Mutation in TRMU Related to Transfer RNA Modification Modulates the Phenotypic Expression of the Deafness-Associated Mitochondrial 12S Ribosomal RNA Mutations

Abstract

The human mitochondrial 12S ribosomal RNA (rRNA) A1555G mutation has been associated with aminoglycoside-induced and nonsyndromic deafness in many families worldwide. Our previous investigation revealed that the A1555G mutation is a primary factor underlying the development of deafness but is not sufficient to produce a deafness phenotype. However, it has been proposed that nuclear-modifier genes modulate the phenotypic manifestation of the A1555G mutation. Here, we identified the nuclear-modifier gene TRMU, which encodes a highly conserved mitochondrial protein related to transfer RNA (tRNA) modification. Genotyping analysis of TRMU in 613 subjects from 1 Arab-Israeli kindred, 210 European (Italian pedigrees and Spanish pedigrees) families, and 31 Chinese pedigrees carrying the A1555G or the C1494T mutation revealed a missense mutation (G28T) altering an invariant amino acid residue (A10S) in the evolutionarily conserved N-terminal region of the TRMU protein. Interestingly, all 18 Arab-Israeli/Italian-Spanish matrilineal relatives carrying both the TRMU A10S and 12S rRNA A1555G mutations exhibited prelingual profound deafness. Functional analysis showed that this mutation did not affect importation of TRMU precursors into mitochondria. However, the homozygous A10S mutation leads to a marked failure in mitochondrial tRNA metabolisms, specifically reducing the steady-state levels of mitochondrial tRNA. As a consequence, these defects contribute to the impairment of mitochondrial-protein synthesis. Resultant biochemical defects aggravate the mitochondrial dysfunction associated with the A1555G mutation, exceeding the threshold for expressing the deafness phenotype. These findings indicate that the mutated TRMU, acting as a modifier factor, modulates the phenotypic manifestation of the deafness-associated 12S rRNA mutations.

Mitochondrial deafness alleles confer misreading of the genetic code

“…The nuclear-encoded proteins thus far linked to the expression of the deafness phenotype are involved in mitochondrial tRNA or rRNA modifications (32)(33)(34). On the basis of a misreadingprone ribosome, any change in translational efficiency, regard- (24), showing the bacterial G1410 -C1490 base pair, which corresponds to the homologous C1494⅐A1555 interaction in human mitochondrial 12S rRNA.…”

Whole mitochondrial genome screening in maternally inherited non-syndromic hearing impairment using a microarray resequencing mitochondrial DNA chip

“…For instance, the common mtDNA mutation A1555G is strictly associated with maternally transmitted sensorineural hearing loss and represents a clear validation of the 'two-hit' model for nuclear -mitochondrial pathologic interaction, as the A1555G mutation is expressed in association with an additional factor such as aminoglycoside, antibiotics and nuclear modifier genes have been recently related to the disease. 5,6 Thus, the penetrance of deafness within the families can be highly variable and mitochondrial deafness is probably underestimated.…”

The 12S rRNA A1555G mutation in the mitochondrial haplogroup D5a is responsible for maternally inherited hypertension and hearing loss in two Chinese pedigrees

“…The Bsp1286I-digested products were analyzed on 1.5% agarose gels. 26 The PCR segments were subsequently analyzed by direct sequencing in an ABI 3700-automated DNA sequencer using the Big Dye Terminator Cycle sequencing reaction kit. The resultant sequence data were compared with the TRMU genomic sequence (GenBank accession number AF448221).…”

“…The resultant sequence data were compared with the TRMU genomic sequence (GenBank accession number AF448221). 26 …”

“…31 Mutational analysis of TRMU gene Our previous study showed that the TRMU A10S mutation modulated the phenotypic manifestation of the A1555G mutation in the Israeli/ European pedigrees. 26 To assess if the TRMU A10S variant also has a role in phenotypic expression of the A1555G mutation in these Chinese families, we carried out a mutational screening of exon 1 in TRMU gene in eight affected matrilineal relatives of these pedigrees. We failed to detect any variant in TRMU exon 1 in these matrilineal relatives of these Chinese pedigrees.…”