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Biochem Biophys Res Commun. 2017 Nov 18;493(2):909-913. doi: 10.1016/j.bbrc.2017.09.122. Epub 2017 Sep 22.

Dominance of yeast aac2R96H and aac2R252G mutations, equivalent to pathological mutations in ant1, is due to gain of function.

Author information

1
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy.
2
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, 43124 Parma, Italy. Electronic address: tiziana.lodi@unipr.it.

Abstract

The mitochondrial ADP/ATP carrier is a nuclear encoded protein, which catalyzes the exchange of ATP generated in mitochondria with ADP produced in the cytosol. In humans, mutations in the major ADP/ATP carrier gene, ANT1, are involved in several degenerative mitochondrial pathologies, leading to instability of mitochondrial DNA. Recessive mutations have been associated with mitochondrial myopathy and cardiomyopathy whereas dominant mutations have been associated with autosomal dominant Progressive External Ophtalmoplegia (adPEO). Recently, two de novo dominant mutations, R80H and R235G, leading to extremely severe symptoms, have been identified. In order to evaluate if the dominance is due to haploinsufficiency or to a gain of function, the two mutations have been introduced in the equivalent positions of the AAC2 gene, the yeast orthologue of human ANT1, and their dominant effect has been studied in heteroallelic strains, containing both one copy of wild type AAC2 and one copy of mutant aac2 allele. Through phenotypic characterization of these yeast models we showed that the OXPHOS phenotypes in the heteroallelic strains were more affected than in the hemiallelic strain indicating that the dominant trait of the two mutations is due to gain of function.

KEYWORDS:

AAC2; ANT1; Gain of function; Mitochondrial diseases; SLC25A4; Yeast

PMID:
28947214
DOI:
10.1016/j.bbrc.2017.09.122
[Indexed for MEDLINE]

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