PXD029861

PXD029861 is an original dataset announced via ProteomeXchange.

Title	Characterisation of a novel CRLS1 variant in multi-system mitochondrial disease pathogenesis identifies mitochondrial and endoplasmic reticular stress responses to cardiolipin dysfunction
Description	Mitochondrial diseases (MD) are a group of inherited diseases with highly varied and complex clinical presentations and their molecular diagnosis has been improved through next generation sequencing. Here, we report four individuals, two of whom are siblings, affected by a progressive mitochondrial encephalopathy who carry biallelic variants in the cardiolipin biosynthesis gene CRLS1. Using patient fibroblasts, we characterised defects in mitochondrial function that were reflective of CRLS1 dysfunctions, providing functional evidence that the CRLS1 I109N variant causes the MD phenotype observed in this patient. Lipid profiling highlighted that the CRLS1 variants reduced cardiolipin levels, altered its acyl-chain composition and caused a significant increase in phosphatidylglycerol, the substrate of cardiolipin synthase. Proteomic profiling of patient cells and Crls1 knockout cell lines identified both endoplasmic reticular and mitochondrial stress responses, and key features that distinguish between varying degrees of cardiolipin insufficiency. Our findings support that deleterious variants in CRLS1 cause a novel autosomal recessive MD, presenting as a severe encephalopathy with multisystemic involvement. Furthermore, we have identified key changes in cardiolipin and proteome profiles across various degrees of cardiolipin dysfunction, facilitating future advances in diagnostic technologies based on curated signatures in high-throughput datasets.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:29:19.565.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Timothy McCubbin
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-22 01:26:17	ID requested
1	2023-03-05 16:19:35	announced
⏵ 2	2023-11-14 08:29:21	announced	2023-11-14: Updated project metadata.

Lee RG, Balasubramaniam S, Stentenbach M, Kralj T, McCubbin T, Padman B, Smith J, Riley LG, Priyadarshi A, Peng L, Nuske MR, Webster R, Peacock K, Roberts P, Stark Z, Lemire G, Ito YA, Boycott KM, Geraghty MT, van Klinken JB, Ferdinandusse S, Zhou Y, Walsh R, Marcellin E, Thorburn DR, Rosciolli T, Fletcher J, Rackham O, Vaz FM, Reid GE, Filipovska A, Deleterious variants in CRLS1 lead to cardiolipin deficiency and cause an autosomal recessive multi-system mitochondrial disease. Hum Mol Genet, 31(21):3597-3612(2022) [pubmed]

submitter keyword: DIA, mitochondrial disease, mitochondria, fibroblast,human

Aleksandra Filipovska
contact affiliation	Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia
contact email	aleksandra.filipovska@uwa.edu.au
lab head
Timothy McCubbin
contact affiliation	University of Queensland
contact email	t.mccubbin@uq.edu.au
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD029861
     1. Label: PRIDE project
     2. Name: Characterisation of a novel CRLS1 variant in multi-system mitochondrial disease pathogenesis identifies mitochondrial and endoplasmic reticular stress responses to cardiolipin dysfunction