The Mitochondrial tRNAHis G12192A Mutation May Modulate the Clinical Expression of Deafness-Associated tRNAThr G15927A Mutation in a Chinese Pedigree

Abstract

Background: Mutations in mitochondrial tRNA (mt-tRNA) genes have been found to be associated with both syndromic and non-syndromic hearing impairment. However, the pathophysiology underlying mt-tRNA mutations in clinical expression of hearing loss remains poorly understood. Objective: The aim of this study was to explore the potential association between mttRNA mutations and hearing loss. Methods and Results: We reported here the molecular features of a pedigree with maternally transmitted non-syndromic hearing loss. Among 12 matrilineal relatives, five of them suffered variable degree of hearing impairment, but none of them had any medical history of using aminoglycosides antibiotics (AmAn). Genetic screening of the complete mitochondrial genomes from the matrilineal relatives identified the coexistence of mt-tRNAHis G12192A and mt-tRNAThr G15927A mutations, together with a set of polymorphisms belonging to human mitochondrial haplogroup B5b1b. Interestingly, the G12192A mutation occurred 2-bp from the 3’ end of the TψC loop of mt-tRNAHis, which was evolutionarily conserved from various species. In addition, the well-known G15927A mutation, which disrupted the highly conserved C-G base-pairing at the anticodon stem of mt-tRNAThr, may lead to the failure in mt-tRNA metabolism. : Furthermore, a significant decreased in ATP production and an increased ROS generation were observed in polymononuclear leukocytes (PMNs) which were isolated from the deaf patients carrying these mt-tRNA mutations, suggested that the G12192A and G15927A mutations may cause mitochondrial dysfunction that was responsible for deafness. However, the absence of any functional mutations/variants in GJB2, GJB3, GJB6 and TRMU genes suggested that the nuclear genes may not play important roles in the clinical expression of non-syndromic hearing loss in this family. Conclusion: Our data indicated that mt-tRNAHis G12192A mutation may increase the penetrance and expressivity of deafness-associated m-tRNAThr G15927A mutation in this family.

Comparative Mitochondrial Genome Analysis of Two Ectomycorrhizal Fungi (Rhizopogon) Reveals Dynamic Changes of Intron and Phylogenetic Relationships of the Subphylum Agaricomycotina

“…In this study, we found that 13 of the 25 tRNA genes shared by Rhizopogon species had site variations between the two Rhizopogon species. Mitochondrial tRNA mutation has been found to affect amino acid transport efficiency and protein synthesis in other eukaryotes [48,49]. The effects of tRNA variations on fungal growth and mitochondrial function are still unknown.…”

Comparative mitogenome analysis of two ectomycorrhizal fungi (Paxillus) reveals gene rearrangement, intron dynamics, and phylogeny of basidiomycetes

“…The tRNA and rRNA genes shared by the two Paxillus species also underwent base and length variations. Base variation in tRNA has been thought to affect the efficiency of amino acid transport and protein synthesis in animals (Ding et al 2019;Lin et al 2019). Further studies are needed to reveal the effect of tRNA variation on the growth and development of basidiomycete species.…”

Screening for deafness-associated mitochondrial 12S rRNA mutations by using a multiplex allele-specific PCR method

“…To analysis the contributions of nuclear genes (GJB2, GJB3, GJB6 and TRMU) in the phenotypic manifestation of A1555G or C1494T-induced deafness, we performed a mutational analysis of these common nuclear genes from the matrilineal relatives (HZD501: II-6, III-4 and III-6; HZD502: III-3 and III-5; HZD503: II-10, III-9 and IV-4) by using the methods as described previously [22]. After PCR amplification and direct Sanger sequence, the data were compared with the wild-type versions of GJB2, GJB3, GJB6 and TRMU sequences (GenBank accession numbers: M86849, AF052692, NG 008323 and AF 448221, respectively) to detect the mutations or variants.…”