Molecular Genetics of high Myopia

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DESCRIPTION (provided by applicant): ABSTRACT Myopia, or nearsightedness, is a visual condition that predisposes individuals in its extreme forms to blinding disorders such as retinal detachments, glaucoma, premature cataracts, and degenerative maculopathy. Myopia pathogenesis has not been precisely defined and there are no consistent effective treatments. Recent studies identifying causal genes in rare, inherited non-syndromic high-grade myopia, including our own study, have associated mutations in at least 3 genes, and each discovery has clarified molecular mechanisms of exaggerated eye growth. To build on this productive line of inquiry, we have ascertained and carefully characterized 230 families with familial extreme high-grade myopia. The objective of this proposal is to use this valuable and unique family resource to systematically identify causal genes for familial high-grade myopia in a subset of these families, using the remainder as cases or controls as well as using other collaborative cohort resources globally for replication purposes. Limitations of current conventional linkage and positional cloning approaches include their requirement for large, multiplex families. In addition, narrowing candidate areas in traditional linkage analysis can be difficult due to large regions that lack recombination events and hence these regions have required cumbersome and lengthy screening for causative mutations. Powerful new genetic tools can facilitate this screening process and improve variant discovery in smaller families. In particular, efficient whole-exome sequencing, the targeted capture of protein- coding gene sequences, should be particularly useful in our studies, as most Mendelian disorders are caused by mutations affecting exomes of the target gene. By combining genome-wide linkage analysis and whole- exome sequencing, we are maximizing the impact of our family data and accelerating novel myopia mutation identification. In recently published studies, we have identified novel genes highly associated with or causative of myopia. In this application, we propose to complete identification of causative loci from the Duke myopia dataset and then focus our characterization on those genes with unknown functions. By adding to the network of myopia-associated genes, and then assigning functions to those which are unknown, we provide essential information for understanding potential connections and pathways involved in this disease. We aim to: 1) Use targeted sequencing and/or whole-exome sequencing with linkage mapping to identify genetic variants associated with familial high-grade myopia, with prevalence determination in the Duke and other myopia datasets of these new causative mutations; 2) Characterize functional consequences of candidate causative mutations in zebrafish models, and perform comparative expression studies of ocular tissues in zebrafish to that in humans and mouse models of induced eye growth; and 3) Perform convergent gene list enrichment analyses and biological pathway analyses of sets of genes determined by refractive error genome wide association studies, whole exome sequencing, and expression studies to develop an integrated view of the mechanisms that might influence the process of emmetropization (normal refractive development). These efforts will significantly improve our understanding of normal eye growth signals and of the pathogenesis of myopia and related disorders with myopia as a cardinal feature. Moreover, our discoveries will reveal new opportunities to develop customized therapies for extreme and common myopia phenotypes.