Molecular Genetic Characterization of Alstrom Syndrome

描述（由申请人提供）：Alstrom综合征（AS）是一种罕见的隐性疾病，其特征为进行性感觉神经视网膜和听觉变性、肥胖、II型糖尿病和在生命的第二至第四个十年死亡。经常遇到的疾病并发症，心肌病，肝衰竭或肾衰竭，对患者的疾病管理提出了挑战。 在以前的工作中，我们确定了一个新的基因，ALMS 1，未知功能的遗传缺陷。为了开始研究以了解ALMS 1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，我们建立了一种小鼠模型，该模型重现了Alstrom患者中报告的许多临床特征。 ALMS 1在中心体和睫状体基底体中的亚细胞定位表明Alstrom综合征是一个不断增长的睫状体疾病家族之一，该家族包括Bardet-Biedl综合征和多囊肾病。这也表明ALMS 1可能在与细胞分裂、纤毛功能和微管运输相关的生物过程中起作用。 为了继续我们对Alstrom综合征的研究，我们将通过比较小鼠中的组织病理学与在终末期死后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，这在人类中无法完成。为了开始了解ALMS 1的细胞功能，我们将进行实验，以测试ALMS 1缺陷是否会影响细胞增殖，纤毛功能和/或细胞内蛋白质运输。最后，我们将确定ALMS 1是否影响不同组织中的常见生化途径。 与公共卫生的相关性： 我们的长期目标是了解ALMS 1蛋白在细胞中的作用，以及该基因的缺陷如何导致多器官系统功能障碍。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，因此了解ALSM 1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.