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

Guan, Min-Xin and Yan, Qingfeng and Li, Xiaoming and Bykhovskaya, Yelena and Gallo-Teran, Jaime and Hajek, Petr and Umeda, Noriko and Zhao, Hui and Garrido, Gema and Mengesha, Emebet and Suzuki, Tsutomu and del Castillo, Ignacio and Peters, Jennifer Lynne and Li, Ronghua and Qian, Yapin and Wang, Xinjian and Ballana, Ester and Shohat, Mordechai and Lu, Jianxin and Estivill, Xavier and Watanabe, Kimitsuna and Fischel-Ghodsian, Nathan (2006) Mutation in TRMU Related to Transfer RNA Modification Modulates the Phenotypic Expression of the Deafness-Associated Mitochondrial 12S Ribosomal RNA Mutations. American Journal of Human Genetics, 79 (2). pp. 291-302. ISSN 0002-9297. PMCID PMC1559489. https://resolver.caltech.edu/CaltechAUTHORS:20110630-093925007

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1086/506389 DOIArticle
http://www.sciencedirect.com/science/article/pii/S000292970763136XPublisherArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1559489/PubMed CentralArticle
Additional Information:© 2006 The American Society of Human Genetics; Published by Elsevier Inc. 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.
Funders:
Funding AgencyGrant Number
NIHRO1DC05230
NIHRO3DC04958
NIHRO1DC01402
Fundacion Ramon Areces UNSPECIFIED
Programa Ramon y CajalUNSPECIFIED
Issue or Number:2
PubMed Central ID:PMC1559489
Record Number:CaltechAUTHORS:20110630-093925007
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20110630-093925007
Official Citation:Min-Xin Guan, Qingfeng Yan, Xiaoming Li, Yelena Bykhovskaya, Jaime Gallo-Teran, Petr Hajek, Noriko Umeda, Hui Zhao, Gema Garrido, Emebet Mengesha, Tsutomu Suzuki, Ignacio del Castillo, Jennifer Lynne Peters, Ronghua Li, Yaping Qian, Xinjian Wang, Ester Ballana, Mordechai Shohat, Jianxin Lu, Xavier Estivill, Kimitsuna Watanabe, Nathan Fischel-Ghodsian, Mutation in TRMU Related to Transfer RNA Modification Modulates the Phenotypic Expression of the Deafness-Associated Mitochondrial 12S Ribosomal RNA Mutations, The American Journal of Human Genetics, Volume 79, Issue 2, August 2006, Pages 291-302, ISSN 0002-9297, DOI: 10.1086/506389. (http://www.sciencedirect.com/science/article/pii/S000292970763136X)
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:24266
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:30 Jun 2011 17:30
Last Modified:03 Oct 2019 02:54

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