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The tRNAMet 4435A>G mutation in the mitochondrial haplogroup G2a1 is responsible for maternally inherited hypertension in a Chinese pedigree.

Lu Z, Chen H, Meng Y, Wang Y, Xue L, Zhi S, Qiu Q, Yang L, Mo JQ, Guan MX - Eur. J. Hum. Genet. (2011)

Bottom Line: 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, structural formation and stabilization of functional tRNAs.However, 41 other mtDNA variants in this pedigree were the known polymorphisms.

View Article: PubMed Central - PubMed

Affiliation: Emergercy Medical Department, The First Affiliated Hospital of Wenzhou Medical College, Zhejiang, China.

ABSTRACT
Mutations in mitochondrial DNA (mtDNA) have been associated with hypertension in several pedigrees with maternal inheritance. However, the pathophysiology of maternally inherited hypertension remains poorly understood. We reported here clinical, genetic evaluations and molecular analysis of mtDNA in a three-generation Han Chinese family with essential hypertension. Eight of 17 matrilineal relatives exhibited a wide range of severity in essential hypertension, whereas none of the offsprings of the affected father had hypertension. The age-at-onset of hypertension in the maternal kindred varied from 31 to 65 years, with an average of 52 years. Sequence analysis of mtDNA in this pedigree identified the known homoplasmic 4435A>G mutation, which is located at immediately 3' end to the anticodon, corresponding to the conventional position 37 of tRNA(Met), and 41 variants belonging to the Asian haplogroup G2a1. In contrast, the 4435A>G mutation occurred among mtDNA haplogroups B5a, D, M7a2 and J. 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, structural formation and stabilization of functional tRNAs. However, 41 other mtDNA variants in this pedigree were the known polymorphisms. The occurrence of the 4435A>G mutation in two genetically unrelated families affected by hypertension indicates that this mutation is involved in hypertension. Our present investigations further supported our previous findings that the 4435A>G mutation acted as an inherited risk factor for the development of hypertension. Our findings will be helpful for counseling families of maternally inherited hypertension.

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Related in: MedlinePlus

Identification of the 4435A>G mutation in the mitochondrial tRNAMet gene. (a) Partial sequence chromatograms of the tRNAMet gene from affected individual II-6 and a married-in control II-7. An arrow indicates the location of the base changes at position 4435. (b) The location of the 4435A>G mutation in the mitochondrial tRNAMet. The cloverleaf structure of human mitochondrial tRNAMet is derived from Florentz et al32 Arrowhead indicates the position of the 4435A>G mutation.
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fig2: Identification of the 4435A>G mutation in the mitochondrial tRNAMet gene. (a) Partial sequence chromatograms of the tRNAMet gene from affected individual II-6 and a married-in control II-7. An arrow indicates the location of the base changes at position 4435. (b) The location of the 4435A>G mutation in the mitochondrial tRNAMet. The cloverleaf structure of human mitochondrial tRNAMet is derived from Florentz et al32 Arrowhead indicates the position of the 4435A>G mutation.

Mentions: The known 4435A>G mutation in the tRNAMet gene, as shown in Figure 2, is located at immediately 3′ end to the anticodon, corresponding to the conventional position 37 of tRNAMet.32 An adenine at this position is an extraordinarily conserved base in every sequenced methionine tRNA from bacteria to human mitochondria.32, 33 The nucleotide at the position 37 is more prone to modification than those at other places of tRNA.34 The nucleotide modification at this position has been shown to have a pivotal role in the stabilization of tertiary structure and the biochemical function of tRNA.34 To determine if the 4435A>G mutation is present in homoplasmy, the fragments spanning the tRNAMet gene were PCR-amplified and subsequently digested with NlaIII. There was no detectable wild-type DNA in all available matrilineal relatives (data not shown), indicating that the 4435A>G mutation was present in homoplasmy in these matrilineal relatives.


The tRNAMet 4435A>G mutation in the mitochondrial haplogroup G2a1 is responsible for maternally inherited hypertension in a Chinese pedigree.

Lu Z, Chen H, Meng Y, Wang Y, Xue L, Zhi S, Qiu Q, Yang L, Mo JQ, Guan MX - Eur. J. Hum. Genet. (2011)

Identification of the 4435A>G mutation in the mitochondrial tRNAMet gene. (a) Partial sequence chromatograms of the tRNAMet gene from affected individual II-6 and a married-in control II-7. An arrow indicates the location of the base changes at position 4435. (b) The location of the 4435A>G mutation in the mitochondrial tRNAMet. The cloverleaf structure of human mitochondrial tRNAMet is derived from Florentz et al32 Arrowhead indicates the position of the 4435A>G mutation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198143&req=5

fig2: Identification of the 4435A>G mutation in the mitochondrial tRNAMet gene. (a) Partial sequence chromatograms of the tRNAMet gene from affected individual II-6 and a married-in control II-7. An arrow indicates the location of the base changes at position 4435. (b) The location of the 4435A>G mutation in the mitochondrial tRNAMet. The cloverleaf structure of human mitochondrial tRNAMet is derived from Florentz et al32 Arrowhead indicates the position of the 4435A>G mutation.
Mentions: The known 4435A>G mutation in the tRNAMet gene, as shown in Figure 2, is located at immediately 3′ end to the anticodon, corresponding to the conventional position 37 of tRNAMet.32 An adenine at this position is an extraordinarily conserved base in every sequenced methionine tRNA from bacteria to human mitochondria.32, 33 The nucleotide at the position 37 is more prone to modification than those at other places of tRNA.34 The nucleotide modification at this position has been shown to have a pivotal role in the stabilization of tertiary structure and the biochemical function of tRNA.34 To determine if the 4435A>G mutation is present in homoplasmy, the fragments spanning the tRNAMet gene were PCR-amplified and subsequently digested with NlaIII. There was no detectable wild-type DNA in all available matrilineal relatives (data not shown), indicating that the 4435A>G mutation was present in homoplasmy in these matrilineal relatives.

Bottom Line: 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, structural formation and stabilization of functional tRNAs.However, 41 other mtDNA variants in this pedigree were the known polymorphisms.

View Article: PubMed Central - PubMed

Affiliation: Emergercy Medical Department, The First Affiliated Hospital of Wenzhou Medical College, Zhejiang, China.

ABSTRACT
Mutations in mitochondrial DNA (mtDNA) have been associated with hypertension in several pedigrees with maternal inheritance. However, the pathophysiology of maternally inherited hypertension remains poorly understood. We reported here clinical, genetic evaluations and molecular analysis of mtDNA in a three-generation Han Chinese family with essential hypertension. Eight of 17 matrilineal relatives exhibited a wide range of severity in essential hypertension, whereas none of the offsprings of the affected father had hypertension. The age-at-onset of hypertension in the maternal kindred varied from 31 to 65 years, with an average of 52 years. Sequence analysis of mtDNA in this pedigree identified the known homoplasmic 4435A>G mutation, which is located at immediately 3' end to the anticodon, corresponding to the conventional position 37 of tRNA(Met), and 41 variants belonging to the Asian haplogroup G2a1. In contrast, the 4435A>G mutation occurred among mtDNA haplogroups B5a, D, M7a2 and J. 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, structural formation and stabilization of functional tRNAs. However, 41 other mtDNA variants in this pedigree were the known polymorphisms. The occurrence of the 4435A>G mutation in two genetically unrelated families affected by hypertension indicates that this mutation is involved in hypertension. Our present investigations further supported our previous findings that the 4435A>G mutation acted as an inherited risk factor for the development of hypertension. Our findings will be helpful for counseling families of maternally inherited hypertension.

Show MeSH
Related in: MedlinePlus