Welcome to the new version of CaltechAUTHORS. Login is currently restricted to library staff. If you notice any issues, please email coda@library.caltech.edu
Published August 2006 | public
Journal Article

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.

Additional Information

© 2006 The American Society of Human Genetics; Published by Elsevier Inc. Under an Elsevier user license. Received 7 March 2006; accepted 12 May 2006. Available online 23 December 2007. This work was supported by Public Health Service grants RO1DC05230 and RO3DC04958 from the National Institute on Deafness and Other Communication Disorders and RO1NS44015 from the National Institute of Neurological Disorders and Stroke (to M.-X.G.) and grant RO1DC01402 from the National Institute on Deafness and Other Communication Disorders (to N.F.-G.) and by grants from Fundacion Ramon Areces and Programa Ramon y Cajal (to I.d.C.). We thank Drs. Gregory Grabowski, John Greinwald, and Richard Wenstrup, for control and deaf DNA samples, and Dr. Fernandez-Silva, for suggestion of mitochondrial-import experiments. We thank Professor Des Clark-Walker for critical comments of this manuscript. We are grateful to Chuck Loftice,William Gibbson, and Li Yang for skilled technical assistance.

Additional details

Created:
August 19, 2023
Modified:
October 23, 2023