Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes
Mouse models of GNAO1-associated movement disorder: Allele- and sex-specific differences in phenotypes
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GNAO1 相关运动障碍的小鼠模型：表型的等位基因和性别特异性差异
作者：
Huijie Feng;C. L. Larrivee;E. Demireva;Huirong Xie;Jeffery Leipprandt;R. Neubig
研究背景GNAO 1显性新生突变的婴儿和儿童表现为运动障碍、癫痫或两者兼有。患有功能丧失（LOF）突变的儿童表现为癫痫样脑病17（EIEE 17）。功能获得性（GOF）突变或功能正常的突变在伴有不自主运动的神经发育障碍（NEDIM）患者中发现。没有具有人类突变GNAO 1等位基因的动物模型。目的在这里，我们开发了一个小鼠模型携带人类GNAO 1突变，并确定是否GNAO 1突变的临床特征，包括运动障碍将是明显的小鼠模型。方法采用CRISPR/Cas9方法构建小鼠Gnao 1基因敲入GOF突变（G203 R）。对产生的后代和同窝对照进行一系列行为测试。还研究了先前报道的GOF突变小鼠敲入（Gnao 1 +/G184 S）以进行比较。结果Gnao 1 +/G203 R突变小鼠存活率高，增重快于对照组。纯合子不能存活。雄性和雌性的握力均降低。雄性Gnao 1 +/G203 R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Gnao 1 +/G203 R小鼠在戊四唑点燃试验中也显示出增强的癫痫发作倾向。G184 S GOF基因敲入的小鼠也表现出运动相关的行为表型，但雌性比雄性受到更强烈的影响。结论Gnao 1 +/G203 R小鼠与GNAO 1 G203 R杂合突变的儿童表型相似，表现出运动障碍和相对较轻的癫痫模式。该小鼠模型应可用于GNAO 1相关运动障碍的机制和临床前研究。
Background Infants 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. Objectives Here we develop a mouse model carrying a human GNAO1 mutation and determine whether clinical features of the GNAO1 mutation including movement disorder would be evident in the mouse model. Methods A 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) was also studied for comparison. Results Gnao1+/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. Conclusions Gnao1+/G203R mice phenocopy children with heterozygous GNAO1 G203R 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.
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影响因子：
2
作者：
Keith Schutsky;Ouyang Ming;S. Thomas
通讯作者：
Keith Schutsky;Ouyang Ming;S. Thomas
RGS 不敏感 G 蛋白突变，用于研究内源性 RGS 蛋白的作用。
DOI：
10.1016/s0076-6879(04)89014-1
发表时间：
2004
期刊：
Methods in enzymology.
影响因子：
--
作者：
Fu,Ying;Zhong,Huailing;Nanamori,Masakatsu;Mortensen,RichardM;Huang,Xinyan;Lan,Kengli;Neubig,RichardR
通讯作者：
Neubig,RichardR
G 蛋白的受体激活。
DOI：
10.1096/fasebj.2.13.3139484
发表时间：
1988
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
--
作者：
Weiss,ER;Kelleher,DJ;Woon,CW;Soparkar,S;Osawa,S;Heasley,LE;Johnson,GL
通讯作者：
Johnson,GL
影响因子：
9.8
作者：
Appenzeller, Silke;Balling, Rudi;Sherr, Elliott
通讯作者：
Sherr, Elliott