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PXD038225

PXD038225 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleIntegrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency
DescriptionMulti-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.
HostingRepositoryMassIVE
AnnounceDate2022-11-22
AnnouncementXMLSubmission_2022-11-22_13:27:26.463.xml
DigitalObjectIdentifier
ReviewLevelNon peer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterSandra Goetze
SpeciesList scientific name: Homo sapiens; common name: human; NCBI TaxID: 9606;
ModificationListCarbamidomethyl; Acetyl; Phospho; Oxidation; Deamidated
InstrumentQ Exactive HF; Q Exactive
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-11-21 14:28:43ID requested
12022-11-22 13:27:26announced
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 affiliationETHZ
contact emailbernd.wollscheid@hest.ethz.ch
lab head
Sandra Goetze
contact affiliationETHZ
contact emailsgoetze@ethz.ch
dataset submitter
Full Dataset Link List
MassIVE dataset URI
Dataset FTP location
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