Complex Mechanisms in Bardet-Biedl Syndrome Retinopathy

描述（由申请人提供）：我们建议继续研究一种遗传异质性、常染色体隐性形式的视网膜变性，称为Bardet-Biedl综合征（BBS）。BBS是一种多效性疾病，其主要临床特征为色素性视网膜病变、肥胖、多指（趾）畸形、学习障碍、肾脏异常和生殖器发育不良。I还与高血压、糖尿病和先天性心脏缺陷有关。BBS的视网膜变性是早发性的，通常在生命的第二个十年中导致失明。然而，BBS视网膜病变的病程和严重程度存在差异。迄今为止，至少有16个BBS基因已被报道，另外的BBS基因，约占病例的30%，仍有待发现。已经观察到BBS表型在家族之间和家族内变化很大，并且表达性的这种变化表明其他基因修饰表型。这种遗传修饰因子可能是BBS基因本身，或其他突变时不会独立引起BBS的基因。另外的BBS基因的鉴定对于充分理解遗传修饰在这种疾病中的作用将是重要的，并且BBS的研究对于理解遗传复杂性的机制是有用的。事实上，我们已经确定了两个蛋白质复合物参与BBS（BBSome和BBS分子伴侣复合物）为我们提供了机会，研究蛋白质复合物内和蛋白质复合物之间的相互作用如何在生化水平上促进遗传复杂性。此外，获得一些动物模型为我们提供了机会，以确定其他生化途径对BBS表型的潜在修饰作用。在拟议的研究中，我们将确定新的BBS基因（具体目标1）。在具体目标2中，我们将在两种模式生物（斑马鱼和小鼠）中评估BBS作为一种复杂的疾病。在特定目标3中，我们将评估特定生化途径修饰BBS表型的程度。我们的研究将导致更好地了解纤毛相关的视网膜病变，复杂的疾病，以及生物化学途径的相互作用。我们建议进行第一次生化研究，以确定是否在一个以上的BBS基因的突变组合影响BBSome的形成和依赖于BBSome的下游途径。拟议的研究有可能确定治疗BBS和其他视网膜病的靶点。

DESCRIPTION (provided by applicant): We propose to continue to study a genetically heterogeneous, autosomal recessive form of retinal degeneration known as Bardet-Biedl syndrome (BBS). BBS is a pleiotropic disorder with the primary clinical features of pigmentary retinopathy, obesity, polydactyly, learning disabilities, renal abnormalities and hypogenitalism. I is also associated with hypertension, diabetes mellitus and congenital heart defects. The retinal degeneration of BBS is early onset and typically leads to blindness in the second decade of life. However, there is variation in the course and severity of BBS retinopathy. At least sixteen BBS genes have been reported to date and additional BBS genes, accounting for approximately 30% of cases, remain to be discovered. It has been observed that the BBS phenotype varies greatly between and within families and this variability in expressivity indicates that other genes modify the phenotype. Such genetic modifiers may be the BBS genes themselves, or other genes that do not independently cause BBS when mutated. The identification of additional BBS genes will be important to fully understand the role of genetic modification in this disorder, and the study o BBS is useful in understanding mechanisms underlying genetic complexity. The fact that we have identified two protein complexes involved in BBS (the BBSome and the BBS chaperone complex) provides us with the opportunity to study how interactions within and between protein complexes contribute to genetic complexity at the biochemical level. In addition, access to a number of animal models provides us with the opportunity to determine the potential modifying effects of other biochemical pathways on BBS phenotypes. In the proposed studies, we will identify novel BBS genes (Specific Aim 1). In Specific Aim 2, we will evaluate BBS as a complex disorder in two model organisms (zebrafish and mice). In Specific Aim 3, we will evaluate the extent to which specific biochemical pathways modify BBS phenotypes. Our studies will lead to a better understanding of cilia-related retinopathies, complex disease, and the interactions of biochemical pathways. We propose to perform the first biochemical studies to determine whether a combination of mutations in more than one BBS gene impacts BBSome formation and downstream pathways dependent on the BBSome. The proposed studies have the potential to identify targets for treatment of BBS and other retinopathies.