A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.
A Comprehensive Genomic Analysis Reveals the Genetic Landscape of Mitochondrial Respiratory Chain Complex Deficiencies.
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DOI：
10.1371/journal.pgen.1005679
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发表时间：
2016-01
期刊：
影响因子：
4.5
通讯作者：
Okazaki Y
中科院分区：
文献类型：
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作者：
Kohda M;Tokuzawa Y;Kishita Y;Nyuzuki H;Moriyama Y;Mizuno Y;Hirata T;Yatsuka Y;Yamashita-Sugahara Y;Nakachi Y;Kato H;Okuda A;Tamaru S;Borna NN;Banshoya K;Aigaki T;Sato-Miyata Y;Ohnuma K;Suzuki T;Nagao A;Maehata H;Matsuda F;Higasa K;Nagasaki M;Yasuda J;Yamamoto M;Fushimi T;Shimura M;Kaiho-Ichimoto K;Harashima H;Yamazaki T;Mori M;Murayama K;Ohtake A;Okazaki Y
线粒体疾病在以生化呼吸链复合体缺陷为特征的先天性代谢疾病中发病率最高。其发生率为1/5，000，具有表型和遗传异质性。约1,500种核编码线粒体蛋白的突变可能导致线粒体能量产生功能障碍和线粒体疾病。迄今为止，已经报道了250多个导致线粒体疾病的基因。然而，患者的确切基因诊断在很大程度上仍然未知。为了揭示这种异质性，我们对142例儿童期发病的线粒体呼吸链复合体缺陷患者进行了全面的基因组分析。该方法包括使用高通量测序的全mtDNA和外显子组分析，以及使用高密度寡核苷酸阵列的染色体畸变分析。我们在已知的线粒体疾病基因中发现了37个新的突变，并将3个线粒体相关基因（MRPS 23，QRSL 1和PNPLA 4）作为新的致病基因。我们还确定了2个已知引起单基因疾病的基因（MECP 2和TNNI 3）和3个染色体畸变（6q24.3-q25.1，17 p12和22q11.21）作为该队列的原因。我们的方法增强了在临床环境中识别生化定义的线粒体呼吸链复合体缺陷患者的致病基因突变的能力。它们还强调了临床和遗传异质性，并将改善这种复杂疾病的患者护理。线粒体在ATP生物合成中起着至关重要的作用，并且包含在核和线粒体基因组中编码的蛋白质。虽然已经报道了超过250个线粒体致病基因，但患者的确切遗传原因在很大程度上仍然未知。在这里，我们的目的是提供进一步的见解线粒体疾病的致病机制。我们研究了142例线粒体呼吸链复合体缺陷患者的核和线粒体基因组中编码的基因，使用全面的基因组分析。我们确定了3个新的致病性线粒体相关基因（MRPS 23，QRSL 1和PNPLA 4）以及其他致病基因和已知线粒体致病基因中的新致病性突变。本研究中的所有致病性突变均通过遗传和/或功能证据进行验证。我们的研究结果，包括142例患者中49例（34.5%）的坚定基因诊断，高于约25%的一般诊断率，并证明了全面基因组分析的价值。因此，我们揭示了线粒体疾病的遗传异质性。
Mitochondrial disorders have the highest incidence among congenital metabolic disorders characterized by biochemical respiratory chain complex deficiencies. It occurs at a rate of 1 in 5,000 births, and has phenotypic and genetic heterogeneity. Mutations in about 1,500 nuclear encoded mitochondrial proteins may cause mitochondrial dysfunction of energy production and mitochondrial disorders. More than 250 genes that cause mitochondrial disorders have been reported to date. However exact genetic diagnosis for patients still remained largely unknown. To reveal this heterogeneity, we performed comprehensive genomic analyses for 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies. The approach includes whole mtDNA and exome analyses using high-throughput sequencing, and chromosomal aberration analyses using high-density oligonucleotide arrays. We identified 37 novel mutations in known mitochondrial disease genes and 3 mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as novel causative genes. We also identified 2 genes known to cause monogenic diseases (MECP2 and TNNI3) and 3 chromosomal aberrations (6q24.3-q25.1, 17p12, and 22q11.21) as causes in this cohort. Our approaches enhance the ability to identify pathogenic gene mutations in patients with biochemically defined mitochondrial respiratory chain complex deficiencies in clinical settings. They also underscore clinical and genetic heterogeneity and will improve patient care of this complex disorder. Mitochondria play a crucial role in ATP biosynthesis and comprise proteins encoded in both the nuclear and mitochondrial genomes. Although more than 250 mitochondrial disease-causing genes have been reported, the exact genetic causes in patients remain largely unknown. Here, we aimed to provide further insights into the pathogenic mechanisms of mitochondrial disorders. We investigated the genes encoded in the nuclear and mitochondrial genomes using comprehensive genomic analysis in 142 patients with mitochondrial respiratory chain complex deficiencies. We identified 3 novel disease-causing mitochondria-related genes (MRPS23, QRSL1, and PNPLA4) as well as other disease-causing genes and novel pathogenic mutations in known mitochondrial disease-causing genes. All pathogenic mutations in this study are validated by genetic and/or functional evidence. Our findings, including the achievement of firm genetic diagnoses for 49 of 142 patients (34.5%), were higher than the general diagnosis rate of approximately 25% and demonstrated the value of comprehensive genomic analysis. Accordingly, we have shed light on the genetic heterogeneity underlying mitochondrial disorders.