Molecular Basis of Human Visual System Disorders

Abstract The primary objective of this proposal is to enhance the molecular diagnosis rate and deepen our understanding of the molecular mechanisms underlying Retinitis Pigmentosa (RP). RP, the most prevalent form of retinal degeneration, affects 1 in 3,000 people worldwide. The genetics and pathways responsible for the disease are highly heterogeneous. Currently, approximately 25% of cases remain unexplained upon molecular mutation screen, representing one of the most significant gaps in our current knowledge of the disease. To address this challenge, we propose to systematically identify novel mutant alleles and genes that are overlooked by the current screening process through a combination of whole-genome sequencing and functional validation experiments. To achieve this goal, during our last funding period, we established a large collection of over 450 well-characterized RP patient families whose pathogenic mutations remain unassigned after screening for coding mutations in known retinal disease genes. Patients from these families are likely affected by mutations missed by current technologies, representing a well-characterized, valuable resource for identifying new mutations and disease-associated genes. During last funding period, whole exome sequencing has been performed for all unsolved probands, including 200 with whole-genome sequencing. Building on this work, our Specific Aims are: Specific Aim 1. Characterize the novel RP associated disease gene DDX41 Specific Aim 2. Unravel the full spectrum of mutations in unsolved RP patients Specific Aim 3. Identify and characterize novel RP disease genes Progress toward these goals is likely to identify multiple novel RP genes whose subsequent study will lead to new insights into disease mechanisms as well as lay the foundation for developing new diagnoses and treatment methods, including gene therapy. Importantly, the protocols and software tools developed from these aims, particularly noncoding mutation identification, will be applicable to other human diseases as well.