Mitochondrial disease manifestations in relation to transcriptome location and function.
Mitochondrial disease manifestations in relation to transcriptome location and function.
复制标题
DOI：
10.1016/j.ymgme.2021.12.008
复制
发表时间：
2022-01
影响因子：
3.8
通讯作者：
Pascual JM
中科院分区：
文献类型：
--
作者：
Jakkamsetti V;Balasubramaniam S;Grover N;Pascual JM
神经系统内的定位为神经系统疾病的表现和治疗提供了背景，其中许多疾病机制表现出预先定位。相比之下，大多数致病基因的分子功能通常被认为与这种脑区域相关性无关，因为大多数基因在整个大脑中表达。我们通过辨别两种不同的遗传疾病机制的可能性来测试这种分离的事实基础：一种是基因特异性的，其中遗传疾病的定位性很差，因为它们在分子水平上是多种形式的，每个突变基因的作用比仅仅通过一种功能的丧失或获得更广泛或更复杂。另一种是更普遍的，即基因组所共有的方面，如维持协调生物过程的基因组成员资格，解释了共同或可定位的表型。我们分析了线粒体底物障碍作为一个范例，显然是异质性疾病时，考虑到从他们的表现和个人功能的角度来看，他们的致病基因。我们使用了公开可用的转录组，发表在同行评审期刊和人类本体分类的疾病表型。使用27种线粒体底物代谢疾病，我们分析了这些疾病是否表现出共同的表型，以及这是否与由其转录组划分的共同脑区域或细胞有关。最常见的表型表现和涉及的脑结构几乎是刻板的，无论受影响的个体基因如何，与线粒体底物代谢的转录组的区域丰度相关。这也适用于抑制性神经元的转录组，这些神经元在一些线粒体疾病中功能失调。这与对其他原因引起的痴呆萎缩的抵抗形成对比，已知这也与转录组的类似部分的更高表达有关。结果表明，脑区域或细胞类型功能障碍源于一个广泛的过程，如线粒体底物代谢是更相关的疾病表现比个别基因参与特定的分子功能。
Localization within the nervous system provides context to neurological disease manifestations and treatment, with numerous disease mechanisms exhibiting predilect localizations. In contrast, the molecular function of most disease-causing genes is generally considered dissociated from such brain regional correlations because most genes are expressed throughout the brain. We tested the factual basis for this dissociation by discerning between two distinct genetic disease mechanism possibilities: One, gene-specific, in which genetic disorders are poorly localizable because they are multiform at the molecular level, with each mutant gene acting more widely or complexly than via mere loss or gain of one function. The other, more general, where aspects shared by groups of genes such as membership in a gene set that sustains a concerted biological process accounts for a common or localizable phenotype. We analyzed mitochondrial substrate disorders as a paradigm of apparently heterogeneous diseases when considered from the point of view of their manifestations and individual function of their causal genes. We used publicly available transcriptomes, disease phenotypes published in peer-reviewed journals and Human Ontology classifications. Using 27 mitochondrial substrate metabolism diseases, we analyzed if these disorders manifest common phenotypes and if this relates to common brain regions or cells as demarcated by their transcriptome. The most frequent phenotypic manifestations and brain structures involved were almost stereotypic regardless of the individual gene affected, correlating with the regional abundance of the transcriptome that served mitochondrial substrate metabolism. This also applied to the transcriptome of inhibitory neurons, which are dysfunctional in some mitochondrial diseases. This stands in contrast with resistance to dementia atrophy from other causes, which is known to also associate with greater expression of a similar fraction of the transcriptome. The results suggest that the brain region or cell type dysfunction stemming from a broad process such as mitochondrial substrate metabolism is more relevant for disease manifestations than individual gene participation in specific molecular function.
登录
查看更多内容
影响因子：
7.7
作者：
Miller JA;Gouwens NW;Tasic B;Collman F;van Velthoven CT;Bakken TE;Hawrylycz MJ;Zeng H;Lein ES;Bernard A
通讯作者：
Bernard A
影响因子：
64.8
作者：
Tasic B;Yao Z;Graybuck LT;Smith KA;Nguyen TN;Bertagnolli D;Goldy J;Garren E;Economo MN;Viswanathan S;Penn O;Bakken T;Menon V;Miller J;Fong O;Hirokawa KE;Lathia K;Rimorin C;Tieu M;Larsen R;Casper T;Barkan E;Kroll M;Parry S;Shapovalova NV;Hirschstein D;Pendergraft J;Sullivan HA;Kim TK;Szafer A;Dee N;Groblewski P;Wickersham I;Cetin A;Harris JA;Levi BP;Sunkin SM;Madisen L;Daigle TL;Looger L;Bernard A;Phillips J;Lein E;Hawrylycz M;Svoboda K;Jones AR;Koch C;Zeng H
通讯作者：
Zeng H
影响因子：
5.3
作者：
Eising E;Huisman SMH;Mahfouz A;Vijfhuizen LS;Anttila V;Winsvold BS;Kurth T;Ikram MA;Freilinger T;Kaprio J;Boomsma DI;van Duijn CM;Järvelin MR;Zwart JA;Quaye L;Strachan DP;Kubisch C;Dichgans M;Davey Smith G;Stefansson K;Palotie A;Chasman DI;Ferrari MD;Terwindt GM;de Vries B;Nyholt DR;Lelieveldt BPF;van den Maagdenberg AMJM;Reinders MJT
通讯作者：
Reinders MJT
影响因子：
13.7
作者：
Taylor, Rachel L.;Parry, Neil R. A.;Sergouniotis, Panagiotis I.
通讯作者：
Sergouniotis, Panagiotis I.
影响因子：
10.6
作者：
Tunbridge, Elizabeth M.;Eastwood, Sharon L.;Harrison, Paul J.
通讯作者：
Harrison, Paul J.