Abstract

Frings audiogenic seizure (AGS)-susceptible mice represent a genetic model of sensory-evoked reflex epilepsy which, unlike the DBA/2J AGS-susceptible mouse, displays a life-long susceptibility to sound-induced seizures. Breeding studies have demonstrated that the Frings phenotype is a monogenic and highly penetrant autosomal recessive trait; whereas, the DBA/2J seizure phenotype is polygenic in origin and results from at least three known loci (i.e., asp1, asp2, and asp3). We have mapped the monogenic audiogenic seizure-susceptible (mass1) locus of the Frings mouse to an approximately 2 cM region on chromosome 13. The identification and characterization of the disease gene in this simple monogenic mouse epilepsy model will add new insight into the pathophysiology of more complex human seizure disorders. The four SPECIFIC AIMS outlined in this proposal will begin to test this hypothesis. The fine mapping studies of SPECIFIC AIM 1 will narrow the mass1 locus and thereby expedite the cloning process. The physical mapping studies outline in SPECIFIC AIM 2 will provide the foundation for the identification of candidate cDNAs and expressed sequence tags (ESTs) which will ultimately lead to the cloning of the mass1 gene. The breeding strategies employed in SPECIFIC AIM 3 will place the mass1 gene onto well-characterized AGS-resistant (C57BL) and AGS-sensitive (DBA/2J) backgrounds to construct new congenic mouse strains. These new congenic strains will be useful for identifying interactions between the mass1 gene and other seizure-susceptibility and seizure-resistance genes. The pharmacologic and phenotypic consequences of placing the mass1 gene on different genetic backgrounds will be characterized in SPECIFIC AIM 4 wherein the AGS-susceptibility and seizure-threshold of mice from the new congenic strains will be evaluated. These studies will provide new insight into the pathophysiologic basis of genetic epilepsy and provide new molecular targets that will be useful for rational antiepileptic drug development and gene therapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS038616-02
Application #
6165281
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (02))
Program Officer
Fureman, Brandy E
Project Start
1999-04-15
Project End
2003-02-28
Budget Start
2000-03-01
Budget End
2001-02-28
Support Year
2
Fiscal Year
2000
Total Cost
$360,542
Indirect Cost

  Institution

Name
University of Utah
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112

  Publications

Klein, Brian D; Fu, Ying-Hui; Ptacek, Louis J et al. (2005) Auditory deficits associated with the frings mgr1 (mass1) mutation in mice. Dev Neurosci 27:321-32
Miller, T M; Dias da Silva, M R; Miller, H A et al. (2004) Correlating phenotype and genotype in the periodic paralyses. Neurology 63:1647-55
Klein, Brian D; Fu, Ying-Hui; Ptacek, Louis J et al. (2004) c-Fos immunohistochemical mapping of the audiogenic seizure network and tonotopic neuronal hyperexcitability in the inferior colliculus of the Frings mouse. Epilepsy Res 62:13-25
Bendahhou, Said; Donaldson, Matthew R; Plaster, Nikki M et al. (2003) Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome. J Biol Chem 278:51779-85
Donaldson, M R; Jensen, J L; Tristani-Firouzi, M et al. (2003) PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology 60:1811-6
Nakayama, Junko; Fu, Ying-Hui; Clark, Anna M et al. (2002) A nonsense mutation of the MASS1 gene in a family with febrile and afebrile seizures. Ann Neurol 52:654-7
Plaster, N M; Tawil, R; Tristani-Firouzi, M et al. (2001) Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell 105:511-9
Bendahhou, S; Cummins, T R; Griggs, R C et al. (2001) Sodium channel inactivation defects are associated with acetazolamide-exacerbated hypokalemic periodic paralysis. Ann Neurol 50:417-20