LGI2 Truncation Causes a Remitting Focal Epilepsy in Dogs
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.
Vyšlo v časopise:
LGI2 Truncation Causes a Remitting Focal Epilepsy in Dogs. PLoS Genet 7(7): e32767. doi:10.1371/journal.pgen.1002194
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002194
Souhrn
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.
Zdroje
1. ArsenaultDZhangZW 2006 Developmental remodelling of the lemniscal synapse in the ventral basal thalamus of the mouse. J Physiol 573 Pt 1 121 132
2. HuttenlocherPR 1990 Morphometric study of human cerebral cortex development. Neuropsychologia 28 6 517 527
3. WatsonREDesessoJMHurttMECapponGD 2006 Postnatal growth and morphological development of the brain: A species comparison. Birth Defects Res B Dev Reprod Toxicol 77 5 471 484
4. RogerJBureauMDravetCGentonPTassinariCA 2005 Epileptic syndromes in infancy, childhood and adolescence (4th edition). John Libbey Eurotext 616
5. TurnbullJLohiHKearneyJARouleauGADelgado-EscuetaAV 2005 Sacred disease secrets revealed: The genetics of human epilepsy. Hum Mol Genet 14 Spec No 2 2491 2500
6. SuzukiTDelgado-EscuetaAVAguanKAlonsoMEShiJ 2004 Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet 36 8 842 849
7. CossettePLiuLBriseboisKDongHLortieA 2002 Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nat Genet 31 2 184 189
8. KalachikovSEvgrafovORossBWinawerMBarker-CummingsC 2002 Mutations in LGI1 cause autosomal-dominant partial epilepsy with auditory features. Nat Genet 30 3 335 341
9. RosanoffMJOttmanR 2008 Penetrance of LGI1 mutations in autosomal dominant partial epilepsy with auditory features. Neurology 71 8 567 571
10. MedinaMTSuzukiTAlonsoMEDuronRMMartinez-JuarezIE 2008 Novel mutations in Myoclonin1/EFHC1 in sporadic and familial juvenile myoclonic epilepsy. Neurology 70 22 Pt 2 2137 2144
11. NobileCMichelucciRAndreazzaSPasiniETosattoSC 2009 LGI1 mutations in autosomal dominant and sporadic lateral temporal epilepsy. Hum Mutat 30 4 530 536
12. JokinenTSMetsahonkalaLBergamascoLViitmaaRSyrjaP 2007 Benign familial juvenile epilepsy in lagotto romagnolo dogs. J Vet Intern Med 21 3 464 471
13. FariasFHJohnsonGSTaylorJFGiulianoEKatzML 2010 An ADAMTS17 splice donor site mutation in dogs with primary lens luxation. Invest Ophthalmol Vis Sci 51 9 4716 21
14. AwanoTJohnsonGSWadeCMKatzMLJohnsonGC 2009 Genome-wide association analysis reveals a SOD1 mutation in canine degenerative myelopathy that resembles amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 106 8 2794 2799
15. AbitbolMThibaudJLOlbyNJHitteCPuechJP 2010 A canine arylsulfatase G (ARSG) mutation leading to a sulfatase deficiency is associated with neuronal ceroid lipofuscinosis. Proc Natl Acad Sci U S A 107 33 14775 14780
16. BerkovicSFIzzilloPMcMahonJMHarkinLAMcIntoshAM 2004 LGI1 mutations in temporal lobe epilepsies. Neurology 62 7 1115 1119
17. SenechalKRThallerCNoebelsJL 2005 ADPEAF mutations reduce levels of secreted LGI1, a putative tumor suppressor protein linked to epilepsy. Hum Mol Genet 14 12 1613 1620
18. FukataYAdesnikHIwanagaTBredtDSNicollRA 2006 Epilepsy-related ligand/receptor complex LGI1 and ADAM22 regulate synaptic transmission. Science 313 5794 1792 1795
19. SaganeKIshihamaYSugimotoH 2008 LGI1 and LGI4 bind to ADAM22, ADAM23 and ADAM11. Int J Biol Sci 4 6 387 396
20. Herranz-PerezVOlucha-BordonauFEMorante-RedolatJMPerez-TurJ 2010 Regional distribution of the leucine-rich glioma inactivated (LGI) gene family transcripts in the adult mouse brain. Brain Res 1307 177 194
21. ZhouYDLeeSJinZWrightMSmithSE 2009 Arrested maturation of excitatory synapses in autosomal dominant lateral temporal lobe epilepsy. Nat Med 15 10 1208 1214
22. FukataYLoveroKLIwanagaTWatanabeAYokoiN 2010 Disruption of LGI1-linked synaptic complex causes abnormal synaptic transmission and epilepsy. Proc Natl Acad Sci U S A 107 8 3799 3804
23. BerendtMGullovCHChristensenSLGudmundsdottirHGredalH 2008 Prevalence and characteristics of epilepsy in the belgian shepherd variants groenendael and tervueren born in denmark 1995-2004. Acta Vet Scand 50 51
24. LohiHYoungEJFitzmauriceSNRusbridgeCChanEM 2005 Expanded repeat in canine epilepsy. Science 307 5706 81
25. JeserevicsJViitmaaRCizinauskasSSainioKJokinenTS 2007 Electroencephalography findings in healthy and finnish spitz dogs with epilepsy: Visual and background quantitative analysis. J Vet Intern Med 21 6 1299 1306
26. WilbeMJokinenPTruveKSeppalaEHKarlssonEK 2010 Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex. Nat Genet 42 3 250 254
27. OwuorKHarelNYEnglotDJHisamaFBlumenfeldH 2009 LGI1-associated epilepsy through altered ADAM23-dependent neuronal morphology. Mol Cell Neurosci 42 4 448 457
28. ChabrolENavarroVProvenzanoGCohenIDinocourtC 2010 Electroclinical characterization of epileptic seizures in leucine-rich, glioma-inactivated 1-deficient mice. Brain 133 9 2749 2762
29. YuYEWenLSilvaJLiZHeadK 2010 Lgi1 null mutant mice exhibit myoclonic seizures and CA1 neuronal hyperexcitability. Hum Mol Genet 19 9 1702 1711
30. BerminghamJRJrShearinHPenningtonJO'MooreJJaegleM 2006 The claw paw mutation reveals a role for Lgi4 in peripheral nerve development. Nat Neurosci 9 1 76 84
31. ParkWJLimYYKwonNSBaekKJKimDS 2010 Leucine-rich glioma inactivated 3 induces neurite outgrowth through akt and focal adhesion kinase. Neurochem Res 35 5 789 796
32. LeeSELeeAYParkWJJunDHKwonNS 2006 Mouse LGI3 gene: Expression in brain and promoter analysis. Gene 372 8 17
33. OzkaynakEAbelloGJaegleMvan BergeLHamerD 2010 Adam22 is a major neuronal receptor for Lgi4-mediated schwann cell signaling. J Neurosci 30 10 3857 3864
34. ParkWJLeeSEKwonNSBaekKJKimDS 2008 Leucine-rich glioma inactivated 3 associates with syntaxin 1. Neurosci Lett 444 3 240 244
35. LaiMHuijbersMGLancasterEGrausFBatallerL 2010 Investigation of LGI1 as the antigen in limbic encephalitis previously attributed to potassium channels: A case series. Lancet Neurol 9 8 776 785
36. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: A tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 3 559 575
37. KilpinenSAutioROjalaKIljinKBucherE 2008 Systematic bioinformatic analysis of expression levels of 17,330 human genes across 9,783 samples from 175 types of healthy and pathological tissues. Genome Biol 9 9 R139
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 7
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