LGI2 truncation causes a remitting focal epilepsy in dogs.
LGI2 truncation causes a remitting focal epilepsy in dogs.
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DOI：
10.1371/journal.pgen.1002194
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发表时间：
2011-07
期刊：
影响因子：
4.5
通讯作者：
Lohi H
中科院分区：
文献类型：
--
作者：
Seppälä EH;Jokinen TS;Fukata M;Fukata Y;Webster MT;Karlsson EK;Kilpinen SK;Steffen F;Dietschi E;Leeb T;Eklund R;Zhao X;Rilstone JJ;Lindblad-Toh K;Minassian BA;Lohi H
在人脑出生后的头两年里，一千万亿个突触被放置，然后被修剪，直到10到500万亿岁，突触组成最终的网络。遗传性癫痫是最常见的神经系统疾病，在修剪过程中起病，影响0.5%的2-10岁儿童，这些癫痫通常以自发缓解为特征。我们之前描述了一种缓解性癫痫的拉各托罗曼诺罗犬品种。在这里，我们确定了基因缺陷和影响神经化学途径。我们重建了大约34只受影响的动物的拉各托谱系。利用来自该家系的11个不一致同胞对的全基因组关联，我们将疾病基因定位到3号染色体上1.7Mb的纯合子区域，在那里我们发现了Lgi2基因的蛋白质截断突变，Lgi2基因是人类癫痫基因LGI1的同源物。我们表明，LGI2和LGI1一样，是神经元分泌的，作用于ADAM神经受体家族中缺乏金属蛋白酶的成员，这些受体在突触重建中发挥作用，而LGI2截断，像LGI1截断一样，阻止分泌和ADAM相互作用。在大多数LGI1突变的人类患者中，导致的癫痫在大约七周(相当于人类两年)开始发作，并在四个月后缓解(人类八年)，而大多数人类患者在八岁后开始发作。最后，我们发现，与Lgi1不同，Lgi2在出生后即刻直到修剪中期高表达，而Lgi1在修剪后期和以后都有表达。LGI2至少部分通过与LGI1相同的ADAM受体发挥作用，但更早，确保在修剪年中的电稳定性(无癫痫)，在LGI1在以后的几年执行相同的功能之前。LGI2基因是儿童癫痫常见缓解期的候选基因，LGI2向LGI1基因转换是儿童癫痫缓解机制的候选基因。神经元突触网络的主要重塑发生在儿童时期。通过加强理想连接、去除多余的连接和形成新的联系的选择性过程，直到两岁结束时形成的一千万亿个突触在10岁时被削减到500万亿。人们对引导这种导致成人大脑大规模重组的基本机制知之甚少。人类最常见的癫痫发生在儿童时期，特征是成年前病情缓解。人们对他们的遗传学和基本缓解机制知之甚少。在这里，我们描述了一种相当于犬类的疾病，并确定了缺陷基因Lgi2。我们证明该基因产物是一种分泌蛋白，并与神经元ADAM受体相互作用，已知的ADAM受体参与了发育中大脑突触重构的调节。我们的工作对儿童最常见的神经系统疾病的基本机制有了重要的了解，并揭示了癫痫缓解的过程。在狗身上识别出第一个局灶性癫痫基因也使基因测试的发展成为可能，以识别用于育种目的的携带者。
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. Major remodeling of the neuronal synaptic network occurs during childhood. The quadrillion synapses formed till the end of age two are trimmed to 500 trillion by age 10 through a selective process of strengthening of ideal connections, removal of redundant ones, and formation of new contacts. Very little is known about the basic mechanisms that direct this massive reorganization that leads to the adult brain. The most common epilepsies of humans occur in childhood and are characterized by remission prior to adulthood. Not much is known about their genetics and basic remission mechanisms. We describe here a canine equivalent disease and identify the defective gene, Lgi2. We show that the gene product is a secreted protein and interacts with neuronal ADAM receptors known to be involved in the regulation of synaptic remodeling in the developing brain. Our work sheds important light on the basic mechanisms of the most common neurological disease of children and discloses processes of epilepsy remission. The identification of the first focal epilepsy gene in dogs has also enabled the development of a genetic test to identify carriers for breeding purposes.
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影响因子：
30.8
作者：
Kalachikov, S;Evgrafov, O;Gilliam, TC
通讯作者：
Gilliam, TC
影响因子：
2.1
作者：
Berendt, Mette;Gullov, Christina Hedal;Alban, Lis
通讯作者：
Alban, Lis
DOI：
10.1523/jneurosci.6287-09.2010
发表时间：
2010-03-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ozkaynak E;Abello G;Jaegle M;van Berge L;Hamer D;Kegel L;Driegen S;Sagane K;Bermingham JR Jr;Meijer D
通讯作者：
Meijer D
影响因子：
56.9
作者：
Lohi, H;Young, EJ;Minassian, BA
通讯作者：
Minassian, BA
影响因子：
2.5
作者：
Park, Woo-Jae;Lee, Sang Eun;Yun, Hye-Young
通讯作者：
Yun, Hye-Young