Principal Investigator/Program Director (Last, first, middle): Semina, Elena V. DESCRIPTION: State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This abstract is meant to serve as a succinct and accurate description of the proposed work when separated from the application. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED. 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 i s 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 initially 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 i s 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. PERFORMANCE SITE(S) (organization, city, state) Department of Pediatrics Children's Research Institute Medical College of Wisconsin 8701 Watertown Plank Road Milwaukee, WI 53226 KEY PERSONNEL. See instructions. Use continuation pages as needed to provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Role on Project Elena V. Semina, PhD Medical College of Wisconsin PI Disclosure Permission Statement. Applicable to SBIR/STTR Only. See instructions. Yes No PHS 398 (Rev. 05/01) Page _2___ Form Page 2

Public Health Relevance

This proposal will investigate the genetic mutations responsible for the development of congenital/juvenile cataracts in some families. The results of this project will provide a better understanding of eye development and will likely identify new causes of human ocular conditions like cataracts, which may lead to new diagnostic and treatment opportunities.

National Institute of Health (NIH)
National Eye Institute (NEI)
Exploratory/Developmental Grants (R21)
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Genetics of Health and Disease Study Section (GHD)
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Araj, Houmam H
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Medical College of Wisconsin
Schools of Medicine
United States
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Deml, Brett; Reis, Linda M; Lemyre, Emmanuelle et al. (2016) Novel mutations in PAX6, OTX2 and NDP in anophthalmia, microphthalmia and coloboma. Eur J Hum Genet 24:535-41
Reis, Linda M; Tyler, Rebecca C; Semina, Elena V (2014) Identification of a novel C-terminal extension mutation in EPHA2 in a family affected with congenital cataract. Mol Vis 20:836-42