PXD038225-1
PXD038225 is an original dataset announced via ProteomeXchange.
Dataset Summary
| Title | Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency |
| Description | Multi-layered omics technologies can help define relationships between genetic factors, biochemical processes and phenotypes thus extending research of monogenic diseases beyond identifying their cause. We implemented a multi-layered omics approach for the inherited metabolic disorder methylmalonic aciduria. We performed whole genome sequencing, transcriptomic sequencing, and mass spectrometry-based proteotyping from matched primary fibroblast samples of 230 individuals (210 affected, 20 controls) and related the molecular data to 105 phenotypic features. Integrative analysis identified a molecular diagnosis for 84% (179/210) of affected individuals, the majority (150) of whom had pathogenic variants in methylmalonyl-CoA mutase (MMUT). Untargeted integration of all three omics layers revealed dysregulation of TCA cycle and surrounding metabolic pathways, a finding that was further supported by multi-organ metabolomics of a hemizygous Mmut mouse model. Stratification by phenotypic severity indicated downregulation of oxoglutarate dehydrogenase and upregulation of glutamate dehydrogenase in disease. This was supported by metabolomics and isotope tracing studies which showed increased glutamine-derived anaplerosis. We further identified MMUT to physically interact with both, oxoglutarate dehydrogenase and glutamate dehydrogenase providing a mechanistic link. This study emphasizes the utility of a multi-modal omics approach to investigate metabolic diseases and highlights glutamine anaplerosis as a potential therapeutic intervention point in methylmalonic aciduria. |
| HostingRepository | MassIVE |
| AnnounceDate | 2022-11-22 |
| AnnouncementXML | Submission_2022-11-22_13:27:26.463.xml |
| DigitalObjectIdentifier | |
| ReviewLevel | Non peer-reviewed dataset |
| DatasetOrigin | Original dataset |
| RepositorySupport | Unsupported dataset by repository |
| PrimarySubmitter | Sandra Goetze |
| SpeciesList | scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606; |
| ModificationList | Carbamidomethyl; Acetyl; Phospho; Oxidation; Deamidated |
| Instrument | Q Exactive HF; Q Exactive |
Dataset History
| Revision | Datetime | Status | ChangeLog Entry |
|---|---|---|---|
| 0 | 2022-11-21 14:28:43 | ID requested | |
| ⏵ 1 | 2022-11-22 13:27:26 | announced |
Publication List
| no publication |
Keyword List
| submitter keyword: methylmalonyl-CoA mutase deficiency, multi-omcis, DIA, genomics, transcriptomics, proteomics, metabolomics, phenomics |
Contact List
| Bernd Wollscheid | |
|---|---|
| contact affiliation | ETHZ |
| contact email | bernd.wollscheid@hest.ethz.ch |
| lab head | |
| Sandra Goetze | |
| contact affiliation | ETHZ |
| contact email | sgoetze@ethz.ch |
| dataset submitter | |
Full Dataset Link List
| MassIVE dataset URI |
| Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://massive.ucsd.edu/MSV000088791/ |
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