PXD029707 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | Splice-Switching Oligonucleotide-mediated Correction of a Deep Intronic Splice-variant in TIMMDC1 in Cells of Patients with Severe Early Onset Neurodegenerative Disorder. |
Description | TIMMDC1 encodes the Translocase of Inner Mitochondrial Membrane Domain-Containing protein 1 (TIMMDC1) subunit of complex I of the electron transport chain responsible for ATP production. We studied a consanguineous family with two affected children, now deceased, who presented with failure to thrive in the early postnatal period, poor feeding, hypotonia, peripheral neuropathy and drug resistant epilepsy. Genome sequencing data revealed a known, deep intronic pathogenic variant TIMMDC1 c.597-1340A>G, also present in gnomAD (~1/5000 frequency), that enhances aberrant splicing. Using RNA and protein analysis we show almost complete loss of TIMMDC1 protein and compromised mitochondrial complex I function. We have designed and applied two different splice- switching antisense oligonucleotides (SSO) to restore normal TIMMDC1 mRNA processing and protein levels in patients’ cells. Quantitative proteomics and real-time metabolic analysis of mitochondrial function on patient fibroblasts treated with SSOs showed restoration of complex I subunit abundance and function. SSO-mediated therapy of this inevitably fatal TIMMDC1 neurologic disorder is an attractive possibility. |
HostingRepository | PRIDE |
AnnounceDate | 2022-02-17 |
AnnouncementXML | Submission_2022-02-17_09:03:01.128.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | David Stroud |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue |
Instrument | Orbitrap Eclipse |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2021-11-12 06:06:42 | ID requested | |
⏵ 1 | 2022-02-17 09:03:01 | announced | |
Publication List
Kumar R, Corbett MA, Smith NJC, Hock DH, Kikhtyak Z, Semcesen LN, Morimoto A, Lee S, Stroud DA, Gleeson JG, Haan EA, Gecz J, Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder. NPJ Genom Med, 7(1):9(2022) [pubmed] |
Keyword List
submitter keyword: Human, TIMMDC1, DIA, mitochondrial disease, SSO |
Contact List
David Stroud |
contact affiliation | Department of Biochemistry & Pharmacology, Bio21 Institute, University of Melbourne |
contact email | david.stroud@unimelb.edu.au |
lab head | |
David Stroud |
contact affiliation | The University of Melbourne |
contact email | david.stroud@unimelb.edu.au |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD029707
- Label: PRIDE project
- Name: Splice-Switching Oligonucleotide-mediated Correction of a Deep Intronic Splice-variant in TIMMDC1 in Cells of Patients with Severe Early Onset Neurodegenerative Disorder.