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的常染色体隐性视网膜变性形式，称为Bardet-Biedl综合征(BBS)。BBS是一种多效性疾病，主要临床特征为视网膜色素变性、肥胖、多指畸形、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病有关。BBS的视网膜变性起病较早，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存在差异。到目前为止，至少已报告了16个BBS基因，还有约占病例30%的其他BBS基因有待发现。已经观察到BBS的表型在家庭之间和家庭内有很大的差异，这种表现力的变化表明其他基因改变了表型。这样的遗传修饰物可能是BBS基因本身，也可能是其他在突变时不独立导致BBS的基因。识别更多的BBS基因对于充分理解遗传修饰在这种疾病中的作用将是重要的，而BBS的研究有助于理解遗传复杂性的机制。我们已经确定了BBS中涉及的两个蛋白质复合体(BBSome和BBS伴侣复合体)，这为我们提供了在生化水平上研究蛋白质复合体内部和之间的相互作用如何导致遗传复杂性的机会。此外，获得一些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，我们将发现新的BBS基因(特定目标1)。在具体目标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。在特定目标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的视网膜病变、复杂疾病以及生化途径之间的相互作用。我们建议进行第一次生化研究，以确定一个以上BBS基因的突变组合是否会影响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.