The Molecular Basis of Syndromic Retinitis Pigmentosa

Oregon Health & Science University, Portland OR

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Abstract

DESCRIPTION (provided by applicant): The overall goal of this project is to delineate the molecular pathogenesis of a form of syndromic retinitis pigmentosa called pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome) and characterized by abnormal electroretinogram, lipofuscin accumulation in the retinal pigment epithelium, and early, rapidly progressive pigmentary retinopathy. This autosomal recessive disorder includes extrapyramidal dysfunction and iron accumulation in the basal ganglia. PKAN is caused by mutations in PANK2, one of four human genes to encode a key regulatory enzyme in coenzyme A (CoA) biosynthesis, called pantothenate kinase. Since PANK2 is uniquely associated with mitochondria, we hypothesize that defects lead to CoA deficiency, energy and lipid metabolic abnormalities, oxidative damage and apoptosis in susceptible tissues. We propose to investigate how PANK2 defects cause retinal and neuronal degeneration. Our specific aims are: 1) to create Pank2 defective mouse mutants representing a spectrum of disease severity and delineate their associated phenotypes; 2) to identify metabolic and molecular perturbations in pantothenate kinase 2 deficiency in vivo and in vitro; and 3) to determine whether mutations in PANK2 are associated with age-related macular degeneration or idiopathic pigmentary retinopathy. Knowledge about the genetic basis of PKAN has enabled delineation of a clinically recognizable disease, as well as the development of a molecular diagnostic test and new ideas for rational therapies. This discovery has linked a previously unsuspected metabolic pathway with retinopathy and neurodegeneration and has illuminated a possible role for defects in this pathway in related, more common disorders that share pathologic features with PKAN, including age-related macular degeneration, retinitis pigmentosa and Parkinson disease.