Jie Ni1, Zhen Liu1, Yanchun Yuan1, Wanzhen Li1, Yiting Hu1, Pan Liu1, Xiaorong Hou1, Xiangyu Zhu1, Xuxiong Tang1, Mingyu Liang2, Siqi Zheng2, Xuan Hou1, Juan Du1, Jianguang Tang3, Hong Jiang1,4,5,6, Lu Shen1,4,5,6, Beisha Tang1,4,5,6, Junling Wang7,8,9,10. 1. Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, Hunan, People's Republic of China. 2. Xiangya School of Medicine, Central South University, Changsha, Hunan, People's Republic of China. 3. Department of Neurology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China. 4. Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 410008, People's Republic of China. 5. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, People's Republic of China. 6. National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China. 7. Department of Neurology, Xiangya Hospital, Central South University, 87 Xiangya Rd, Changsha, Hunan, People's Republic of China. junling.wang@csu.edu.cn. 8. Laboratory of Medical Genetics, Central South University, Changsha, Hunan, 410008, People's Republic of China. junling.wang@csu.edu.cn. 9. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan, 410008, People's Republic of China. junling.wang@csu.edu.cn. 10. National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China. junling.wang@csu.edu.cn.
Abstract
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder. Mitochondrial dysfunction is involved in the complex pathophysiology of ALS; however, the role of mitochondrial DNA (mtDNA) variants in ALS is poorly understood. We aimed to elucidate the role of mtDNA variants in the pathogenesis of ALS. METHODS: The mitochondrial haplogroups of 585 ALS patients and 371 healthy controls were determined; 38 ALS patients and 42 controls underwent long-range polymerase chain reaction combined with next-generation sequencing technology to analyze whole mitochondrial genome variants. RESULTS: A higher percentage of variants accumulated in ALS patients than in controls. Analysis of coding region variations that were further stratified by mtDNA genes revealed that nonsynonymous variants were more vulnerable in ALS patients than in controls, particularly in the ND4L, ND5, and ATP8 genes. Moreover, pathogenic nonsynonymous variants tended to over-represent in ALS patients. Unsurprisingly, nonsynonymous variants were not related to the phenotype. Haplogroup analysis did not found evidence of association between haplogroups with the risk of ALS, however, patients belonging to haplogroup Y and M7c were prone to develop later onset of ALS. CONCLUSIONS: This is the first study to profile mtDNA variants in ALS patients from mainland China. Our results suggest that an increase in the number of nonsynonymous variants is linked to the pathogenesis of ALS. Moreover, haplogroup Y and M7c may modulate the clinical expression of ALS. Our findings provide independent, albeit limited, evidence for the role of mtDNA in the pathogenesis of ALS.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder. Mitochondrial dysfunction is involved in the complex pathophysiology of ALS; however, the role of mitochondrial DNA (mtDNA) variants in ALS is poorly understood. We aimed to elucidate the role of mtDNA variants in the pathogenesis of ALS. METHODS: The mitochondrial haplogroups of 585 ALS patients and 371 healthy controls were determined; 38 ALS patients and 42 controls underwent long-range polymerase chain reaction combined with next-generation sequencing technology to analyze whole mitochondrial genome variants. RESULTS: A higher percentage of variants accumulated in ALS patients than in controls. Analysis of coding region variations that were further stratified by mtDNA genes revealed that nonsynonymous variants were more vulnerable in ALS patients than in controls, particularly in the ND4L, ND5, and ATP8 genes. Moreover, pathogenic nonsynonymous variants tended to over-represent in ALS patients. Unsurprisingly, nonsynonymous variants were not related to the phenotype. Haplogroup analysis did not found evidence of association between haplogroups with the risk of ALS, however, patients belonging to haplogroup Y and M7c were prone to develop later onset of ALS. CONCLUSIONS: This is the first study to profile mtDNA variants in ALS patients from mainland China. Our results suggest that an increase in the number of nonsynonymous variants is linked to the pathogenesis of ALS. Moreover, haplogroup Y and M7c may modulate the clinical expression of ALS. Our findings provide independent, albeit limited, evidence for the role of mtDNA in the pathogenesis of ALS.
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