Cosegregation of the mitochondrial DNA A1555G and G4309A mutations results in deafness and mitochondrial myopathy

Abstract

We report a patient with progressive external ophthalmoplegia (PEO), exercise intolerance, and deafness after aminoglycoside exposure, harboring two pathogenic mutations in her mtDNA: an A1555G in the 12S rRNA gene and a G4309A in the tRNA(Ile) gene. Muscle histochemistry showed abundant ragged-red fibers, and biochemistry revealed normal respiratory chain function. The A1555G mutation was homoplasmic in blood from the proband and from all maternal relatives. The G4309A mutation was abundant in the proband's muscle, less abundant in her blood, still less abundant in the mother's blood, and absent in blood from other maternal relatives. Family members were asymptomatic. Our data suggest that the former mutation resulted in aminoglycoside-induced deafness and the latter caused PEO plus exercise intolerance.

Novel mitochondrial tRNAIlem.4282A>G gene mutation leads to chronic progressive external ophthalmoplegia plus phenotype

“…In an elderly patient harbouring the m.4302A>G mutation, in addition to the myopathy, lipomas developed and diplopia became apparent, of which the latter showed improvement by L-carnitine and coenzyme Q10 treatment 2. Mutations in the MTTI gene causing CPEO phenotype are m.4274T>C,17 m.4298G>A,19 m.4308G>A,1 m.4309G>A20 and for PEO m.4285T>C 21 Table 2. compiles all disease-associated mutations of the MTTI gene known to date.…”

Mitochondrial ribosome and Ménière’s disease: a pilot study

“…Thus, A10S genetic variant in the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase (TRMU) gene leads to a marked failure in mt-tRNA metabolism and contributes to the impairment of mitochondrial protein synthesis, thus aggravating the mitochondrial dysfunction associated with mt-rRNA mutations [20]. In this sense, genetic variation in mt-tRNA genes could also affect mitochondrial protein synthesis and, second, the susceptibility to aminoglycosides [21,22]. …”

The Human Gene Map for Performance and Health-Related Fitness Phenotypes: The 2002 Update

“…Karadimas and coworkers (49) reported a new patient with a previously charac-terized G12315A mutation in the mitochondrial tRNA(Leu(CUN)) gene. Finally, a G4309A mutation in the mitochondrial tRNA(Ile) gene was reported in a 32-yr-old woman with exercise intolerance since childhood (17). All four mitochondrial gene mutations were heteroplasmic.…”