关眼部疾病影响的人类患者进行这些基因突变的检查，来验证先天性/青少年白内障中新因子的参与。鉴定与儿童白内障相关的基因/突变等位基因并确定其对疾病的具体贡献将指导基因检测的开发和利用，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上级咨询。除此之外，了解白内障的遗传机制将提高我们对透镜生物学的认识，并导致更好地治疗和管理所有年龄段的透镜混浊。