Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Rodent cell – per se
Reexamination Certificate
2002-09-03
2004-09-21
Spector, Lorraine (Department: 1646)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Rodent cell, per se
C435S252300, C536S023500, C530S350000
Reexamination Certificate
active
06794187
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the isolation and characterization of a novel gene relating to epilepsy. More specifically, the invention relates to the isolation and characterization of the Monogenic Audiogenic Seizure-susceptible gene, hereinafter mass1 gene.
TECHNICAL BACKGROUND
Epilepsy is a common neurological disorder that affects nearly 2.5 million people in the United States. Epilepsy is characterized by recurrent seizures resulting from a sudden burst of electrical energy in the brain. The electrical discharge of brain cells causes a change in a person's consciousness, movement, and/or sensations. The intensity and frequency of the epileptic seizures varies from person to person.
Epilepsies in humans can be separated into two forms, symptomatic and non-symptomatic. Symptomatic epilepsy is a seizure disorder related to a known cause such as metabolic disease, brain malformations, or brain tumors. In these cases, seizures presumably occur because of a very abnormal focus (or foci) in the brain. Genetic models of symptomatic epilepsy include the weaver mouse (wv), in which a mutation of the G protein-gated inwardly rectifying potassium channel GIRK2 results in neuro-developmental abnormalities and seizures. Signorini, S. et al. (1997),
Proc Natl Acad Sci USA
94: 923-7. Fragile X-associated protein knock-out mice have a neurodevelopmental syndrome with lowered thresholds to audiogenic seizures. Musumeci, S. A. et al.(2000),
Epilepsia
41: 19-23. Audiogenic seizures can also be induced in seizure-resistant mice such as C57BL/6 by repetitive sound stimulation, suggesting that seizure-susceptibility can be influenced by multiple genetic and environmental factors. Henry, K. R. (1967),
Science
158: 938-40.
Non-symptomatic epilepsies are defined when no structural or metabolic lesions are recognized and the patients have no other neurological findings between seizures. This latter group of patients is more likely to have primary neuronal hyperexcitability that is not caused by metabolic, developmental or structural lesions. Molecular characterization of electrical hyperexcitability in human muscle diseases led to the hypothesis that such disorders might be the result of mutations in neuronal ion channels, the primary determinants of neuronal membrane excitability. Ptacek, L. J. et al. (1991),
Cell
67: 1021-7.
All non-symptomatic human epilepsy syndromes and genetic mouse seizure models that have been characterized at a molecular level are caused by mutations in ion channels. Ptacek, L. J. (1999),
Semin Neurol
19: 363-9; Jen, J. & L. J. Ptacek (2000), Channelopathies: Episodic Disorders of the Nervous System. Metabolic and Molecular Bases of Inherited Disease. C. R. Schriver, A. L. Beaudet, W. S. Sly and D. Valle. New York, McGraw-Hill. pp. 5223-5238; Noebels, J. L. (2000), The Inherited Epilepsies. Metabolic and Molecular Bases of Inherited Disease. C. R. Schriver, A. L. Beaudet, W. S. Sly and D. Valle. New York, McGraw-Hill. pp 5807-5832. Some patients with febrile seizures have been recognized to have mutations in sodium channel &agr; and &bgr;1 subunits while some patients with epilepsy and episodic ataxia were shown to have calcium channel &bgr;-subunit mutations. Wallace, R. H. et al. (1998),
Nat Genet
19: 366-70; Escayg, A. et al. (2000),
Am J Hum Genet
66: 1531-9; Escayg, A. et al. (2000),
Nat Genet
24: 343-5. The voltage-gated potassium channel genes KCNQ2 and KCNQ3, when mutated, result in benign familial neonatal convulsions. Biervert, C. et al. (1998),
Science
279: 403-6; Charlier, C. et al. (1998),
Nat Genet
18: 53-5; Singh, N. A. et al. (1998),
Nat Genet
18: 25-9. Ligand-gated channels can also result in epilepsy as demonstrated by mutations in the &agr;4 subunit of the neuronal nicotinic acetylcholine receptor that result in autosomal dominant nocturnal frontal lobe epilepsy. Steinlein, O. K. et al. (1995),
Nat Genet
11: 201-3. In mice, the &agr;, &bgr; and &ggr; subunits of the voltage-sensitive calcium channel have been associated with the tottering (tg), lethargic (lh) and stargazer (stg) models of absence seizures. Fletcher, C. F. et al (1996),
Cell
87: 607-17; Burgess, D. L. et al. (1997),
Cell
88: 385-92; Letts, V. A. et al. (1998),
Nat Genet
19: 340-7. Finally, audiogenic seizure-susceptibility has been characterized in a mouse knockout model of the 5-HT
2C
receptor; homozygous mice have audiogenic seizures and altered feeding behavior. Tecott, L. H. et al. (1995),
Nature
374: 542-6; Brennan, T. J. et al. (1997),
Nat Genet
16: 387-90.
The Frings mouse represents one of many strains of mice and rats that are sensitive to audiogenic seizures (AGS). These AGS-susceptible rodents represent models of generalized reflex epilepsy and include the well-studied DBA/2 mouse and GEPR-9 rat. The Frings mouse seizure phenotype is similar to other described audiogenic seizes and is characterized by wild running, loss of righting reflex, tonic flexion and tonic extension in response to high intensity sound stimulation Schreiber, R. A. et al. (1980), Genet 10: 537-43. This strain was characterized 50 years ago when it arose as a spontaneous mutation on the Swiss Albino background. Frings, H. et al. (1951),
J Mammal
32: 60-76. Selective inbreeding for seizure-susceptibility produced the current homozygous Frings strain with >99% penetrance of audiogenic seizures. The Frings mouse seizure phenotype was due to the autosomal recessive transmission of a single gene.
Audiogenic seizures have been observed in polygenic rodent models, such as the DBA/2 mouse and GEPR-9 rat. Collins, R. L. (1970),
Behav Genet
1: 99-109; Seyfried, T. N. et al. (1980),
Genetics
94: 701-718; Seyfried, T. N. & G. H. Glaser (1981),
Genetics
99: 117-126; Neumann, P. E. & T. N. Seyfried (1990),
Behav Genet
20: 307-23; Neumann, P. E. & R. L. Collins (1991),
Proc Natl Acad Sci USA
88: 5408-12; Ribak, C. E. et al. (1988),
Epilepsy Res
2: 345-55. While no genes associated with audiogenic seizures in spontaneous mutant models have been cloned, three putative loci associated with seizure-susceptibility in the DBA/2 mouse (asp1, asp2, and asp3) have been mapped to chromosomes 12, 4, and 7, respectively. Neumann & Seyfried, supra; Neumann, P. E. & R. L. Collins, supra. As a monogenic audiogenic seizures model, the Frings mice provided a unique opportunity for cloning and characterization of an audiogenic seizures gene. The Frings mice are an important naturally occurring monogenic model of a discrete non-symptomatic epilepsy and provide significant information on a novel mechanism of seizure-susceptibility as well as central nervous system excitability in general.
In light of the foregoing, it will be appreciated that it would be an advancement in the art to identify and characterize nucleic acid sequences that are associated with the monogenic AGS susceptibility in Frings mice. It would be a further advancement to identify and characterize the human orthologue of this gene. It would be a further advancement if the nucleic acid sequences could provide additional understanding of how epileptic seizures are triggered in disease. It would be a further advancement to provide a transgenic animal model wherein the endogenous gene associated with the Frings phenotype is mutated.
Such nucleic acid sequences and animals are disclosed and claimed herein.
BRIEF SUMMARY OF THE INVENTION
The present invention relates to an isolated novel gene which has been imputed in audiogenic seizure-susceptibility in mice known as the mass1 gene. Provided herein are nucleic acid molecules that encode the MASS1 protein. The nucleic acid molecules of the present invention may also comprise the nucleotide sequence for human mass1 (SEQ ID NO: 3) and murine mass1 (SEQ ID NO: 1). In certain other embodiments, the present invention provides nucleic acid molecules that code for the amino acid sequence of human MASS1 (SEQ ID NO: 4) and murine MASS1 (SEQ ID NO: 2). The invention also provides nucleic acid molecules complementary to the nucleic acid molecules of SEQ ID N
Fu Ying-Hui
Ptacek Louis J.
Skradski Shana
White H. Steve
Madson & Metcalf
O'Hara Eileen B.
Spector Lorraine
University of Utah Research Foundation
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