Mitochondrial DNA disorders: from pathogenic variants to preventing transmission.
Mitochondrial DNA disorders: from pathogenic variants to preventing transmission.
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线粒体DNA疾病：从致病变异到防止传播。
DOI：
10.1093/hmg/ddab156
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发表时间：
2021-10-01
影响因子：
3.5
通讯作者：
Vincent AE
中科院分区：
文献类型：
--
作者：
Bernardino Gomes TM;Ng YS;Pickett SJ;Turnbull DM;Vincent AE
线粒体 DNA (mtDNA) 疾病被认为是遗传性代谢紊乱的最常见原因之一。线粒体基因组存在多个拷贝，导致同质和异质致病性 mtDNA 变异。当致病性变异水平达到阈值时，就会出现生化缺陷，该阈值因变异体而异。此外，变异体可以分离、克隆扩增或从细胞群中丢失，从而导致氧化缺陷的动态和组织特异性镶嵌模式。 MtDNA 是母系遗传的，但异质性致病变异的传播模式很复杂。在卵子发生过程中，线粒体瓶颈导致后代的变异水平与其母亲存在很大差异，而高度有害的变异（例如缺失）则不会传播。再加上线粒体和核基因组之间复杂的相互作用，这些特殊的遗传学产生了显着的表型变异，给患者的诊断和临床管理带来了挑战。目前正在研究新型治疗化合物和几种基因疗法，但经过验证的疾病缓解疗法仍然难以捉摸。携带致病性线粒体 DNA 变异的女性需要定制遗传咨询来确定她们的生育选择。体外受精技术的最新进展极大地改善了生殖选择，但也面临着挑战。自 30 多年前首次发现致病性 mtDNA 变异以来，我们对这些疾病的了解取得了显着进展。然而，许多问题仍未得到解答，需要未来的研究来调查疾病进展的机制并确定新的疾病特异性治疗靶点。
Mitochondrial DNA (mtDNA) disorders are recognized as one of the most common causes of inherited metabolic disorders. The mitochondrial genome occurs in multiple copies resulting in both homoplasmic and heteroplasmic pathogenic mtDNA variants. A biochemical defect arises when the pathogenic variant level reaches a threshold, which differs between variants. Moreover, variants can segregate, clonally expand, or be lost from cellular populations resulting in a dynamic and tissue-specific mosaic pattern of oxidative deficiency. MtDNA is maternally inherited but transmission patterns of heteroplasmic pathogenic variants are complex. During oogenesis, a mitochondrial bottleneck results in offspring with widely differing variant levels to their mother, whilst highly deleterious variants, such as deletions, are not transmitted. Complemented by a complex interplay between mitochondrial and nuclear genomes, these peculiar genetics produce marked phenotypic variation, posing challenges to the diagnosis and clinical management of patients. Novel therapeutic compounds and several genetic therapies are currently under investigation, but proven disease-modifying therapies remain elusive. Women who carry pathogenic mtDNA variants require bespoke genetic counselling to determine their reproductive options. Recent advances in in vitro fertilization techniques, have greatly improved reproductive choices, but are not without their challenges. Since the first pathogenic mtDNA variants were identified over 30 years ago, there has been remarkable progress in our understanding of these diseases. However, many questions remain unanswered and future studies are required to investigate the mechanisms of disease progression and to identify new disease-specific therapeutic targets.
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影响因子：
82.9
作者：
Gammage PA;Viscomi C;Simard ML;Costa ASH;Gaude E;Powell CA;Van Haute L;McCann BJ;Rebelo-Guiomar P;Cerutti R;Zhang L;Rebar EJ;Zeviani M;Frezza C;Stewart JB;Minczuk M
通讯作者：
Minczuk M
影响因子：
64.8
作者：
GOTO, Y;NONAKA, I;HORAI, S
通讯作者：
HORAI, S
与成年线粒体疾病有关的核和线粒体DNA突变的患病率。
影响因子：
11.2
作者：
Gorman GS;Schaefer AM;Ng Y;Gomez N;Blakely EL;Alston CL;Feeney C;Horvath R;Yu-Wai-Man P;Chinnery PF;Taylor RW;Turnbull DM;McFarland R
通讯作者：
McFarland R
影响因子：
2.8
作者：
HIRANO, M;RICCI, E;ROWLAND, LP
通讯作者：
ROWLAND, LP
影响因子：
9.8
作者：
Elliott, Hannah R.;Samuels, David C.;Eden, James A.;Relton, Caroline L.;Chinnery, Patrick F.
通讯作者：
Chinnery, Patrick F.