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(Hypertension. 2009;53:1083.)
© 2009 American Heart Association, Inc.

Original Articles

Mitochondrial Transfer RNA^Met 4435A>G Mutation Is Associated With Maternally Inherited Hypertension in a Chinese Pedigree

Yuqi Liu; Ronghua Li; Zongbin Li; Xin-Jian Wang; Li Yang; Shiwen Wang; Min-Xin Guan

From the Institute of Geriatric Cardiology (Y.L., Z.L., S.W.), Chinese People’s Liberation Army General Hospital, Beijing, China; Division of Human Genetics (R.L., X.-J.W., L.Y., M.-X.G.), Cincinnati Children’s Hospital Medical Center, Ohio; and the Department of Pediatrics (M.-X.G.), University of Cincinnati College of Medicine, Ohio.

Correspondence to Min-Xin Guan, Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45229-3039. E-mail min-xin.guan{at}cchmc.org or Shiwen Wang, Institute of Geriatric Cardiology, Chinese PLA General Hospital, Beijing, China.

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 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.

Key Words: hypertension • mitochondria • mutation • tRNA metabolism • maternal inheritance • risk factor • Chinese

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