Dataset Information

Splice-Switching Oligonucleotide-mediated Correction of a Deep Intronic Splice-variant in TIMMDC1 in Cells of Patients with Severe Early Onset Neurodegenerative Disorder.

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin, Fibroblast

DISEASE(S): Mitochondrial Complex I Deficiency

SUBMITTER: David Stroud

LAB HEAD: David Stroud

PROVIDER: PXD029707 | Pride | 2022-02-17

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	20210811_Library_Fibroblasts_95min.psar	Other
	210806_Dani_DH-2825_TIMMDC1_SSO_raws.zip	Other
	210909_Liana_LS-2938_TIMMDC1_controls.zip	Other
	TIMMDC1_SSO_search.zip	Other
	TIMMDC1_controls_search.zip	Other

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Publications

Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder.

Kumar Raman R Corbett Mark A MA Smith Nicholas J C NJC Hock Daniella H DH Kikhtyak Zoya Z Semcesen Liana N LN Morimoto Atsushi A Lee Sangmoon S Stroud David A DA Gleeson Joseph G JG Haan Eric A EA Gecz Jozef J

NPJ genomic medicine 20220128 1

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.597-1340 ...[more]

PMID: 35091571

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