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NIH Award from the National Institute of Neurological Disorders and Stroke

Tippy a Novel Mouse Model for Human Ataxia Epilepsy

  • Principal Investigator: Kathleen Joyce Millen, PhD, Associate Professor, Department of Human Genetics, Committee on Neurobiology Committee on Genetics Committee on Developmental Biology
  • Start Date: June 1, 2009
  • Total Award Amount: $78,000 (first year) $78,000 (second year)

Public Health Relevance

This proposal is focused on defining the etiology of congenital ataxia and epilepsy. These are two co-morbid neurodevelopmental disorders that are often associated with devastating cognitive and motor deficits. An improved understanding of the developmental mechanisms leading to the underlying cerebellar and hippocampal malformations will provide valuable diagnostic and prognostic information and influence treatment.

Project Description

Spontaneous and ENU-induced mouse mutants are a tremendously valuable resource for their ability to model human disease. The study of these mutants has provided new insights into basic clinically relevant biological mechanisms, which would not have been apparent through standard gene-targeting approaches. The key value of these mutants is the ability to associate novel phenotypes with the causative genotype. However, despite their significance, many mouse mutants have not been sufficiently phenotypically characterized to spark appropriate scientific interest. Further, many investigators are hesitant to invest resources into the required positional cloning efforts to identify the causative molecular lesions. As a result, many extant mouse mutant resources are significantly underutilized and of limited to value to the scientific community, despite the already significant resources invested into their generation and maintenance. One such mutant is the spontaneous neurological mouse mutant tippy.

The tippy mutation arose at Jackson Labs in 1977 but has remained essentially uncharacterized, both phenotypically and genotypically since its first report in 1995. Homozygous tippy mutants exhibit ataxia and epilepsy and do not survive past weaning ages. Congenital ataxia and epilepsy are common human pediatric neurological disorders that are often co-morbid, and their developmental and pathogenesis poorly understood. We have determined that tippy mice have two very interesting neurological phenotypes, which are of broad interest to both basic and clinical neuroscientists. Our preliminary analysis has revealed novel cerebellar Purkinje cell dendritic abnormalities that likely underlie the ataxia in tippy mutants.

Further, we have characterized a complex hippocampal malformation in these mutants likely causative for epilepsy. This malformation is similar to hippocampal dysplasias commonly observed in human temporal lobe epilepsy, a phenotype which has not been previously modeled in mice. Thus, we have demonstrated that the cerebellar and hippocampal phenotypes of tippy mutants are of broad interest to both basic and clinical neuroscientists.

In this proposal, we present electrophysiological and immunohistochemical experiments to more completely define the cellular and functional basis of the observed tippy mutant morphological CNS abnormalities. We also propose to identify the underlying molecular genetic lesion in tippy mutants, which we have localized to a small critical region on distal mouse chromosome 9, to associate the tippy genotype with the clinically important tippy neurological phenotypes. Together these experiments will provide a comprehensive characterization of the tippy mutation which will provide new insights into the basic neurobiology of ataxia and epilepsy. These experiments will also significantly enhance the value and accessibility of tippy mutant mice, so that others may more readily exploit this valuable mouse reagent.

This award is funded under the American Recovery and Reinvestment Act of 2009, NIH Award number: 1R03NS065382-01

Kathleen Joyce Millen

Kathleen Joyce Millen, PhD,
Associate Professor, Department of Human Genetics, Committee on Neurobiology Committee on Genetics Committee on Developmental Biology