The goal of this project is to better understand the molecular mechanisms of Leber congenital amaurosis (LCA), the most common hereditary cause of visual impairment in infants and children. To accomplish this, functional studies of CWC27, a newly identified LCA-associated disease gene that encodes a splicing factor, will be performed using both in vitro and in vivo methods. In addition, several novel candidate genes whose mutations cause LCA have been identified by characterizing our collection of over 1,000 unrelated LCA patient families. We will establish mouse models for five of these newly LCA associated disease genes, and through follow up functional studies of these models we expect to gain new insights into disease mechanisms as well as lay the foundation for developing new diagnoses and treatment methods. One significant gap in our current understanding of LCA is that about 1/3 of patients cannot be explained by mutations in known retinal disease genes. To close this gap, we have collected over 1,000 unrelated LCA patient families across the world. Screens for mutations in known LCA and other related inherited retinal disease genes has led to the identification of causal mutations in 705 probands, leaving about 350 patient families that remain unsolved. Patients from these families are likely due to carry mutations in novel LCA disease genes, representing a well characterized, rich resource for identifying new genes that can cause LCA. Indeed, whole exome sequencing of these unassigned patient families has led to the publication of four novel disease genes. One of these genes is CWC27, for which we have established knock out and knock in mouse models that mimic human patient phenotypes. In parallel, we plan to identify the underlying mutations in the remaining probands using a combination of whole exome and genome sequencing, bioinformatics, and statistics. Functional studies will be performed on five of the top candidates to elucidate the underlying molecular mechanisms for LCA disease pathology.
Our Specific Aims are to:
Specific Aim 1. Characterize the novel LCA disease gene CWC27 Specific Aim 2. Identify and perform functional studies of novel LCA disease genes Specific Aim 3. Investigate the full spectrum of mutations contributing to LCA Discovery and functional characterization of novel LCA genes will assist the development of new diagnostic tools and treatments. In addition, since mutations in LCA disease genes also cause other retinal dystrophies, functional studies of additional LCA disease genes will provide important insights into the molecular mechanisms underlying retinal dystrophies in general.
The goal of this research project is to understand the underlying molecular mechanisms of human Leber congenital amaurosis (LCA), the most common hereditary cause of visual impairment in infants and children. Through studying of the Cwc27 mutant mice model just established, we plan to reveal how defects in mRNA splicing pathway leads to retinal degeneration in human. In parallel, we propose to identify novel LCA genes that will address a major gap of the field and provide the basis for accurate diagnosis as well as developing new treatment methods for the disease.
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