title: 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.
authors.affiliation: Division and Program in Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA. min-xin.guan@chmcc.org
authors.forename: Min-Xin
authors.initials: MX
authors.lastname: Guan
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Yan
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Li
authors.forename: Yelena
authors.initials: Y
authors.lastname: Bykhovskaya
authors.forename: Jaime
authors.initials: J
authors.lastname: Gallo-Teran
authors.forename: Petr
authors.initials: P
authors.lastname: Hajek
authors.forename: Noriko
authors.initials: N
authors.lastname: Umeda
authors.forename: Hui
authors.initials: H
authors.lastname: Zhao
authors.forename: Gema
authors.initials: G
authors.lastname: Garrido
authors.forename: Emebet
authors.initials: E
authors.lastname: Mengesha
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Suzuki
authors.forename: Ignacio
authors.initials: I
authors.lastname: del Castillo
authors.forename: Jennifer Lynne
authors.initials: JL
authors.lastname: Peters
authors.forename: Ronghua
authors.initials: R
authors.lastname: Li
authors.forename: Yaping
authors.initials: Y
authors.lastname: Qian
authors.forename: Xinjian
authors.initials: X
authors.lastname: Wang
authors.forename: Ester
authors.initials: E
authors.lastname: Ballana
authors.forename: Mordechai
authors.initials: M
authors.lastname: Shohat
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lu
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Kimitsuna
authors.initials: K
authors.lastname: Watanabe
authors.forename: Nathan
authors.initials: N
authors.lastname: Fischel-Ghodsian
mesh_terms: D000595:Amino Acid Sequence; D003638:Deafness / Q000235:genetics*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012313:RNA / Q000235:genetics*; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal / Q000235:genetics*; D012343:RNA, Transfer / Q000378:metabolism*; D012359:tRNA Methyltransferases / Q000235:genetics* / Q000502:physiology
chemical_list: D024101:Mitochondrial Proteins; D000077278:RNA, Mitochondrial; D012335:RNA, Ribosomal; C075526:RNA, ribosomal, 12S; D012313:RNA; D012343:RNA, Transfer; D012359:tRNA Methyltransferases; C496706:TRMU protein, human