Mutations of mitochondrial genome in spinocerebellar degeneration

脊髓小脑变性中线粒体基因组的突变

• 批准号: 03807048
• 负责人: TANAKA Masashi
• 金额: $ 1.15万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1991
• 资助国家: 日本
• 起止时间: 1991 至 1992
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-03807048/
• 关键词: Spinocerebellar degeneration; Mitochondria; Mitochondrial DNA; Ataxia; Nucleotide sequencing; Point mutation; Energy production; Ageing; 脊髄小脳変性症; ミトコンドリア; ミトコンドリアDNA; 運動失調; 塩基配列決定; 遺伝子増幅; エネルギー産生; 加齢; エネルギ-産生

Spinocerebellar degeneration represents a group of heterogeneous degenerative diseases showing ataxia as the main symptom. This disorder is clinically characterized by slowly progressive course,and various combinations of signs and symptoms of the pyramidal and extrapyramidal tracts and the peripheral nervous system. In order to investigate the possible role of mitochondrial dysfunction in the pathogenesis of extensive neuronal degeneration in this disorder,we have analyzed the mutations of mitochondrial DNA in patients with spinocerebellar degeneration. Mitochondrial DNA(mtDNA)was amplified by the polymerase chain reaction (PCR)from DNA isolated from platelets of each patient.The single strand DNA was amplified from the first PCR product by using the asymmetric PCR method. The second PCR product was used as the template for the fluorescence-based direct PCR sequencing. Sequences of these mtDNA fragments were analyzed by an automated DNA sequencer. In 43 cases of spinocerebellar degene … More ration,sequence analysis and restriction fragment analysis revealed neither the 8344 A-to-G nucleotide substitution reported in patients with MERRF syndrome nor the 8993 G-to-T transversion reported in a patient with cerebellar ataxia,retinitis pigmentosa, and cardiomyopathy. Sequence analysis of the whole mtDNA from two patients whose family histories were consistent with maternal inheritance revealed multiple mutations in the non-coding regions,rRNA genes,and mRNA genes. Although some of these mutations in these two patients were also observed in other disease and normal controls,several nonsynonymous mutations in Patient 2 were not found in the normal controls. Both of the mutations in the ND2 and ATP6 genes in Patient 2 were also found in a paient with Parkinson's disease as well as in Control 1,who died at the age of 55 from gastric cancer. The possible involvement of these mutations in the pathogenesis of spinocerebellar degeneration must be evaluated from further study on the sequence heterogeneity of mtDNA among normal controls as well as disease controls. Less

脊髓小脑变性是一组以共济失调为主要症状的异质性退行性疾病，这种疾病的临床特征是缓慢进行性进展，以及锥体束和锥体外束以及周围神经系统的各种体征和症状的组合。为了了解线粒体功能障碍在这种疾病中广泛神经元变性的发病机制中的可能作用，我们分析了脊髓小脑变性患者的线粒体 DNA 突变。通过聚合酶链式反应（PCR）从每位患者血小板中分离的DNA中扩增DNA（mtDNA）。使用不对称PCR方法从第一次PCR产物中扩增出单链DNA。以第二次PCR产物为模板通过自动 DNA 测序仪对这些 mtDNA 片段进行了基于荧光的直接 PCR 测序，在 43 例脊髓小脑退化病例中，序列分析和限制性片段分析均未发现。第 8344 章 MERRF 综合征患者的 A-G 核苷酸替换，以及小脑性共济失调、色素性视网膜炎和心肌病患者的 8993 例 G-T 颠换，对两名家族史患者的整个线粒体 DNA 进行了序列分析。与母系遗传一致，揭示了非编码区、rRNA 基因和 mRNA 基因的多个突变，尽管在这两名患者的其他疾病和正常人中也观察到了其中一些突变。与对照组相比，患者 2 中的几个非同义突变在正常对照中未发现。患者 2 中的 ND2 和 ATP6 基因突变也在帕金森病患者以及同龄死亡的对照 1 中发现。 55 个来自胃癌的突变必须通过对正常对照和疾病对照 mtDNA 序列异质性的进一步研究来评估。较少的

项目成果

Ozawa T,Tanaka M,Sugiyama S,Ino H,Ohno K,Hattori K,Ohbayashi T,Ito T,Deguchi H,Kawamura K and et al: "Patients with idiopathic cardiomyopathy belong to the same mitochondrial DNA gene family of Parkinson's disease and mitochondrial encephalomyopathy." Bio

Ozawa T,Tanaka M,Sugiyama S,Ino H,Ohno K,Hattori K,Ohbayashi T,Ito T,Deguchi H,Kawamura K 等人：“特发性心肌病患者与帕金森病属于同一线粒体 DNA 基因家族，并且

Ota Y,Tanaka M,Sato W,Ohno K,Yamamoto T,Maehara M,Negoro T,Watanabe K,Awaya S and Ozawa T: "Detection of platelet mitochondrial DNA deletions in Kearns-Sayre syndrome." Invest Ophthalmol Vis Sci. 32. 2667-75 (1991)

Ota Y、Tanaka M、Sato W、Ohno K、Yamamoto T、Maehara M、Negoro T、Watanabe K、Awaya S 和 Ozawa T：“Kearns-Sayre 综合征中血小板线粒体 DNA 缺失的检测。”

H.Ino: "Mitochondrial leucine tRNA mutation in a mitochondrial encephalomyopathy" Lancet. 337. 234-235 (1991)

H.Ino：“线粒体脑肌病中的线粒体亮氨酸 tRNA 突变”《柳叶刀》。

Hattori K,Ogawa T,Kondo T,Mochizuki M,Tanaka M,Sugiyama S,Ito T,Satake T and Ozawa T: "Cardiomyopathy with mitochondrial DNA mutations." Am Heart J. 866-9 (1991)

Hattori K、Okawa T、Kondo T、Mochizuki M、Tanaka M、Sugiyama S、Ito T、Satake T 和 Ozawa T：“线粒体 DNA 突变的心肌病。”

M.Tanaka: "Biochem.Biophys.Res.Commun." Mitochondrial DNA mutations in mitochondrial myopathy,encephalopathy,lactic acidosis,and strokeーlike episodes(MELAS). 174. 861-868 (1991)

M.Tanaka：“Biochem.Biophys.Res.Commun。”线粒体肌病、脑病、乳酸性酸中毒和中风样发作的线粒体 DNA 突变 (MELAS)。