LGI 2 Truncation Causes a Remitting Focal Epilepsy in Dogs Seppälä

One quadrillion synapses are laid in the first two years of postnatal construction of the human brain, which are then pruned until age 10 to 500 trillion synapses composing the final network. Genetic epilepsies are the most common neurological diseases with onset during pruning, affecting 0.5% of 2–10-year-old children, and these epilepsies are often characterized by spontaneous remission. We previously described a remitting epilepsy in the Lagotto romagnolo canine breed. Here, we identify the gene defect and affected neurochemical pathway. We reconstructed a large Lagotto pedigree of around 34 affected animals. Using genome-wide association in 11 discordant sib-pairs from this pedigree, we mapped the disease locus to a 1.7 Mb region of homozygosity in chromosome 3 where we identified a protein-truncating mutation in the Lgi2 gene, a homologue of the human epilepsy gene LGI1. We show that LGI2, like LGI1, is neuronally secreted and acts on metalloproteinase-lacking members of the ADAM family of neuronal receptors, which function in synapse remodeling, and that LGI2 truncation, like LGI1 truncations, prevents secretion and ADAM interaction. The resulting epilepsy onsets at around seven weeks (equivalent to human two years), and remits by four months (human eight years), versus onset after age eight in the majority of human patients with LGI1 mutations. Finally, we show that Lgi2 is expressed highly in the immediate post-natal period until halfway through pruning, unlike Lgi1, which is expressed in the latter part of pruning and beyond. LGI2 acts at least in part through the same ADAM receptors as LGI1, but earlier, ensuring electrical stability (absence of epilepsy) during pruning years, preceding this same function performed by LGI1 in later years. LGI2 should be considered a candidate gene for common remitting childhood epilepsies, and LGI2-to-LGI1 transition for mechanisms of childhood epilepsy remission. Citation: Seppälä EH, Jokinen TS, Fukata M, Fukata Y, Webster MT, et al. (2011) LGI2 Truncation Causes a Remitting Focal Epilepsy in Dogs. PLoS Genet 7(7): e1002194. doi:10.1371/journal.pgen. 1002194 Editor: Marshall S. Horwitz, University of Washington, United States of America Received December 7, 2010; Accepted June 5, 2011; Published July 28, 2011 Copyright: 2011 Seppälä et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was supported in part by the Academy of Finland, the Sigrid Juselius Foundation, Biocentrum Helsinki, the Jane and Aatos Erkko Foundation, the University of Helsinki Research Funds, the Albert-Heim-Foundation, a Vanier Canada Graduate Scholarship from Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, and the European Commission (FP7-LUPA, GA-201370). KL-T is the recipient of a EURYI award from the European Science Foundation. BAM holds the Canada Research Chair in Paediatric Neurogenetics. HL is a member of Biocentrum Helsinki and the Nordic Center of Excellence in Disease Genetics, and is the recipient of a ERCStG award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: A DNA test for the Lagotto breed is commercially available through Genoscoper Oy (Ltd), which is partly owned by HL. * E-mail: hannes.lohi@helsinki.fi