Frameshift mutation of Timm8a1 gene in mouse leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment
Frameshift mutation of Timm8a1 gene in mouse leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment
复制标题
小鼠 Timm8a1 基因的移码突变导致大脑中线粒体结构异常，与听力和记忆障碍相关
DOI：
10.1136/jmedgenet-2020-106925
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发表时间：
2021-09-01
影响因子：
4
通讯作者：
Hu，Yafang
中科院分区：
文献类型：
--
作者：
Song，Pingping;Guan，Yuqing;Hu，Yafang
背景：耳聋-肌张力障碍-视神经病变（DDON）综合征是一种以耳聋、肌张力障碍、共济失调和视力下降为特征的进行性X连锁隐性遗传疾病。致病基因耳聋/肌张力障碍蛋白1（DDP 1）/内膜转位酶8A（TIMM 8A）编码线粒体膜间隙伴侣。DDON的分子机制尚不清楚，动物模型的详细信息尚未报道。方法和结果我们描述了一个DDON综合征家系，其中患病成员在DDP 1基因中携带一种新的半合子变异（NM_004085. 3，c.82C>T，p.Q28X）。然后，我们使用成簇的规律间隔的短回文重复序列/Cas9技术产生了在Timm 8a 1基因中具有半合子突变（p.I23fs49X）的小鼠系。Western blot分析证实DDP 1蛋白缺失。对突变小鼠大脑样本的电子显微镜分析表明，几个大脑区域的线粒体结构异常。Timm 8a 1 I23 fs 49 X/y突变不影响线粒体内成员蛋白Tim 23和外成员蛋白Tom 40的输入，也不影响线粒体氧化磷酸化系统和锰超氧化物歧化酶（MnSOD / SOD-2）蛋白的生物合成。Timm 8a 1 I23 fs 49 X/y突变的雄性小鼠表现出较少的体重增加、听力障碍和认知缺陷。结论Timm 8a 1基因移码突变导致小鼠脑线粒体结构异常，并与听力和记忆障碍相关。综上所述，我们已经成功地产生了Timm 8a 1功能缺失突变的小鼠模型。
Background Deafness-dystonia-optic neuronopathy (DDON) syndrome is a progressive X-linked recessive disorder characterised by deafness, dystonia, ataxia and reduced visual acuity. The causative gene deafness/dystonia protein 1 (DDP1)/translocase of the inner membrane 8A (TIMM8A) encodes a mitochondrial intermembrane space chaperon. The molecular mechanism of DDON remains unclear, and detailed information on animal models has not been reported yet. Methods and results We characterized a family with DDON syndrome, in which the affected members carried a novel hemizygous variation in the DDP1 gene (NM_004085.3, c.82C>T, p.Q28X). We then generated a mouse line with the hemizygous mutation (p.I23fs49X) in the Timm8a1 gene using the clustered regularly interspaced short palindromic repeats /Cas9 technology. The deficient DDP1 protein was confirmed by western blot assay. Electron microscopic analysis of brain samples from the mutant mice indicated abnormal mitochondrial structure in several brain areas. However, Timm8a1 I23fs49X/y mutation did not affect the import of mitochondria inner member protein Tim23 and outer member protein Tom40 as well as the biogenesis of the proteins in the mitochondrial oxidative phosphorylation system and the manganese superoxide dismutase (MnSOD / SOD-2). The male mice with Timm8a1 I23fs49X/y mutant exhibited less weight gain, hearing impairment and cognitive deficit. Conclusion Our study suggests that frameshift mutation of the Timm8a1 gene in mice leads to an abnormal mitochondrial structure in the brain, correlating with hearing and memory impairment. Taken together, we have successfully generated a mouse model bearing loss-of-function mutation in Timm8a1.