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Author Notes:

Email: min-xin.guan@cchmc.org or Shiwen Wang, Institute of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China

Y.L., R.L., and Z.L. contributed equally to this work.

Disclosures: None.

Subjects:

Research Funding:

This work was supported by National Institutes of Health grants RO1DC05230 and RO1DC07696 from the National Institute on Deafness and Other Communication Disorders (to M.-X.G.) and National Key Basic Research and Development Project 973 Fund 2007CB07403 (to S.W.).

Keywords:

  • Adult
  • Asian Continental Ancestry Group
  • Blood Pressure Determination
  • DNA Mutational Analysis
  • DNA, Mitochondrial
  • Genetic Predisposition to Disease
  • Heterozygote
  • Humans
  • Hypertension
  • Male
  • Mitochondrial Proteins
  • Mutation
  • Pedigree
  • RNA, Transfer
  • Risk Assessment

Mitochondrial transfer RNAMet 4435A>G mutation is associated with maternally inherited hypertension in a Chinese pedigree.

Tools:

Journal Title:

Hypertension

Volume:

Volume 53, Number 6

Publisher:

, Pages 1083-1090

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Mitochondrial DNA mutations have been associated with cardiovascular disease. We report here the clinical, genetic, and molecular characterization of 1 Han Chinese family with suggestively maternally transmitted hypertension. Matrilineal relatives in this family exhibited the variable degree of hypertension at the age at onset of 44 to 55 years old. Sequence analysis of entire mitochondrial DNA in this pedigree identified the known homoplasmic 4435A>G mutation, which is located immediately at the 3 prime end to the anticodon, corresponding with the conventional position 37 of tRNA(Met), and 35 other variants belonging to the Asian haplogroup B5a. The adenine (A37) at this position of tRNA(Met) is extraordinarily conserved from bacteria to human mitochondria. This modified A37 was shown to contribute to the high fidelity of codon recognition, the structural formation, and stabilization of functional tRNAs. In fact, a 40% reduction in the levels of tRNA(Met) was observed in cells carrying the 4435A>G mutation. As a result, a failure in mitochondrial tRNA metabolism, caused by the 4435A>G mutation, led to approximately 30% reduction in the rate of mitochondrial translation. However, the homoplasmic form, mild biochemical defect, and late onset of hypertension in subjects carrying the 4435A>G mutation suggest that the 4435A>G mutation itself is insufficient to produce a clinical phenotype. The other modifier factors, such as nuclear modifier genes, environmental, and personal factors may also contribute to the development of hypertension in the subjects carrying this mutation. Our findings imply that the 4435A>G mutation may act as an inherited risk factor for the development of hypertension in this Chinese pedigree.
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