PXD029707

PXD029707 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2021-11-12 06:06:42	ID requested
⏵ 1	2022-02-17 09:03:01	announced

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]

submitter keyword: Human, TIMMDC1, DIA, mitochondrial disease, SSO

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

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PRIDE project URI

• PRIDE
  1. PXD029707
     1. Label: PRIDE project
     2. Name: Splice-Switching Oligonucleotide-mediated Correction of a Deep Intronic Splice-variant in TIMMDC1 in Cells of Patients with Severe Early Onset Neurodegenerative Disorder.