PhD

dissertationFrings audiogenic seizure-susceptible mice are a model for sensory-evoked reflex seizures. Their seizure phenotype is characterized by wild running, loss of righting reflex, tonic flexion, and tonic extension in response to high intensity sound stimulation. The present study determined that the mode of inheritance for audiogenic seizure-susceptibility in Frings mice is due to the autosomal recessive inheritance of a single gene. This gene locus was named mass1 for monogenic audiogenic seizure susceptible and was mapped by linkage analysis to the middle region of chromosome 13. further genetic mapping refined the nonrecombinant interval to a distant of approximately 80 kilobases, and a dense physical map spanning the region was developed. Analysis of genomic sequence from the region identified a single novel gene. Within this gene, a single base pair deletion was detected exclusively in Frings mouse DNA, which produces a truncated protein in vitro. The conclusion from these data is that the novel gene is mass1 and the protein truncation is associated with Frings mouse audiogenic seizures. Characterization of mass1 show that is a larger gene multiple exons that encodes three putative alternate transcripts. Expression of mass1 was detected in brain, lung, and kidney. To predict the function of mass1 protein (MASS1), we analyzed the amino acid sequence for homology to known proteins and found significant matches with a cytosolic loop region of the sodium+/calcium2+ exchanger protein family. This homology is due to a repetitive domain within MADD1. MASS1 also contains a multicopper oxidase consensus sequence that is located near the COOH terminus of the protein and would be missing in Frings mutant MASS1 protein. This motif is an important putative domain that will be characterized to determine if it is functional in MASS1. Further study of the MASS1 protein will elucidate its exact function in cells, particularly neurons, which will ultimately determine the role of the wild type protein, and how the Frings mutant MASS1 leads to audiogenic seizure-susceptibility. Understanding the function of this protein and its role in neuronal excitability may provide novel targets for anticonvulsant agent leading to new therapies for the treatment of epilepsy