bims-cytox1 2019-04-21 papers

Issue of 2019–04–21
two papers selected by
Gavin McStay, Staffordshire University

Hum Mutat. 2019 Apr 13.

A patient with homozygous nonsense variants in two Leigh syndrome disease genes: Distinguishing a dual diagnosis from a hypomorphic protein-truncating variant.

Nicole J Lake, Luke E Formosa, David A Stroud, Michael T Ryan, Sarah E Calvo, Vamsi K Mootha, Bharti Morar, Peter G Procopis, John Christodoulou, Alison G Compton, David R Thorburn.

Leigh syndrome is a mitochondrial disease caused by pathogenic variants in over 85 genes. Whole exome sequencing of a patient with Leigh-like syndrome identified homozygous protein-truncating variants in two genes associated with Leigh syndrome; a reported pathogenic variant in PDHX (NP_003468.2:p.(Arg446*)), and an uncharacterized variant in complex I (CI) assembly factor TIMMDC1 (NP_057673.2:p.(Arg225*)). The TIMMDC1 variant was predicted to truncate 61 amino acids at the C-terminus and functional studies demonstrated a hypomorphic impact of the variant on CI assembly. However, the mutant protein could still rescue CI assembly in TIMMDC1 knockout cells and the patient's clinical phenotype was not clearly distinct from that of other patients with the same PDHX defect. Our data suggest that the hypomorphic effect of the TIMMDC1 protein-truncating variant does not constitute a dual diagnosis in this individual. We recommend cautious assessment of variants in the C-terminus of TIMMDC1 and emphasize the need to consider the caveats detailed within the American College of Medical Genetics and Genomics (ACMG) criteria when assessing variants.

Keywords: ACMG guidelines; Leigh syndrome; TIMMDC1; complex I; protein truncation

DOI: https://doi.org/10.1002/humu.23753

Mitochondrion. 2019 Apr 11. pii: S1567-7249(18)30037-0. [Epub ahead of print]46 15-21

Intramitochondrial transfer and engineering of mammalian mitochondrial genomes in yeast.

Young Geol Yoon, Michael D Koob.

Mitochondrial genomes (mtDNA) depend on the nuclear genome with which they have evolved to provide essential replication functions and have been known to replicate as xenotransplants only in the cells of closely related species. We now report that complete mouse mitochondrial genomes can be stably transplanted into the mitochondrial network in yeast devoid of their own mtDNA. Our analyses of these xenomitochondrial yeast cells show that they are accurately replicating intact mouse mtDNA genomes without rearrangement and that these mtDNA genomes have the same overall topology as the mtDNA present in the mouse mitochondrial network (i.e., circular monomers). Moreover, non-mtDNA replication and selection sequences required for maintaining the mitochondrial genomes in bacterial hosts are dispensable in these yeast mitochondria and could be efficiently and seamlessly removed by targeted homologous recombination within the mitochondria. These findings demonstrate that the yeast mtDNA replication system is capable of accurately replicating intact mammalian mtDNA genomes without sequence loss or rearrangement and that yeast mitochondria are a highly versatile host system for engineering complete mammalian mitochondrial genomes.

Keywords: Mitochondrial genome; Mitochondrial host; Non-mtDNA sequence; Petite mutant; Xenomitochondrial yeast; mtDNA engineering

DOI: https://doi.org/10.1016/j.mito.2019.03.006