A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families.
A homozygous splice variant in ATP5PO, disrupts mitochondrial complex V function and causes Leigh syndrome in two unrelated families.
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DOI：
10.1002/jimd.12526
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发表时间：
2022-09
影响因子：
4.2
通讯作者：
Chung, Wendy K.
中科院分区：
文献类型：
--
作者：
Ganapathi, Mythily;Friocourt, Gaelle;Gueguen, Naig;Friederich, Marisa W.;Le Gac, Gerald;Okur, Volkan;Loaec, Nadege;Ludwig, Thomas;Ka, Chandran;Tanji, Kurenai;Marcorelles, Pascale;Theodorou, Evangelos;Lignelli-Dipple, Angela;Voisset, Cecile;Walker, Melissa A.;Briere, Lauren C.;Bourhis, Amelie;Blondel, Marc;LeDuc, Charles;Hagen, Jacob;Cooper, Cathleen;Muraresku, Colleen;Ferec, Claude;Garenne, Armelle;Lelez-Soquet, Servane;Rogers, Cassandra A.;Shen, Yufeng;Strode, Dana K.;Bizargity, Peyman;Iglesias, Alejandro;Goldstein, Amy;High, Frances A.;Sweetser, David A.;Ganetzky, Rebecca;Van Hove, Johan L. K.;Procaccio, Vincent;Le Marechal, Cedric;Chung, Wendy K.
关键词：
线粒体复合物V通过催化ATP的产生在氧化磷酸化中起重要作用。大多数复杂的V亚基是核编码的，尚未与公认的孟德尔疾病相关。使用外显子组测序，我们确定了一个罕见的纯合剪接变异体（c.87+3A>G）在ATP 5 PO，复杂的V亚基，编码寡霉素敏感性赋予蛋白，在三个人从两个无关的家庭，临床怀疑线粒体疾病。这些个体患有类似的严重婴儿期且通常致命的多系统疾病，包括张力减退、发育迟缓、肥厚性心肌病、进行性癫痫性脑病、进行性脑萎缩和脑MRI上与Leigh综合征一致的白色异常。cDNA研究表明，主要缩短的转录与跳跃的外显子2和低水平的正常全长转录。受影响的个体的成纤维细胞表现出降低的ATP 5 PO蛋白，有缺陷的组装复合物V的外周柄蛋白的量大大减少，并大大降低复合物V水解活性。此外，与野生型构建体（hATP 5 PO-WT）相比，在缺失yATP 5（ATP 5 PO同系物）的酵母细胞中表达不含外显子2的人ATP 5 PO cDNA（hATP 5 PO-Δ ex 2）无法挽救需要氧化磷酸化的培养基上的生长，表明外显子2缺失导致无功能蛋白。总的来说，我们的发现支持ATP 5 PO c.87+3A>G变体的致病性，其显著降低但不消除复合物V活性。这些数据沿着最近报告的患有ATP 5 PO变体的受影响个体，增加了ATP 5 PO中罕见的双等位基因变体导致有缺陷的复合体V组装、功能并与Leigh综合征相关的证据。
Mitochondrial complex V plays an important role in oxidative phosphorylation by catalyzing the generation of ATP. Most complex V subunits are nuclear encoded and not yet associated with recognized Mendelian disorders. Using exome sequencing, we identified a rare homozygous splice variant (c.87+3A>G) in ATP5PO, the complex V subunit which encodes the oligomycin sensitivity conferring protein, in three individuals from two unrelated families, with clinical suspicion of a mitochondrial disorder. These individuals had a similar severe infantile and often lethal multi-systemic disorder that included hypotonia, developmental delay, hypertrophic cardiomyopathy, progressive epileptic encephalopathy, progressive cerebral atrophy, and white matter abnormalities on brain MRI consistent with Leigh syndrome. cDNA studies showed a predominant shortened transcript with skipping of exon 2 and low levels of the normal full-length transcript. Fibroblasts from the affected individuals demonstrated decreased ATP5PO protein, defective assembly of complex V with greatly reduced amounts of peripheral stalk proteins, and greatly reduced complex V hydrolytic activity. Further, expression of human ATP5PO cDNA without exon 2 (hATP5PO-Δex2) in yeast cells deleted for yATP5 (ATP5PO homolog) was unable to rescue growth on media which requires oxidative phosphorylation when compared to the wild type construct (hATP5PO-WT), indicating that exon 2 deletion leads to a non-functional protein. Collectively, our findings support the pathogenicity of the ATP5PO c.87+3A>G variant, which significantly reduces but does not eliminate complex V activity. These data along with the recent report of an affected individual with ATP5PO variants, add to the evidence that rare biallelic variants in ATP5PO result in defective complex V assembly, function and are associated with Leigh syndrome.
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线粒体能量和治疗学。
DOI：
10.1146/annurev.pathol.4.110807.092314
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Wallace DC;Fan W;Procaccio V
通讯作者：
Procaccio V
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
作者：
Morava, E;Rodenburg, RJ;Smeitink, J
通讯作者：
Smeitink, J
影响因子：
3.9
作者：
Ganetzky, Rebecca D.;Stendel, Claudia;Falk, Marni J.
通讯作者：
Falk, Marni J.
影响因子：
4.4
作者：
Jonckheere, An I.;Huigsloot, Merei;Rodenburg, Richard J. T.
通讯作者：
Rodenburg, Richard J. T.