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针对 FSHD 的荟萃分析揭示了神经肌肉接头、核膜和剪接体的失调。

Meta-analysis towards FSHD reveals misregulation of neuromuscular junction, nuclear envelope, and spliceosome.

机构信息

Institute of Precision Medicine, Furtwangen University, Furtwangen, Germany.

Friedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, Ludwig Maximilian University, Munich, Germany.

出版信息

Commun Biol. 2024 May 25;7(1):640. doi: 10.1038/s42003-024-06325-z.


DOI:10.1038/s42003-024-06325-z
PMID:38796645
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11127974/
Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common autosomal dominant muscle disorders, yet no cure or amelioration exists. The clinical presentation is diverse, making it difficult to identify the actual driving pathomechanism among many downstream events. To unravel this complexity, we performed a meta-analysis of 13 original omics datasets (in total 171 FSHD and 129 control samples). Our approach confirmed previous findings about the disease pathology and specified them further. We confirmed increased expression of former proposed DUX4 biomarkers, and furthermore impairment of the respiratory chain. Notably, the meta-analysis provides insights about so far not reported pathways, including misregulation of neuromuscular junction protein encoding genes, downregulation of the spliceosome, and extensive alterations of nuclear envelope protein expression. Finally, we developed a publicly available shiny app to provide a platform for researchers who want to search our analysis for genes of interest in the future.

摘要

面肩肱型肌营养不良症(FSHD)是最常见的常染色体显性肌肉疾病之一,但目前尚无治愈或改善方法。其临床表现多种多样,使得许多下游事件之间的实际致病机制难以确定。为了解开这种复杂性,我们对 13 个原始组学数据集(总共 171 个 FSHD 和 129 个对照样本)进行了荟萃分析。我们的方法证实了以前关于疾病病理的发现,并进一步对其进行了说明。我们证实了以前提出的 DUX4 生物标志物的表达增加,以及呼吸链的损伤。值得注意的是,荟萃分析提供了关于迄今为止未报道的途径的见解,包括神经肌肉接头蛋白编码基因的失调、剪接体的下调以及核膜蛋白表达的广泛改变。最后,我们开发了一个可公开获取的 shiny 应用程序,为未来希望在我们的分析中搜索感兴趣基因的研究人员提供了一个平台。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/bdc450afae9f/42003_2024_6325_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/25424c40c030/42003_2024_6325_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/ca0af8383f53/42003_2024_6325_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/c43fe3c82f33/42003_2024_6325_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/f17d7f55b0d7/42003_2024_6325_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/bdc450afae9f/42003_2024_6325_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/25424c40c030/42003_2024_6325_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/ca0af8383f53/42003_2024_6325_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/c43fe3c82f33/42003_2024_6325_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/f17d7f55b0d7/42003_2024_6325_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/32ad/11127974/bdc450afae9f/42003_2024_6325_Fig5_HTML.jpg

相似文献

[1]
Meta-analysis towards FSHD reveals misregulation of neuromuscular junction, nuclear envelope, and spliceosome.

Commun Biol. 2024-5-25

[2]
Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity.

Skelet Muscle. 2020-4-11

[3]
Facioscapulohumeral muscular dystrophy family studies of DUX4 expression: evidence for disease modifiers and a quantitative model of pathogenesis.

Hum Mol Genet. 2012-7-13

[4]
MATR3 is an endogenous inhibitor of DUX4 in FSHD muscular dystrophy.

Cell Rep. 2023-9-26

[5]
DUX4 expressing immortalized FSHD lymphoblastoid cells express genes elevated in FSHD muscle biopsies, correlating with the early stages of inflammation.

Hum Mol Genet. 2020-8-11

[6]
The evolution of DUX4 gene regulation and its implication for facioscapulohumeral muscular dystrophy.

Biochim Biophys Acta Mol Basis Dis. 2022-5-1

[7]
Influence of Expression in Facioscapulohumeral Muscular Dystrophy and Possible Treatments.

Int J Mol Sci. 2023-5-30

[8]
Deciphering transcription dysregulation in FSH muscular dystrophy.

J Hum Genet. 2012-6-21

[9]
Nuclear bodies reorganize during myogenesis in vitro and are differentially disrupted by expression of FSHD-associated DUX4.

Skelet Muscle. 2016-12-1

[10]
SIX transcription factors are necessary for the activation of DUX4 expression in facioscapulohumeral muscular dystrophy.

Skelet Muscle. 2024-12-3

引用本文的文献

[1]
Interplay between microtubule interactome, myonuclei mechanotransduction, and positioning in myopathies.

Nucleus. 2025-12

[2]
Comparative Analysis of Splicing Alterations in Three Muscular Dystrophies.

Biomedicines. 2025-3-1

本文引用的文献

[1]
FSHD muscle shows perturbation in fibroadipogenic progenitor cells, mitochondrial function and alternative splicing independently of inflammation.

Hum Mol Genet. 2024-1-7

[2]
Reply: An epigenetic basis for genetic anticipation in facioscapulohumeral muscular dystrophy type 1.

Brain. 2023-12-1

[3]
The FSHD jigsaw: are we placing the tiles in the right position?

Curr Opin Neurol. 2023-10-1

[4]
Metabolic, fibrotic and splicing pathways are all altered in Emery-Dreifuss muscular dystrophy spectrum patients to differing degrees.

Hum Mol Genet. 2023-3-6

[5]
simplifyEnrichment: A Bioconductor Package for Clustering and Visualizing Functional Enrichment Results.

Genomics Proteomics Bioinformatics. 2023-2

[6]
Interplay between mitochondrial reactive oxygen species, oxidative stress and hypoxic adaptation in facioscapulohumeral muscular dystrophy: Metabolic stress as potential therapeutic target.

Redox Biol. 2022-5

[7]
The assembly, regulation and function of the mitochondrial respiratory chain.

Nat Rev Mol Cell Biol. 2022-2

[8]
ggVennDiagram: An Intuitive, Easy-to-Use, and Highly Customizable R Package to Generate Venn Diagram.

Front Genet. 2021-9-7

[9]
MACF1 controls skeletal muscle function through the microtubule-dependent localization of extra-synaptic myonuclei and mitochondria biogenesis.

Elife. 2021-8-27

[10]
Transcriptome Analysis in a Primary Human Muscle Cell Differentiation Model for Myotonic Dystrophy Type 1.

Int J Mol Sci. 2021-8-10

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