Inheretence Of Epilepsy

[sandgrubber]

The clip below turned up under EIC in Labradors . . . mostly inviting guffaws cause it's so full of jargon. On rereading it I think it has some interesting things to say about the state of the art re epilepsy.

1. They are breeding mutant mice that are prone to partial and generalised seizures (no doubt inbreeding with very high COI).

2. the genes involved are autosomal DOMINANT (perhaps with incomplete penetrance?)

3. they're starting to get a handle on the biochemistry . . . which may yield effective, specific drugs for treating epilepsy.

Of course mice aren't dogs, and there may be more than one genetic condition that leads to epilepsy.

Still . . . it gives hope that they are starting to get a handle on the disease and we may someday have both tests and a quality form of treatment.

Would love to see other references about recent work on genetics and biochemistry of epilepsy. I read a Danish study one time that found ~3% of Danish Labradors have seizures . . . mostly partial seizures. If this is coming from a dominant gene that isn't always expressed it has some rather confusing ramifications for breeders.

http://www.pnas.org/content/106/33/14085.a...24-f1561bcfabfb

Mutation I810N in the α3 isoform of Na+,K+-ATPase causes impairments in the sodium pump and hyperexcitability in the CNS

Steven J. Clapcotea,b,1, Steven Duffya, Gang Xiea, Greer Kirshenbauma,c, Allison R. Becharda, Vivien Rodacker Schackd, Janne Petersend, Laleh Sinaia,c, Bechara J. Saaba,c, Jason P. Lerche, Berge A. Minassianc,e, Cameron A. Ackerleye, John G. Sledc,e, Miguel A. Cortezc,e, Jeffrey T. Hendersonc, Bente Vilsend and John C. Rodera,c

+ Author Affiliations

aSamuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5;

bInstitute of Membrane and Systems Biology, University of Leeds, Leeds LS2 9JT, United Kingdom;

cDepartments of Medical Biophysics, Medical Genetics, Paediatrics, and Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada M5S 1A1;

dDepartment of Physiology and Biophysics, Centre for Membrane Pumps in Cells and Disease–PUMPKIN, Danish National Research Foundation, University of Aarhus, DK-8000 Aarhus, Denmark; and

eMouse Imaging Centre, Program in Genetics and Genome Biology, and Divisions of Neurology and Pathology, Hospital for Sick Children, Toronto, ON, Canada M5G 1X8

Abstract

In a mouse mutagenesis screen, we isolated a mutant, Myshkin (Myk), with autosomal dominant complex partial and secondarily generalized seizures, a greatly reduced threshold for hippocampal seizures in vitro, posttetanic hyperexcitability of the CA3-CA1 hippocampal pathway, and neuronal degeneration in the hippocampus. Positional cloning and functional analysis revealed that Myk/+ mice carry a mutation (I810N) which renders the normally expressed Na+,K+-ATPase α3 isoform inactive. Total Na+,K+-ATPase activity was reduced by 42% in Myk/+ brain. The epilepsy in Myk/+ mice and in vitro hyperexcitability could be prevented by delivery of additional copies of wild-type Na+,K+-ATPase α3 by transgenesis, which also rescued Na+,K+-ATPase activity. Our findings reveal the functional significance of the Na+,K+-ATPase α3 isoform in the control of epileptiform activity and seizure behavior.

[Rysup]

Mode of inheritance is vastly different in the Keeshond, being by single autosomal recessive gene.