Molecular Genetic Characterization of Alstrom Syndrome

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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.