Mutations in the mitochondrial tRNASer(AGY) gene are associated with deafness, retinal degeneration, myopathy and epilepsy

Abstract

Although over 200 pathogenic mitochondrial DNA (mtDNA) mutations have been reported to date, determining the genetic aetiology of many cases of mitochondrial disease is still not straightforward. Here, we describe the investigations undertaken to uncover the underlying molecular defect(s) in two unrelated Caucasian patients with suspected mtDNA disease, who presented with similar symptoms of myopathy, deafness, neurodevelopmental delay, epilepsy, marked fatigue and, in one case, retinal degeneration. Histochemical and biochemical evidence of mitochondrial respiratory chain deficiency was observed in the patient muscle biopsies and both patients were discovered to harbour a novel heteroplasmic mitochondrial tRNA (mt-tRNA) Ser(AGY) (MTTS2) mutation (m.12264C4T and m.12261T4C, respectively). Clear segregation of the m.12261T4C mutation with the biochemical defect, as demonstrated by single-fibre radioactive RFLP, confirmed the pathogenicity of this novel variant in patient 2. However, unusually high levels of m.12264C4T mutation within both COX-positive (98.4 ± 1.5%) and COX-deficient (98.2 ±2.1%) fibres in patient 1 necessitated further functional investigations to prove its pathogenicity. Northern blot analysis demonstrated the detrimental effect of the m.12264C4T mutation on mt-tRNA Ser(AGY) stability, ultimately resulting in decreased steady-state levels of fully assembled complexes I and IV, as shown by blue-native polyacrylamide gel electrophoresis. Our findings expand the spectrum of pathogenic mutations associated with the MTTS2 gene and highlight MTTS2 mutations as an important cause of retinal and syndromic auditory impairment.

Human mitochondrial disease-like symptoms caused by a reduced tRNA aminoacylation activity in flies

“…As example, an insertion in the mt-tRNA Ser that cause sensorineural hearing loss, results in a reduction in serylation efficiency, a moderate mitochondrial dysfunction, morphological alterations and lactate elevation (65,66). Mutations in mt-tRNA Ser related to Multisystem Disease with Cataracts (67) and deafness, retinal degeneration, myopathy and epilepsy (68) cause defects in mitochondrial function, abnormal mitochondrial morphology and proliferation, and those involved in MELAS/MERRF result in a group of features, such as pleomorphic mitochondria, increment in lactate, decrease in respiratory chain activity and increase in mitochondrial density (69), that coincide with the phenotypes observed in our model. On the other hand, similar symptoms have also been observed in patients with HUPRA syndrome (hyperuricemia, pulmonary hypertension, renal failure in infancy and alkalosis), which is caused by a mutation in the SRS2 gene (18).…”

Splicing Defect in Mitochondrial Seryl-tRNA Synthetase Gene Causes Progressive Spastic Paresis Instead of HUPRA Syndrome

“…The vast majority of mtDNA mutations locate to tRNA genes but mutations affecting tRNA Ser AGY are among the least common tRNA mutations. Instability of tRNA Ser AGY has been reported in fibroblasts of a patient with m.12264C>T mutation, which was associated with myopathy, deafness, neurodevelopmental delay, epilepsy, and marked fatigue [Tuppen et al., ]. This patient's cells had 30% of the control level tRNA Ser AGY .…”

Mitochondrial epilepsy in pediatric and adult patients

“…Syndromic MIDs due to tRNA mutations, which present frequently with mitochondrial epilepsy, include mitochondrial encephalopathy, lactacidosis and stroke‐like episodes (MELAS)‐syndrome or myoclonic epilepsy with ragged‐red fibers (MERRF)‐syndrome . Epilepsy is less frequent in other syndromic MIDs due to tRNA mutations, such as in maternally inherited diabetes and deafness (MIDD) , progressive external ophthalmoplegia (PEO) , or Kearns‐Sayre‐syndrome (KSS) , which is only rarely due to tRNA mutations, and in a number of non‐syndromic MIDs . Epilepsy may be even the sole manifestation of the phenotype in non‐syndromic MIDs due to tRNA(Phe), tRNA(Lys), or tRNA(His) mutations .…”