Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes (Retracted Article)
Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes (Retracted Article)
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DOI：
10.1371/journal.pone.0211066
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发表时间：
2019-01-25
期刊：
影响因子：
3.7
通讯作者：
Neubig, Richard R.
中科院分区：
文献类型：
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作者：
Feng, Huijie;Larrivee, Casandra L.;Neubig, Richard R.
背景 GNAO1 显性新生突变的婴儿和儿童表现出运动障碍、癫痫或两者兼而有之。患有功能丧失 (LOF) 突变的儿童表现出癫痫样脑病 17 (EIEE17)。在患有不自主运动的神经发育障碍 (NEDIM) 患者中发现了功能获得 (GOF) 突变或功能正常的突变。目前尚无含有人类突变 GNAO1 等位基因的动物模型。目的在此我们开发一种携带人类 GNAO1 突变（G203R）的小鼠模型，并确定携带该 GNAO1 突变的患者的临床特征（包括癫痫和运动障碍）是否会在小鼠模型中表现出来。方法通过 CRISPR/Cas9 方法创建小鼠 Gnao1 敲入 GOF 突变（G203R）。由此产生的后代和同窝对照动物接受了一系列行为测试。之前报道的 GOF 突变小鼠敲入 (Gnao1(+/G184S)) 尚未在患者中发现，也进行了比较。结果 Gnao1(+/G203R) 突变小鼠具有存活能力，并且与对照组相比体重增加。纯合子是不能存活的。男性和女性的握力均有所下降。雄性 Gnao1(+/G203R) 小鼠在运动测定（RotaRod 和 DigiGait）中受到强烈影响，而雌性则没有。雄性 Gnao1(+/G203R) 小鼠在戊四唑点燃试验中也表现出癫痫发作倾向增强。 G184S GOF 敲入的小鼠也表现出与运动相关的行为表型，但雌性比雄性受到的影响更严重。结论 Gnao(1+/G203R) 小鼠表型与 GNAO1G203R 杂合突变儿童相同，显示出运动障碍和相对轻微的癫痫模式。该小鼠模型应可用于 GNAO1 相关运动障碍的机制和临床前研究。
BackgroundInfants and children with dominant de novo mutations in GNAO1 exhibit movement disorders, epilepsy, or both. Children with loss-of-function (LOF) mutations exhibit Epileptiform Encephalopathy 17 (EIEE17). Gain-of-function (GOF) mutations or those with normal function are found in patients with Neurodevelopmental Disorder with Involuntary Movements (NEDIM). There is no animal model with a human mutant GNAO1 allele.ObjectivesHere we develop a mouse model carrying a human GNAO1 mutation (G203R) and determine whether the clinical features of patients with this GNAO1 mutation, which includes both epilepsy and movement disorder, would be evident in the mouse model.MethodsA mouse Gnao1 knock-in GOF mutation (G203R) was created by CRISPR/Cas9 methods. The resulting offspring and littermate controls were subjected to a battery of behavioral tests. A previously reported GOF mutant mouse knock-in (Gnao1(+/G184S)), which has not been found in patients, was also studied for comparison.ResultsGnao1(+/G203R) mutant mice are viable and gain weight comparably to controls. Homozygotes are non-viable. Grip strength was decreased in both males and females. Male Gnao1(+/G203R) mice were strongly affected in movement assays (RotaRod and DigiGait) while females were not. Male Gnao1(+/G203R) mice also showed enhanced seizure propensity in the pentylenetetrazole kindling test. Mice with a G184S GOF knock-in also showed movement-related behavioral phenotypes but females were more strongly affected than males.ConclusionsGnao(1+/G203R) mice phenocopy children with heterozygous GNAO1G203R mutations, showing both movement disorder and a relatively mild epilepsy pattern. This mouse model should be useful in mechanistic and preclinical studies of GNAO1-related movement disorders.