Mutations in the two ribosomal RNA genes in mitochondrial DNA among Finnish children with hearing impairment

Abstract

BackgroundMutations in the two MT-RNR genes in mitochondrial DNA can cause hearing impairment that presents with variable severity and age of onset. In order to study the prevalence of mutations in MT-RNR1 and MT-RNR2 genes among Finnish children, we studied a ten-year cohort of hearing impaired children born in Northern Finland.MethodsWe studied children, who had been born in Northern Finland in 1993–2002 and who had been ascertained to have hearing impairment by 31 December 2007. Samples from 103 children were sequenced in order to find mutations in the MT-RNR1 and MT-RNR2 genes.ResultsOne child harboured the pathogenic m.1555A > G mutation in MT-RNR1 suggesting a frequency of 4.4/100,000 in the Finnish paediatric population. In addition, eight rare variants and 13 polymorphisms were found in MT-RNR1 and MT-RNR2 genes. Five of the rare variants were deemed to be haplogroup-specific polymorphisms rather than putative pathogenic mutations, while the remaining three variants have been reported in various haplogroups. Among them m.990 T > C occurs at a conserved site.ConclusionsThe presence of m.990 T > C variant in various haplogroups and the rather high degree of conservation at this site suggest that this transition is a pathogenic rather than homoplasic neutral variant. Identification of further patients with m.990 T > C and segregation analysis in their families should help in determining the pathogenic potential of this variant.

Ribosome-Targeting Antibiotics Impair T Cell Effector Function and Ameliorate Autoimmunity by Blocking Mitochondrial Protein Synthesis

“…Mitoribosomes contain 12S and 16S ribosomal RNA (rRNA), encoded by the MT-RNR1 and MT-RNR2 genes, respectively. These rRNAs differ among individuals depending on their mitochondrial haplotype ( Chen et al., 2012 ; Häkli et al., 2015 ; Pacheu-Grau et al., 2010 ). This has the potential to modulate the susceptibility of mitoribosomes to Linezolid ( Pacheu-Grau et al., 2013 ).…”

Mutational Analysis and mtDNA Haplogroup Characterization in Three Serbian Cases of Mitochondrial Encephalomyopathies and Literature Review

“…In Proband one, thirty three different homoplasmic sequence variants were identified; twenty eight of them are haplotypes for haplogroup U2e regarding PhyloTree build 17, included defining mutational haplogroup U markers at m.11467A>G, m.12308A>G and m.12372G>A, and ancestral markers motifs at m.73A>G, m.263A>G, m.750A>G, m.1438A>G, m.2706A>G, m.4769A>G, m.7028C>T, m.8860A>G, m.11719G>A, m.14766C>T and m.15326A>G. All were found to be widely distributed across our sample. Furthermore, the characteristic mutation m.1811A>G for U'2'3'4'7'8'9 the common ancestor of haplogroup U was detected, with subdivision to European U2e on the basis of our finding of characteristic non-coding variants at m.152T>C, m.508A>G, m.15907A>G, m.16051A>G, m.16129G>C and m.16189T>C and the synonymous SNPs at m.3720A>G, m.5390A>G, m.5426T>C, m.6045C>T, m.6152T>C, m.10876A>G and m.13020T>C. The other five variants were detected in our analysis at m.739C>T, m.3116C>T, m.11197C>T, m.13359G>A and m.16183A>C, which are considered nonspecific to haplogroup U2e regarding PhyloTree build 17, although all of them with the exception of m.13359G>A have lower frequencies in haplogroup U2e by Mitomaster analysis (0.29%, 22.71%, 22.42% and 75.52%, respectively) (GenBank ID KY930472.1 and AY339545.1); interestingly, three of them, m.739C>T, m.3116C>T and m.13359G>A, were detected as polymorphisms and pathogenic mutations in different other diseases associated with aminoglycoside-induced hearing loss [94][95][96][97], whereas haplotypes for haplogroup H, a subclass of haplogroup HV, were shown to be associated with the second MELAS proband. Ancestral marker motifs were detected at m.263A>G, m.750A>G, m.1438A>G, m.4769A>G, m.8860A>G, m.15326A>G, and m.16519C>T; haplogroup H selected markers were detected at m.2706G>A and m.7028C>T. This MELAS proband was characterized as the H15 subclass, and we detected variants for haplogroup H15 at m.55T>C and m.6253T>C which further subdivided to H15b in the presence of m.3847T>C. In addition we detected two other non-coding variants: insertion C at m.56, which has very low frequency in association to haplogroup H15b on MITOMASTER (GenBank ID KF162889.1), and m.143G>A that did not reported previously in association to that haplogroup.…”

Mitochondrial translation defects and human disease

“…Mutations in MTRNR1 are associated with hearing impairment with or without aminoglycoside exposure. The MTRNR1 mutations m.1555A>G [38] and m.1494C>T [39] have been described as a cause of maternally inherited deafness in numerous case reports but the phenotype is variable and not completely penetrant. The identification of a pedigree in which deafness manifested when the m.1555A>G variant was co-inherited with a loss-of-function SSBP1 variant suggests that SSBP1 may be a phenotypic modifier of m.1555A>G-associated deafness [40] .…”