Pathogenic variants in glutamyl-tRNAGln amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder

Abstract

Mitochondrial protein synthesis requires charging a mitochondrial tRNA with its amino acid. Here, the authors describe pathogenic variants in the GatCAB protein complex genes required for the generation of glutaminyl-mt-tRNAGln, that impairs mitochondrial translation and presents with cardiomyopathy.

C6orf203 controls OXPHOS function through modulation of mitochondrial protein biosynthesis

“…We observed a clear reduction of the mitochondrial-encoded complex IV subunits MT-CO1 and MT-CO2 as well as MT-ND1, a complex I subunit, in C6orf203-KO cells compared to wild type cells. We also observed a reduction in NDUFB8 and UQCRC2 levels, two nuclear-encoded complex I and complex III subunits, respectively, which are unstable if are not incorporated into their corresponding complexes [24]. Taken together, these observations explained the sum of our previous results, and demonstrate that the absence of C6orf203 leads to a reduction of the steady state levels of mtDNA encoded OXPHOS subunits.…”

“…Thus, discovering missing OXPHOS-related functional genes opens up the possibility of understanding, diagnosing and of thinking about possible therapeutic approaches for patients with OXPHOS diseases. In our lab, by data mining the Drosophila genome and by ortholog analysis, we have identified several genes essential for mitochondrial function, which are coded within bicistronic mRNAs [23] [22,24], leading us to suggest that this arrangement of mitochondrial genes may be a tendency in this organism (manuscript in preparation). A few weeks ago, Kotrys and collaborators, by a proteomic analysis of the human mitochondria, identified C6orf203/MTRES1 as a new mitochondrial gene [28].…”

“…Total DNA was isolated from cultured cells using a commercial kit (Qiagen, UK), following the manufacturer's recommendations. The mtDNA content in 50 ng of total DNA was measured by SYBR green real-time polymerase chain reaction (PCR) using the Applied Biosystems Step-One Plus real-time thermocycler according to [24] consisting of an initial 10 min denaturation step at 95°C followed by 40 cycles of denaturation (15 sec at 95°C) and annealing/extension (1min at 60°C). The analyzed genes were the mitochondrial 12S-rRNA gene (or MT-RNR1) and the nuclear HPRT1 mtDNA copy number values were expressed by the ratio 12S rRNA/HPRT1.…”

“…In addition, we observed that GATC was a new Drosophila melanogaster protein, ortholog to the corresponding subunit of the bacterial Glutamyl-tRNAGln amidotransferase, and candidate for mitochondrial localization. We described that this amidotransferase activity is essential for mammalian mitochondrial translation in vivo [23] and recently that mutations in any of its subunits (GATA, GATB and GATC) provoke severe mitochondrial diseases [24]. Ccdc56 and GatC are transcribed in bicistronic mRNAs in Drosophila melanogaster together with the mitochondrial translation factor mt-Tfb1 gene and the mitochondrial DNA polymerase PolγB subunit respectively [21] (Peña et al manuscript in preparation).…”

Effects of Oxidative Stress on Protein Translation: Implications for Cardiovascular Diseases

“…Similarly, a mitochondrial mutation resulting in a m 1 G37 modification of tRNA Met is related to maternally inherited hypertension [162]. A genetic study of nine infants belonging to five different families and suffering from severe cardiomyopathy revealed mutations in the GatCAB aminoacyl-tRNA amidotransferase complex, which charges the mt-tRNA Gln via a transamidation reaction [163]. Instability of mitochondrial alanyl-tRNA synthetase (mt-AlaRS) causes fatal infantile cardiomyopathy [164].…”