title: Maternally inherited essential hypertension is associated with the novel 4263A>G mutation in the mitochondrial tRNAIle gene in a large Han Chinese family.
abstract: BACKGROUND
  Despite maternal transmission of hypertension in some pedigrees, pathophysiology of maternally inherited hypertension remains poorly understood.
  
  
  OBJECTIVE
  To establish a causative link between mitochondrial dysfunction and essential hypertension.
  
  
  RESULTS
  A total of 106 subjects from a large Chinese family underwent clinical, genetic, molecular, and biochemical evaluations. Fifteen of 24 adult matrilineal relatives exhibited a wide range of severity in essential hypertension, whereas none of the offspring of affected fathers had hypertension. The age at onset of hypertension in the maternal kindred varied from 20 years to 69 years, with an average of 44 years. Mutational analysis of their mitochondrial genomes identified a novel homoplasmic 4263A>G mutation located at the processing site for the tRNA(Ile) 5'-end precursor. An in vitro processing analysis showed that the 4263A>G mutation reduced the efficiency of the tRNA(Ile) precursor 5'-end cleavage catalyzed by RNase P. tRNA Northern analysis revealed that the 4263A>G mutation caused ≈46% reduction in the steady-state level of tRNA(Ile). An in vivo protein-labeling analysis showed ≈32% reduction in the rate of mitochondrial translation in cells carrying the 4263A>G mutation. Impaired mitochondrial translation is apparently a primary contributor to the reductions in the rate of overall respiratory capacity, malate/glutamate-promoted respiration, succinate/glycerol-3-phosphate-promoted respiration, or N,N,N',N'-tetramethyl-p-phenylenediamine/ascorbate-promoted respiration and the increasing level of reactive oxygen species in cells carrying the 4263A>G mutation.
  
  
  CONCLUSIONS
  These data provide direct evidence that mitochondrial dysfunction caused by mitochondrial tRNA(Ile) 4263A>G mutation is involved in essential hypertension. Our findings may provide new insights into pathophysiology of maternally transmitted hypertension.
authors: Institute of Genetics, Zhejiang University, Hangzhou, Zhejiang, China. wangshiwen4290@163.com
authors: Shiwen
authors: S
authors: Wang
authors: Ronghua
authors: R
authors: Li
authors: Andrea
authors: A
authors: Fettermann
authors: Zongbin
authors: Z
authors: Li
authors: Yaping
authors: Y
authors: Qian
authors: Yuqi
authors: Y
authors: Liu
authors: Xinjian
authors: X
authors: Wang
authors: Anna
authors: A
authors: Zhou
authors: Jun Qin
authors: JQ
authors: Mo
authors: Li
authors: L
authors: Yang
authors: Pingping
authors: P
authors: Jiang
authors: Andreas
authors: A
authors: Taschner
authors: Walter
authors: W
authors: Rossmanith
authors: Min-Xin
authors: MX
authors: Guan
mesh_terms: D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000235:genetics; D002681:China; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D006801:Humans; D006973:Hypertension / Q000208:ethnology* / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation / Q000235:genetics*; D012355:RNA, Transfer, Ile / Q000235:genetics*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D012355:RNA, Transfer, Ile; D017382:Reactive Oxygen Species