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，主要临床特征为色素视网膜病变、肥胖、多指畸形、学习障碍、肾脏异常和性功能减退。I还与高血压、糖尿病和先天性心脏缺陷有关。BBS的视网膜变性早发，通常在生命的第二个十年导致失明。然而，BBS视网膜病变的病程和严重程度各不相同。迄今为止，至少有16个BBS基因已被报道，另有大约30%的BBS基因尚未被发现。已经观察到，家族之间和家族内部的BBS表型差异很大，这种表达性的变异性表明其他基因修饰了表型。这些基因修饰物可能是BBS基因本身，也可能是发生突变时不会独立引起BBS的其他基因。鉴定更多的BBS基因对于充分了解基因修饰在这种疾病中的作用是重要的，BBS的研究对于理解遗传复杂性的机制是有用的。事实上，我们已经确定了两种参与BBS的蛋白质复合物（BBS some和BBS伴侣复合物），这为我们提供了研究蛋白质复合物内部和之间的相互作用如何在生化水平上促进遗传复杂性的机会。此外，获得大量动物模型为我们提供了确定其他生化途径对BBS表型的潜在修饰作用的机会。在拟议的研究中，我们将鉴定新的BBS基因（Specific Aim 1）。在特异性目标2中，我们将评估BBS作为两种模式生物（斑马鱼和小鼠）的复杂疾病。在特异性目标3中，我们将评估特定生化途径改变BBS表型的程度。我们的研究将有助于更好地理解纤毛相关视网膜病变、复杂疾病和生化途径的相互作用。我们建议进行第一次生化研究，以确定多个BBS基因突变的组合是否影响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和其他视网膜病变的靶点。

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.