m.3685T > C是一种导致Leigh综合征的新型线粒体DNA变异

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL
Jeffrey Jean, Eirini Christodoulou, Xiaowu Gai, B. Tamrazi, M. Vera, W. Mitchell, Ryan J. Schmidt
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引用次数: 0

摘要

线粒体基因组的变异可导致电子传递链内复合物I的功能障碍,从而导致氧化磷酸化的破坏。MT-ND1 (NADH:泛醌氧化还原酶核心亚基1)基因的致病变异导致复合体I功能障碍是Leigh综合征的已知原因。患者为一名4岁女性,最初表现为全身性强直-阵挛性癫痫发作,癫痫发作后出现Leigh综合征的其他症状。一个三代人的家谱显示没有线粒体疾病的家族史。实验室研究显示血乳酸、丙氨酸和GDF15显著升高。t2加权磁共振成像(MRI)显示双侧基底节区不对称信号高,特别是双侧壳核和右侧尾状核。磁共振波谱显示局部葡萄糖和乳酸水平升高。皮肤成纤维细胞的线粒体呼吸链酶分析显示复合物I功能略有降低。一个16个基因的肌张力障碍小组和染色体微阵列分析没有发现任何致病变异。联合外显子组和线粒体基因组测序鉴定出m.3685T > C (MT-ND1 p.Tyr127His)变异具有62.3%的异质性,没有其他原因导致患者的病情。母亲的线粒体基因组测序表明,m.3685T > C变异是从头发生的。m.3685T > C变异在种群数据库中不存在。酪氨酸127残基是高度保守的,MT-ND1基因中几个附近的致病变异先前与Leigh综合征有关。我们提出m.3685T > C变异是导致Leigh综合征的一种新的线粒体DNA变异,我们根据目前可用的信息将这种变异分类为可能的致病性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
m.3685T > C is a novel mitochondrial DNA variant that causes Leigh syndrome
Variants in the mitochondrial genome can result in dysfunction of Complex I within the electron transport chain, thus causing disruptions in oxidative phosphorylation. Pathogenic variants in the MT-ND1 (NADH:ubiquinone oxidoreductase core subunit 1) gene that result in Complex I dysfunction are a known cause of Leigh syndrome. The patient is a 4-yr-old female who initially presented with generalized tonic–clonic seizures, with other symptoms of Leigh syndrome becoming apparent after the seizures. A three-generation pedigree revealed no family history of mitochondrial disorders. Laboratory studies were remarkable for elevated blood lactate, alanine, and GDF15. T2-weighted magnetic resonance imaging (MRI) revealed bilateral asymmetric signal hyperintensities in the basal ganglia, specifically in the bilateral putamen and right caudate. Magnetic resonance spectroscopy showed regionally elevated glucose and lactate. Mitochondrial respiratory chain enzyme analysis on skin fibroblasts demonstrated slightly reduced Complex I function. A 16-gene dystonia panel and chromosomal microarray analysis did not identify any disease-causing variants. Combined exome and mitochondrial genome sequencing identified the m.3685T > C (MT-ND1 p.Tyr127His) variant with 62.3% heteroplasmy with no alternative cause for the patient's condition. Mitochondrial genome sequencing of the mother demonstrated that the m.3685T > C variant occurred de novo. The m.3685T > C variant is absent from population databases. The tyrosine 127 residue is highly conserved, and several nearby pathogenic variants in the MT-ND1 gene have been previously associated with Leigh syndrome. We propose that the m.3685T > C variant is a novel mitochondrial DNA variant that causes Leigh syndrome, and we classify this variant as likely pathogenic based on currently available information.
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
期刊介绍: Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.
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