Research Grant Award

Joseph G. Gleeson, MD

University of California, San Diego School of Medicine
A mouse model for X-linked Congenital Ataxia-histological and behavioral study in OPHN 1 knockout mice

X-linked congenital ataxia (XCA) is a group of inherited and non-progressive neurological disorders characterized by instability of posture, gait abnormalities and tremors that severely affects various daily-living skills. Our overall goal is to gain an understanding of the pathogenesis of neuronal dysfunction in XCA patients. Recent genetic studies implicated that OPHN1 gene is mutated in several families with XCA and mental retardation. We propose to generate mice deficient in OPHN1 gene to study how genetic impairment results in clinical manifestation of congenital ataxia. To determine the role of OPHN1 gene in the pathogenesis of XCA the proposed project will focus on the cerebellum, the brain structure involved in the coordination of movement and the cerebellum dependent behavioral tasks. The information that can be obtained from human patients is limited and therefore a mouse model that closely mimics both genetic and phenotypic deficits in human patients will be a useful tool in probing mechanisms of motor coordination deficits in congenital ataxia. We expect that our mouse model will closely recapitulate the pathology in human patients and should provide the information necessary to design therapy to improve or even recover motor control that is lost in X-linked congenital ataxia.