Maternally transmitted nonsyndromic hearing impairment may be associated with mitochondrial tRNA^Ala 5601C>T and tRNA^Leu(CUN) 12311T>C mutations

Abstract

Background: Sequence alternations in mitochondrial genomes, especially in genes encoding mitochondrial tRNA (mt-tRNA), were the important contributors to nonsyndromic hearing loss (NSHL); however, the molecular mechanisms remained largely undetermined. Methods:A maternally transmitted Chinese pedigree with NSHL underwent clinical, genetic, and biochemical assessment. PCR and direct sequence analyses were performed to detect mitochondrial DNA (mtDNA), GJB2, and SLC26A4 gene mutations from matrilineal relatives of this family. Mitochondrial functions including mitochondrial membrane potential (MMP), ATP, and ROS were evaluated in polymononuclear leukocytes (PMNs) derived from three deaf patients and three controls from this pedigree.Results: Four of nine matrilineal relatives developed hearing loss at the variable age of onset. Two putative pathogenic mutations, m.5601C>T in tRNA Ala and m.12311T>C in tRNA Leu(CUN) , were identified via PCR-Sanger sequencing, as well as 34 variants that belonged to mtDNA haplogroup G2b2. Intriguingly, m.5601C>T mutation resided at very conserved nucleotide in the TψC loop of tRNA Ala (position 59), while the T-to-C substitution at position 12311 located at position 48 in the variable stem of tRNA Leu(CUN) and was believed to alter the aminoacylation and the steady-state level of tRNA. Biochemical analysis revealed the impairment of mitochondrial functions including the significant reductions of ATP and MMP, whereas markedly increased ROS levels were found in PMNs derived from NSHL patients with m.5601C>T and m.12311T>C mutations. However, we did not detect any mutations in GJB2 and SLC26A4 genes. Conclusion:Our data indicated that mt-tRNA Ala m.5601C>T and tRNA Leu(CUN) 12311T>C mutations were associated with NSHL.

4‐octyl itaconate improves the viability of D66H cells by regulating the KEAP1‐NRF2‐GCLC/HO‐1 pathway

“…32,33 This process would be possibly explained by oxidation, which was revealed in the hair cell damage caused by GJB2 gene mutations. 34 These results were consistent with the findings revealed in our study, showing that the D66H mutation could promote oxidative damage that disturbed the balance between apoptosis and proliferation in keratinized epithelial cells.…”

“…This intercellular communication mainly relies on the junction protein, that is the CX26, which regulates the balance between apoptosis and proliferation to determine the survival of early cells 32,33 . This process would be possibly explained by oxidation, which was revealed in the hair cell damage caused by GJB2 gene mutations 34 . These results were consistent with the findings revealed in our study, showing that the D66H mutation could promote oxidative damage that disturbed the balance between apoptosis and proliferation in keratinized epithelial cells.…”

Mitochondrial Diabetes Is Associated with the ND4 G11696A Mutation

“…At the molecular level, the m.C5601T mutation resided at the extremely conserved nucleotide of tRNA Ala (position 59); the mutation at that position was involved in the biochemical and molecular interactions between the TψC loop and D-arm [ 49 ]. Importantly, the m.C5601T mutation created a novel Watson–Crick base-pairing (55T-59C) [ 32 , 33 , 34 ]. Furthermore, the novel m.T5813C mutation occurred at position 14 in the D-arm of tRNA Cys ; intriguingly, the m.T7501C mutation, which was located at the same position of tRNA Ser(UCN) , was found to be associated with cardiovascular diseases [ 50 , 51 ].…”

The Association Between Mitochondrial tRNAGlu Variants and Hearing Loss: A Case-Control Study

“… 15 The PTA was performed in a sound-controlled room at frequencies ranging from 250 to 8000 Hz, as suggested in a recent study. 16 The levels of hearing loss were divided into five grades according to a previous study: normal: <20 decibels (dB); mild: 20–40 dB; moderate: 41–70 dB; severe: 71–95 dB; and profound >95 dB. 17 …”