Aminoacyl-transfer ribonucleic acid synthetases (ARSs) catalyze the attachment of each amino acids to their cognate tRNAs. Mitochondrial ARSs (mtARSs), that ensure protein synthesis within mitochondrial compartment, are encoded by nuclear genes and imported in the organelle after translation in the cytosol. To date, thanks to the extensive use of next generation sequencing (NGS), an increasing number of variants in mtARS genes have been identified and associated with mitochondrial disease. The similarities between yeast and human mitochondrial translation machineries makes yeast a good model to evaluate the effect of variants in mtARSs genes in a quick and efficient way. We identified compound heterozygous missense WARS2 variants in a child with spastic paraparesis, tremor and ataxia and in another one with infantile parkinsonism, while compound heterozygous missense NARS2 variants were found in a baby with developmental delay, epilepsy and complex I deficiency. We have recently constructed two new yeast models to assess the functional consequences of novel mutations found in NARS2 and WARS2, encoding mitochondrial asparaginyl-tRNA (AsnRS) and tryptophanyl‐tRNA synthetases (TrpRS), respectively. Mitochondrial phenotypes such as oxidative growth, oxygen consumption rate (OCR) and Cox2 protein level were analyzed in yeast strains deleted in SLM5 and MSW1, the yeast orthologues of NARS2 and WARS2, and expressing the wild type or the mutant alleles both individually and in combination, confirming the pathogenicity of most the identified variants. Moreover, the beneficial effects deriving from supplementation of asparagine in the growth medium was investigated in the NARS2 yeast model. The results obtained suggest asparagine supplementation as a potential therapeutic approach.

Yeast as a model for mitochondrial aminoacyl-tRNA synthetase disorders: validation of mutations in NARS2 and WARS2 / CECCATELLI BERTI, Camilla; Figuccia, Sonia; Legati, Andrea; Nasca, Alessia; Ghezzi, Daniele; Goffrini, Paola. - (2021). ((Intervento presentato al convegno Mitochondrial Medicine - Therapeutic Development 2021 - tenutosi a VIRTUAL event nel 30 November–02 December 2021.

Yeast as a model for mitochondrial aminoacyl-tRNA synthetase disorders: validation of mutations in NARS2 and WARS2

Camilla Ceccatelli Berti;Sonia Figuccia;Paola Goffrini
2021

Abstract

Aminoacyl-transfer ribonucleic acid synthetases (ARSs) catalyze the attachment of each amino acids to their cognate tRNAs. Mitochondrial ARSs (mtARSs), that ensure protein synthesis within mitochondrial compartment, are encoded by nuclear genes and imported in the organelle after translation in the cytosol. To date, thanks to the extensive use of next generation sequencing (NGS), an increasing number of variants in mtARS genes have been identified and associated with mitochondrial disease. The similarities between yeast and human mitochondrial translation machineries makes yeast a good model to evaluate the effect of variants in mtARSs genes in a quick and efficient way. We identified compound heterozygous missense WARS2 variants in a child with spastic paraparesis, tremor and ataxia and in another one with infantile parkinsonism, while compound heterozygous missense NARS2 variants were found in a baby with developmental delay, epilepsy and complex I deficiency. We have recently constructed two new yeast models to assess the functional consequences of novel mutations found in NARS2 and WARS2, encoding mitochondrial asparaginyl-tRNA (AsnRS) and tryptophanyl‐tRNA synthetases (TrpRS), respectively. Mitochondrial phenotypes such as oxidative growth, oxygen consumption rate (OCR) and Cox2 protein level were analyzed in yeast strains deleted in SLM5 and MSW1, the yeast orthologues of NARS2 and WARS2, and expressing the wild type or the mutant alleles both individually and in combination, confirming the pathogenicity of most the identified variants. Moreover, the beneficial effects deriving from supplementation of asparagine in the growth medium was investigated in the NARS2 yeast model. The results obtained suggest asparagine supplementation as a potential therapeutic approach.
Yeast as a model for mitochondrial aminoacyl-tRNA synthetase disorders: validation of mutations in NARS2 and WARS2 / CECCATELLI BERTI, Camilla; Figuccia, Sonia; Legati, Andrea; Nasca, Alessia; Ghezzi, Daniele; Goffrini, Paola. - (2021). ((Intervento presentato al convegno Mitochondrial Medicine - Therapeutic Development 2021 - tenutosi a VIRTUAL event nel 30 November–02 December 2021.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/2907371
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