A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.
A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode.
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研究基因旁系同源功能和疾病的反向遗传学和基因组学方法：肌颤搐和并列旁节。
DOI：
10.1016/j.ajhg.2022.07.006
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发表时间：
2022
影响因子：
9.8
通讯作者：
Froukh,
中科院分区：
文献类型：
--
作者：
Marafi,Dana;Kozar,Nina;Duan,Ruizhi;Bradley,Stephen;Yokochi,Kenji;AlMutairi,Fuad;Saadi,NebalWaill;Whalen,Sandra;Brunet,Theresa;Kotzaeridou,Urania;Choukair,Daniela;Keren,Boris;Nava,Caroline;Kato,Mitsuhiro;Arai,Hiroshi;Froukh,
富含亮氨酸的神经胶质瘤失活 (LGI) 家族由四个高度保守的旁系同源基因 LGI1-4 组成，它们在哺乳动物中枢和/或周围神经系统中高度表达。 LGI1 抗体可在患有自身免疫性边缘脑炎和周围神经过度兴奋综合征 (PNHS)（如艾萨克斯综合征和莫文综合征）的受试者中检测到。 LGI1和LGI4的致病性变异与神经系统疾病相关，包括家族性颞叶癫痫和伴有髓磷脂缺陷的神经源性多发性先天性关节弯曲1。目前尚无与 LGI2 或 LGI3 相关的人类疾病的报道。我们实施了外显子组测序和基于家族的基因组学来识别具有 LGI3 有害变异的个体，并利用 GeneMatcher 连接世界各地的从业者和研究人员，以研究受影响受试者的临床和电生理表型。我们还生成了 Lgi3 缺失小鼠，并进行周围神经解剖和免疫组织化学检查近旁节点 LGI3 微结构。结果，我们鉴定出来自 8 个不相关家族的 16 名个体在 LGI3 中具有功能丧失 (LoF) 双等位基因变异。深层表型表征表明，LGI3LoF 会导致潜在的临床可识别的 PNHS 特征，其特征是整体发育迟缓、智力障碍、远端畸形伴反射减弱、可见的面部肌颤以及提示运动神经不稳定的独特肌电图特征。Lgi3 缺失小鼠在有髓鞘的外周轴突中表现出减少和错误定位的 Kv1 通道复合体。我们的数据表明，LGI3 中的双等位基因 LoF 变异会导致临床上可区分的 PNHS 疾病特征，很可能是由于在 LGI3 缺失的情况下 Kv1 通道分布受到干扰所致。
The leucine-rich glioma-inactivated (LGI) family consists of four highly conserved paralogous genes,LGI1-4, that are highly expressed in mammalian central and/or peripheral nervous systems. LGI1 antibodies are detected in subjects with autoimmune limbic encephalitis and peripheral nerve hyperexcitability syndromes (PNHSs) such as Isaacs and Morvan syndromes. Pathogenic variations ofLGI1andLGI4are associated with neurological disorders as disease traits including familial temporal lobe epilepsy and neurogenic arthrogryposis multiplex congenita 1 with myelin defects, respectively. No human disease has been reported associated with eitherLGI2orLGI3. We implemented exome sequencing and family-based genomics to identify individuals with deleterious variants inLGI3and utilized GeneMatcher to connect practitioners and researchers worldwide to investigate the clinical and electrophysiological phenotype in affected subjects. We also generatedLgi3-null mice and performed peripheral nerve dissection and immunohistochemistry to examine the juxtaparanode LGI3 microarchitecture. As a result, we identified 16 individuals from eight unrelated families with loss-of-function (LoF) bi-allelic variants inLGI3. Deep phenotypic characterization showedLGI3LoF causes a potentially clinically recognizable PNHS trait characterized by global developmental delay, intellectual disability, distal deformities with diminished reflexes, visible facial myokymia, and distinctive electromyographic features suggestive of motor nerve instability.Lgi3-null mice showed reduced and mis-localized Kv1 channel complexes in myelinated peripheral axons. Our data demonstrate bi-allelic LoF variants inLGI3cause a clinically distinguishable disease trait of PNHS, most likely caused by disturbed Kv1 channel distribution in the absence of LGI3.
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LGI4（一种参与雪旺细胞髓鞘形成的分泌配体）的功能丧失突变是导致先天性多发性关节弯曲的原因。
影响因子：
9.8
作者：
Shifeng Xue;J. Maluenda;F. Marguet;M. Shboul;L. Quevarec;C. Bonnard;A. Y. Ng;S. Tohari;T. Tan;M. K. Kong;K. Monaghan;M. Cho;C. Siskind;J. Sampson;C. Rocha;F. Alkazaleh;M. Gonzalès;L. Rigonnot;S. Whalen;M. Gut;I. Gut;M. Bucourt;B. Venkatesh;A. Laquérriere;B. Reversade;J. Melki
通讯作者：
J. Melki
面部肌颤。
影响因子：
2.4
作者：
E. W. Radü;V. Skorpil;H. E. Kaeser
通讯作者：
H. E. Kaeser
艾萨克斯综合征血清抑制 PC-12 细胞系中的钾通道
影响因子：
3.4
作者：
Y. Sonoda;K. Arimura;A. Kurono;M. Suehara;M. Kameyama;Seiichi Minato;Akito Hayashi;M. Osame
通讯作者：
M. Osame
影响因子：
30.8
作者：
Kalachikov, S;Evgrafov, O;Gilliam, TC
通讯作者：
Gilliam, TC
影响因子：
9.8
作者：
Pehlivan, Davut;Bayram, Yavuz;Lupski, James R.
通讯作者：
Lupski, James R.