Failures in Mitochondrial tRNA and tRNA Metabolism Caused by the Novel 4401A>G Mutation Are Involved in Essential Hypertension in a Han Chinese Family

We report here on the clinical, genetic, and molecular characterization of 1 Han Chinese family with maternally transmitted hypertension. Three of 7 matrilineal relatives in this 4-generation family exhibited the variable degree of essential hypertension at the age at onset, ranging from 35 to 60 years old. Sequence analysis of the complete mitochondrial DNA in this pedigree identified the novel homoplasmic 4401A G mutation localizing at the spacer immediately to the 5 end of tRNA and tRNA genes and 39 other variants belonging to the Asian haplogroup C. The 4401A G mutation was absent in 242 Han Chinese controls. Approximately 30% reductions in the steady-state levels of tRNA and tRNA were observed in 2 lymphoblastoid cell lines carrying the 4401A G mutation compared with 2 control cell lines lacking this mutation. Failures in mitochondrial metabolism are apparently a primary contributor to the reduced rate of mitochondrial translation and reductions in the rate of overall respiratory capacity, malate/glutamatepromoted respiration, succinate/glycerol-3-phosphate–promoted respiration, or N,N,N ,N -tetramethyl-p-phenylenediamine/ ascorbate-promoted respiration in lymphoblastoid cell lines carrying the 4401A G mutation. The homoplasmic form, mild biochemical defect, late onset, and incomplete penetrance of hypertension in this family suggest that the 4401A G mutation itself is insufficient to produce a clinical phenotype. Thus, the other modifier factors, eg, nuclear modifier genes and environmental and personal factors, may also contribute to the development of hypertension in these subjects carrying this mutation. These data suggest that mitochondrial dysfunctions, caused by the 4401A G mutation, are involved in the development of hypertension in this Chinese pedigree. (Hypertension. 2009;54:00-00.)