Biochemical characterization of the mitochondrial tRNASer(UCN) T7511C mutation associated with nonsyndromic deafness

被引:111
作者
Li, XM
Fischel-Ghodsian, N
Schwartz, F
Yan, QF
Friedman, RA
Guan, MX
机构
[1] Childrens Hosp, Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA
[2] Childrens Hosp, Med Ctr, Program Human Genet, Cincinnati, OH 45229 USA
[3] Childrens Hosp, Med Ctr, Ctr Hearing & Deafness Res, Cincinnati, OH 45229 USA
[4] Cedars Sinai Med Ctr, Ahmanson Dept Pediat, Los Angeles, CA 90048 USA
[5] Boston Univ, Sch Med, Boston, MA 02118 USA
[6] House Ear Clin, Los Angeles, CA 90057 USA
[7] House Ear Res Inst, Los Angeles, CA USA
[8] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA
关键词
D O I
10.1093/nar/gkh226
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
We report here the biochemical characterization of the deafness-associated mitochondrial tRNA(Ser(UCN)) T7511C mutation, in conjunction with homoplasmic ND1 T3308C and tRNA(Ala) T5655C mutations using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from an African family into human mtDNA-less (rho(o)) cells. Three cybrids derived from an affected matrilineal relative carrying the homoplasmic T7511C mutation, exhibited similar to75% decrease in the tRNA(Ser(UCN)) level, compared with three control cybrids. This amount of reduction in the tRNA(Ser(UCN)) level is below a proposed threshold to support a normal rate of mitochondrial protein synthesis in lymphoblastoid cell lines. This defect is likely a primary contributor to similar to52% reduction in the rate of mitochondrial protein synthesis and marked defects in respiration and growth properties in galactose-containing medium. Interestingly, the T5655C mutation produces similar to50% reduction in the tRNA(Ala) level in mutant cells. Strikingly, the T3308C mutation causes a significant decrease both in the amount of ND1 mRNA and co-transcribed tRNA(Leu(UUR)) in mutant cells. Thus, mitochondrial dysfunctions caused by the T5655C and T3308C mutations may modulate the phenotypic manifestation of the T7511C mutation. These observations imply that a combination of the T7511C mutation with two mtDNA mutations accounts for the high penetrance of deafness in this family.
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页码:867 / 877
页数:11
相关论文
共 52 条
  • [1] SEQUENCE AND ORGANIZATION OF THE HUMAN MITOCHONDRIAL GENOME
    ANDERSON, S
    BANKIER, AT
    BARRELL, BG
    DEBRUIJN, MHL
    COULSON, AR
    DROUIN, J
    EPERON, IC
    NIERLICH, DP
    ROE, BA
    SANGER, F
    SCHREIER, PH
    SMITH, AJH
    STADEN, R
    YOUNG, IG
    [J]. NATURE, 1981, 290 (5806) : 457 - 465
  • [2] Anderson S., 1982, MITOCHONDRIAL GENES, P5
  • [3] Two large French pedigrees with non syndromic sensorineural deafness and the mitochondrial DNA T7511C mutation:: evidence for a modulatory factor
    Chapiro, E
    Feldmann, D
    Denoyelle, F
    Sternberg, D
    Jardel, C
    Eliot, MM
    Bouccara, D
    Weil, D
    Garabédian, EN
    Couderc, R
    Petit, C
    Marlin, S
    [J]. EUROPEAN JOURNAL OF HUMAN GENETICS, 2002, 10 (12) : 851 - 856
  • [4] Chomyn A, 1996, Methods Enzymol, V264, P197, DOI 10.1016/S0076-6879(96)64020-8
  • [5] The mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode syndrome-associated human mitochondrial tRNALeu(UUR) mutation causes aminoacylation deficiency and concomitant reduced association of mRNA with ribosomes
    Chomyn, A
    Enriquez, JA
    Micol, V
    Fernandez-Silva, P
    Attardi, G
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (25) : 19198 - 19209
  • [6] Control region mtDNA variants: Longevity, climatic adaptation, and a forensic conundrum
    Coskun, PE
    Ruiz-Pesini, E
    Wallace, DC
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (05) : 2174 - 2176
  • [7] del Castillo F J, 2002, J Med Genet, V39, pe82, DOI 10.1136/jmg.39.12.e82
  • [8] MTDNA MUTATION IN MERRF-SYNDROME CAUSES DEFECTIVE AMINOACYLATION OF TRNA(LYS) AND PREMATURE TRANSLATION TERMINATION
    ENRIQUEZ, JA
    CHOMYN, A
    ATTARDI, G
    [J]. NATURE GENETICS, 1995, 10 (01) : 47 - 55
  • [9] Familial progressive sensorineural deafness is mainly due to the mtDNA A1555G mutation and is enhanced by treatment with aminoglycosides
    Estivill, X
    Govea, N
    Barceló, A
    Perelló, E
    Badenas, C
    Romero, E
    Moral, L
    Scozzari, R
    D'Urbano, L
    Zeviani, M
    Torroni, A
    [J]. AMERICAN JOURNAL OF HUMAN GENETICS, 1998, 62 (01) : 27 - 35
  • [10] Fischel-Ghodsian N, 1999, HUM MUTAT, V13, P261, DOI 10.1002/(SICI)1098-1004(1999)13:4<261::AID-HUMU1>3.0.CO