Mitochondrial tRNAPhe mutation as a cause of end-stage renal disease in childhood

Abstract

Background We identified a mitochondrial tRNA mutation (m.586G>A) in a patient with renal failure and symptoms consistent with a mitochondrial cytopathy. This mutation was of unclear significance because there were neither consistent reports of linkage to specific disease phenotypes nor an existing analysis of effects upon mitochondrial function. Case-Diagnosis/Treatment A 16-month-old girl with failure-to-thrive, developmental regression, persistent lactic acidosis, hypotonia, GI dysmotility, adrenal insufficiency and hematologic abnormalities developed hypertension and renal impairment with chronic tubulointerstitial fibrosis, progressing to renal failure with need for peritoneal dialysis. Evaluation of her muscle and blood identified a mutation of the mitochondrial tRNA for phenylalanine, m.586G>A. Conclusions The m.586G>A mutation is pathogenic and is a cause of end-stage renal disease in childhood. The mutation interferes with the stability of tRNAPhe and affects the translation of mitochondrial proteins and the stability of the electron transport chain.

Mitochondrial disease—an important cause of end-stage renal failure

“…How does the case presented by D'Aco et al [7] fit with the literature to date on renal involvement in mitochondrial disease? This is a rapidly evolving field, and much remains to be learned about the complex relationship between genotype and phenotype.…”

“…In the following sections we will apply this approach to briefly summarise the expanding volume of literature describing renal involvement in mitochondrial disease. Overall, it can be concluded that tubulo-interstitial disease is the most common renal phenotype in children presenting at a young age with severe multisystem disease (as in the case described by D'Aco et al [7]), usually due to widely expressed nuclear DNA mutations or large-scale mtDNA deletions. However, as discussed below, there are some notable exceptions to this generalisation.…”

“…Mutations of FARS2 were recently identified in an exome sequencing study [21]. These mutations would be expected to impair the insertion of phenylalanine onto the tRNA phenylalanine molecule, and so it would be interesting to determine whether affected patients shared any of the clinical features previously associated with MT-TF mutations, specifically endstage renal failure as reported by D'Aco et al in this issue of the Pediatric Nephrology [7]. However, affected patients with FARS2 mutations actually present with a severe seizure disorder in the Alpers syndrome spectrum-and not with renal disease [21].…”

“…Indeed, it is increasingly the case that patients with 'classical' mitochondrial disease represent the minority, while the majority of cases do not fit neatly into a recognised syndrome. In this edition of Pediatric Nephrology, D'Aco et al present a case of end-stage renal disease (ESRD) caused by a mtDNA point mutation, m.586G>A, in the MT-TF gene encoding the mitochondrial tRNA for phenylalanine [7]. This 16-month-old patient did not have a classical mitochondrial syndrome, but did have multisystem disease features, including developmental regression, persistent lactic acidosis, hypotonia, faltering growth, gastro-intestinal dysmotility, pancreatitis, adrenal insufficiency, anaemia and neutropaenia, which alerted the physicians to the suspicion of an underlying mitochondrial disorder.…”

“…In order to address this, D'Aco et al employed the gold standard method of transmitochondrial cybrid generation in which enucleated patient cells are fused with a donor cell line lacking mtDNA (so-called rho zero cells) to determine whether the biochemical phenotype tracks with the patient's mtDNA [9]. Their findings showed that cybrids with 100 % m.586G > A mutation had significantly reduced oxygen consumption and reduced tRNA phenylalanine levels and that the amount of mutation influenced the degree of respiratory impairment in a dose-dependent manner, thereby providing overwhelming evidence that this mutation is pathogenic [7].…”