Research Grant Award

David M. Ornitz, M.D.,Ph.D.

Washington University School of Medicine, St. Louis, MO
Biological tools to investigate Spinocerebellar Ataxia 27 (SCA27)

Intracellular Fibroblast Growth Factors (iFGFs) are important regulators of the activity of many different neurons in the brain and throughout the body. FGF14 is one of four iFGF genes. When the Ornitz laboratory completely inactivated the FGF14 gene in mice (FGF14 knockout mouse), the mice developed an ataxia syndrome in which they were uncoordinated, showed spontaneous abnormal movements (called paroxysmal dystonia) and occasionally had a tremor. The published phenotype of the FGF14 knockout mouse directly led to the discovery of a mutation in the FGF14 gene in a large human family in which affected individuals have a progressive spinocerebellar ataxia, which is now classified as SCA27. One major difference between the existing mouse model and the human disease is that the knockout mice completely lack a functional FGF14 gene, whereas affected humans have one normal copy of the FGF14 gene and one mutant copy. Thus, although the existing mouse model and human disease phenotypes resemble each other, the underlying molecular mechanism that causes the disease in knockout mice and humans must be different. The Ornitz laboratory, with expertise in making and studying mouse models, is collaborating with the Nerbonne laboratory, with expertise in neurophysiology, to understand the role of FGF14 in regulating the activity (excitability) of neurons and why, in the absence of FGF14, mice develop an ataxia syndrome. A key question that we will answer is how a single mutation in one copy of human FGF14 results in a disease similar to that found in mice that are missing both copies of their FGF14 genes. To fully understand the human SCA27 disease mechanism and to be able to test possible interventional strategies, we will construct a mouse model with a mutation that is identical to the human SCA27 mutation. We will also generate and test antibodies that will allow us to detect the normal and mutant FGF14 protein in mice and humans. With the availability of these essential tools, we will be in an excellent position to apply for NIH funding so that we can expand our research program and investigate detailed molecular mechanisms and therapeutic interventional strategies that could benefit patients with SCA27 and potentially patients with other forms of ataxia and other movement disorders.