Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy
Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy
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DOI：
10.1093/brain/awab056
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发表时间：
2021-04-15
期刊：
影响因子：
14.5
通讯作者：
De Giorgio, Roberto
中科院分区：
文献类型：
--
作者：
Bonora, Elena;Chakrabarty, Sanjiban;De Giorgio, Roberto
肠道运动异常是几种线粒体脑肌病的一个特征，而TYMP和POLG等基因的突变与这些罕见疾病有关。人类基因组编码三种DNA连接酶，其中只有一种连接酶III （LIG3）具有线粒体剪接变体，对线粒体健康至关重要。我们研究了来自三个独立家庭的7名患者的LIG3活性降低和线粒体功能障碍的影响，这些患者普遍出现肠道运动障碍和线粒体神经胃肠道脑肌病的神经学表现。对这些患者的DNA进行全外显子组测序。在所有患者中，发现了一种新的疾病基因LIG3的复合杂合变异体。据预测，所有的变异都会对这种蛋白质产生破坏性影响。LIG3基因编码唯一的线粒体DNA （mtDNA）连接酶，因此在mtDNA的修复和复制中起关键作用。在患者来源的细胞中进行的传入试验显示，LIG3蛋白水平和连接酶活性降低。我们证明了LIG3基因缺陷影响mtDNA的维持，导致mtDNA耗尽，而不会像在其他线粒体疾病中观察到的那样积累多重缺失。线粒体功能障碍可能导致在这些患者中观察到的表型。最突出和一致的临床症状是严重的肠道运动障碍和神经系统异常，包括白质脑病、癫痫、偏头痛、卒中样发作和神经源性膀胱。肠系膜神经元数量减少，纤维化和弹性蛋白水平增加是肠道最显著的变化。骨骼肌细胞色素c氧化酶（COX）缺乏纤维也被观察到。在斑马鱼中，lig3的破坏再现了大脑的改变和iuo的肠道运输受损。总之，我们确定了导致线粒体疾病的LIG3基因变异，其特征是主要的肠道运动障碍、脑病和神经肌肉异常。
Abnormal gut motility is a feature of several mitochondrial encephalomyopathies, and mutations in genes such as TYMP and POLG, have been linked to these rare diseases. The human genome encodes three DNA ligases, of which only one, ligase III (LIG3), has a mitochondrial splice variant and is crucial for mitochondrial health.We investigated the effect of reduced LIG3 activity and resulting mitochondrial dysfunction in seven patients from three independent families, who showed the common occurrence of gut dysmotility and neurological manifestations reminiscent of mitochondrial neurogastrointestinal encephalomyopathy. DNA from these patients was subjected to whole exome sequencing. In all patients, compound heterozygous variants in a new disease gene, LIG3, were identified. All variants were predicted to have a damaging effect on the protein. The LIG3 gene encodes the only mitochondrial DNA (mtDNA) ligase and therefore plays a pivotal role in mtDNA repair and replication. In intro assays in patient-derived cells showed a decrease in LIG3 protein levels and ligase activity. We demonstrated that the LIG3 gene defects affect mtDNA maintenance, leading to mtDNA depletion without the accumulation of multiple deletions as observed in other mitochondrial disorders. This mitochondrial dysfunction is likely to cause the phenotypes observed in these patients. The most prominent and consistent clinical signs were severe gut dysmotility and neurological abnormalities, including leukoencephalopathy, epilepsy, migraine, stroke-like episodes, and neurogenic bladder. A decrease in the number of myenteric neurons, and increased fibrosis and elastin levels were the most prominent changes in the gut. Cytochrome c oxidase (COX) deficient fibres in skeletal muscle were also observed. Disruption of lig3 in zebrafish reproduced the brain alterations and impaired gut transit in uiuo.In conclusion, we identified variants in the LIG3 gene that result in a mitochondrial disease characterized by predominant gut dysmotility, encephalopathy, and neuromuscular abnormalities.