Oligonucleotide correction of an intronic TIMMDC1 variant in cells of patients with severe neurodegenerative disorder
NPJ GENOMIC MEDICINE(2022)
摘要
TIMMDC1 encodes the T ranslocase of I nner M itochondrial M embrane D omain- C ontaining 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.
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关键词
Clinical genetics,Molecular medicine,Biomedicine,general,Human Genetics,Internal Medicine,Bioinformatics,Gene Therapy,Gene Function
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