The Molecular Basis of Syndromic Retinitis Pigmentosa

描述(由申请人提供)：本项目的总体目标是描述一种名为泛酸激酶相关神经变性(PKAN，以前称为Heller vorden-Spatz综合征)的综合征性视网膜色素变性的分子发病机制，其特征是视网膜电信号异常，视网膜色素上皮中脂褐素积聚，以及早期、快速进展的色素视网膜病变。这种常染色体隐性遗传病包括锥体外系功能障碍和基底节中铁蓄积。PKAN是由PANK2突变引起的，PANK2是人类四个基因之一，编码辅酶A(CoA)生物合成的关键调节酶，称为泛酸激酶。由于PANK2与线粒体是唯一相关的，我们假设缺陷会导致CoA缺乏，能量和脂肪代谢异常，氧化损伤和易感组织中的细胞凋亡。我们建议研究PANK2缺陷如何导致视网膜和神经元退化。 我们的具体目标是：1)建立代表疾病严重程度的Pank2缺陷小鼠突变株，并描述其相关的表型；2)鉴定体内和体外泛酸激酶2缺陷的代谢和分子扰动；以及3)确定PANK2突变是否与年龄相关性黄斑变性或特发性视网膜色素变性有关。 对PKAN的遗传基础的了解使临床可识别疾病的描述成为可能，以及分子诊断测试的发展和合理治疗的新想法。这一发现将先前未知的代谢途径与视网膜病变和神经退行性变联系在一起，并阐明了这一途径的缺陷在相关的、更常见的疾病中可能发挥的作用，这些疾病与PKAN的病理特征相同，包括老年性黄斑变性、视网膜色素变性和帕金森病。

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.