A novel mitochondrial tRNA ^Phe mutation causes MERRF syndrome

Abstract

A woman with typical features of myoclonic epilepsy with ragged red fibers (MERRF) had a novel heteroplasmic mutation (G611A) in the mitochondrial DNA tRNA phenylalanine gene. The mutation was heteroplasmic (91%) in muscle but undetectable in accessible tissues from the patient and her maternal relatives. Single-fiber PCR analysis showed that the proportion of mutant genomes was higher in cytochrome c oxidase (COX)-negative ragged red fibers (RRFs) than in COX-positive non-RRFs. This report shows that typical MERRF syndrome is not always associated with tRNA lysine mutations.

Pathogenic mechanism of a human mitochondrial tRNA Phe mutation associated with myoclonic epilepsy with ragged red fibers syndrome

“…1) (2)(3)(4)(38)(39)(40)(41)(42). To investigate the pathogenic mechanisms of these mutations, we used the corresponding WT and mutant forms of in vitro-transcribed hmttRNA Phe in aminoacylation experiments.…”

“…Since the completion of the hmt genome sequence (1), a variety of diseases have been directly linked to hmt DNA point mutations, with over half being coupled to changes in hmt-tRNA genes (MITOMAP: A Human Mitochondrial Genome Database; http://www.mitomap.org). Diseases associated with hmt-tRNA point mutations include MERRF (myoclonic epilepsy with ragged red fibers), MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), and deafness (2)(3)(4). Pathogenic mutations of hmt-tRNAs have been shown to affect global tRNA structure (5)(6)(7)(8), tRNA processing (9-13), modification (14)(15)(16)(17)(18)(19)(20), aminoacylation (7,(21)(22)(23)(24)(25)(26), and translation efficiency (27)(28)(29).…”

“…1) (2)(3)(4)(38)(39)(40)(41)(42), including a G34A anticodon variant associated with MERRF syndrome. Anticodon pathogenic mutations are rare in hmt-tRNAs, the only other known example being the G36A mutation of hmt-tRNA Pro (G15990A) for which the pathogenic mechanism remains obscure (43).…”

From evolutionary bystander to master manipulator: the emerging roles for the mitochondrial genome as a modulator of nuclear gene expression

“…For humans alone, B500 potentially disease-causing mtDNA variants are known, 10 affecting both the coding and noncoding regions of the mitochondrial genome, and it is estimated that approximately one in 200 healthy individuals carries a pathogenic mtDNA mutation that could cause disease to the offspring of female carriers. 11 Various human diseases result from mutations to specific mtDNA sites, as is the case for the myoclonic epilepsy with ragged red fibers syndrome, 12 whereas other disease states are caused by single point mutations at one of a multitude of sites in the mtDNA, for example, Leber's hereditary optic neuropathy. 13 In the majority of instances, however, despite its small size and the ease with which mitochondrial genomes are sequenced (and mutations revealed), the search for disease-causing or fitness-reducing mutations in the mitochondrial genome is often marked by a struggle to link consequence to cause.…”

Identification of causative mutations in patients with Leigh syndrome and MERRF by mitochondrial DNA-targeted next-generation sequencing

“…In addition to mutations in MT-TK, defects in many other genes have also been reported to present the MERRF phenotype. These include MT-TL1 (mitochondrially encoded tRNA leucine 1, MIM# 590050) [4,11], MT-TH (mitochondrially encoded tRNA histidine, MIM# 590040) [12], MT-TS1 (mitochondrially encoded tRNA serine 1, MIM# 590080) [3], MT-TS2 (MIM# 590085), MT-TF (mitochondrially encoded tRNA phenylalanine, MIM# 590070) [13], and MT-ND5 (NADH-ubiquinone oxidoreductase chain 5, MIM# 516005) [14]. Transfer of mtDNA carrying a tRNA gene mutation to cell lines results in a severe defect in mitochondrial translation in the recipient cells, implying that the tRNA mutation itself is sufficient to cause the disease.…”