Molecular Genetic Characterization of Alstrom Syndrome

描述(申请人提供)：阿尔斯特罗姆综合征(AS)是一种罕见的隐性疾病，其特征是进行性神经感觉性视网膜和听觉退化、肥胖、II型糖尿病和在生命的第二到第四个十年死亡。常见的疾病并发症，如心肌病、肝功能衰竭或肾功能衰竭，对患者的疾病管理构成了挑战。 在之前的工作中，我们发现了一个新基因ALMS1的遗传缺陷，该基因的功能未知。为了开始研究ALMS1发挥作用的生物学途径以及导致器官功能障碍的病理变化的原因和进展，我们创建了一个小鼠模型，概括了Alstrom患者报告的许多临床特征。 ALMS1在中心体和睫状体基底体的亚细胞定位表明，Alstrom综合征是一种日益增多的睫状体疾病家族，包括Bardet-Biedl综合征和多囊肾病。这也表明ALMS1可能在与细胞分裂、纤毛功能和微管运输相关的生物学过程中发挥作用。 为了继续我们对阿尔斯特罗姆综合症的研究，我们将通过比较小鼠体内的组织病理学和在死后末期组织中观察到的组织病理学来验证小鼠模型。我们将通过使用小鼠模型来扩展这些研究，以确定组织病理学的进展，这在人类身上是做不到的。为了开始了解ALMS1的细胞功能，我们将进行实验，测试ALMS1缺乏是否影响细胞增殖、纤毛功能和/或细胞内蛋白质运输。最后，我们将确定ALMS1是否影响不同组织中常见的生化途径。 与公共卫生的相关性： 我们的长期目标是了解ALMS1蛋白在细胞中扮演的角色，以及该基因的缺陷如何导致多器官系统的功能障碍。这些知识对于确定降低Alstrom患者临床发病率的方法至关重要。由于该综合征的特征是普通人群中常见的疾病，如肥胖、2型糖尿病和失明，了解ALSM1的功能也有助于更好地了解这些疾病的常见形式。

DESCRIPTION (provided by applicant): Alstrom Syndrome (AS) is a rare recessive disorder characterized by progressive neurosensory retinal and aural degeneration, obesity, Type II diabetes and death by the second through fourth decade of life. Frequently encountered complications of the disease, cardiomyopathy, liver failure, or renal failure, pose challenges in the management of the disease in patients. In previous work, we identified genetic defects in a novel gene, ALMS1, of unknown function. In order to begin studies to understand the biological pathways through which ALMS1 acts and the causes and progression of the pathological changes leading to organ dysfunction, we have created a mouse model that recapitulates many of the clinical features reported in Alstrom patients. The subcellular localization of ALMS1 in centrosomes and ciliary basal bodies suggests that Alstrom Syndrome is one of a growing family of ciliary diseases, which include Bardet-Biedl Syndrome and Polycystic Kidney Disease. It also suggests that ALMS1 may function in biological processes linked to cell division, ciliary function and microtubular trafficking. To continue our studies on Alstrom Syndrome, we will validate the mouse model by comparing histopathology in the mouse with that observed in end-stage post mortem tissues. We will extend these studies by using the mouse model to ascertain the progression of tissue pathology, which cannot be done in humans. To begin to understand the cellular function of ALMS1, we will carry out experiments that will test whether ALMS1 deficiency affects cell proliferation, cilia function, and/or intracellular protein trafficking. Finally, we will determine whether ALMS1 affects common biochemical pathways in different tissues. Relevance to public health: Our long term goal is to understand the role that the ALMS1 protein plays in the cell and how defects in this gene cause the dysfunction of multiple organ systems. This knowledge will be essential to identify ways to reduce clinical morbidity in Alstrom patients. Since the syndrome is characterized by diseases that are common in the general population such as obesity, type 2 diabetes, and blindness, understanding the function of ALSM1 may also contribute to better understanding of the common forms of these diseases.