RESUMEN

INTRODUCTION: Methylenetetrahydrofolate reductase (MTHFR) is essential in mediating folate metabolism, and thus plays an important role in diabetes and diabetic complications. MTHFR C677T (rs1801133 C>T) polymorphism has been proposed to be linked with type 2 diabetes mellitus (T2DM) susceptibility. However, the conclusions are inconsistent. Therefore, we rechecked their linkage aiming to obtain a more reliable estimation by performing an updated meta-analysis. METHODS: We searched electronic databases PubMed, EMBASE, CNKI, and Wanfang to obtain studies updated to October 2019. RESULTS: After carefully screening, we finally incorporated 68 studies with 10,812 cases and 8,745 controls. The genotype frequency of C677T polymorphism was analyzed pooled to generate odds ratios (ORs) and 95% confidence intervals (CIs). Pooled results presented that MTHFR C677T polymorphism was significantly associated with T2DM under homozygous (OR = 1.64, 95% CI = 1.39-1.94), heterozygous (OR = 1.38, 95% CI = 1.20-1.59), recessive (OR = 1.41, 95% CI = 1.23-1.61), dominant (OR = 1.47, 95% CI = 1.27-1.70), and allele (OR = 1.37, 95% CI = 1.23-1.52) genetic models. Stratified analysis demonstrated that C677T genotype was associated with T2DM in Asian populations, but not Caucasian and African populations. CONCLUSION: Our results indicated that MTHFR C677T polymorphism confers to T2DM, especially in Asian populations. Much more large-scale case-control studies are needed to strengthen such conclusion in the future.

Asunto(s)

Pueblo Asiatico/genética , Diabetes Mellitus Tipo 2/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Oportunidad Relativa

RESUMEN

Mitochondrial tRNA genes are the hot spots for mutations associated with essential hypertension. We report here the clinical and molecular genetic characterization of two Han Chinese pedigrees with materially inherited essential hypertension. Clinical evaluation revealed the variable severity and age-at-onset of hypertension among matrilineal relatives. In particular, the age-at-onset of hypertension in the maternal kindred ranged from 36 years to 79 years. The sequence analysis of entire mitochondrial genome in two probands showed that two probands carried the identical homoplasmic tRNAMet/tRNAGlnA4401G and tRNACysG5821A mutations and distinct sets of polymorphisms belonging to East Asian haplogroup C. The A4401G mutation may affect the processing of the precursors of tRNAMet and tRNAGln , thereby altering the tRNA metabolism. The tRNACys G5821A mutation is located in the acceptor stem of tRNACys. This mutation may abol-ish the predicted G6-C67 pairing and consequently affect the structure and stability of mitochondrial tRNACys, thereby leading to mitochondrial dysfunction. Therefore, these data suggested that the tRNAMet/tRNAGlnA4401G and tRNACys G5821A mutations are likely associated with essential hypertension in these two Chinese pedigrees.

Asunto(s)

Pueblo Asiatico/etnología , Etnicidad/genética , Hipertensión/genética , Mitocondrias/genética , Mutación , Linaje , ARN de Transferencia Aminoácido-Específico/genética , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Secuencia de Bases , Niño , Femenino , Genotipo , Humanos , Hipertensión/etnología , Masculino , Persona de Mediana Edad , ARN de Transferencia de Cisteína/genética , ARN de Transferencia de Glutamina/genética , ARN de Transferencia de Metionina/genética

RESUMEN

Coronary heart disease (CHD) is the leading cause of death worldwide. Mitochondrial genetic determinant for the development of CHD remains poorly explored. We report there the clinical, genetic, molecular and biochemical characterization of a four-generation Chinese family with maternally inherited CHD. Thirteen of 32 adult members in this family exhibited variable severity and age-at-onset of CHD. Mutational analysis of their mitochondrial genomes identified the tRNA(Thr) 15927G>A mutation belonging to the Eastern Asian haplogroup B5. The anticipated destabilization of a highly conserved base-pairing (28C-42G) by the 15927G>A mutation affects structure and function of tRNA(Thr). Northern analysis revealed ≈80% decrease in the steady-state level of tRNA(Thr) in the mutant cell lines carrying the 15927G>A mutation. The 15927G>A mutation changed the conformation of tRNA(Thr), as suggested by slower electrophoretic mobility of mutated tRNA with respect to the wild-type molecule. In addition, ∼39% reduction in aminoacylated efficiency of tRNA(Thr) was observed in mutant cells derived from this Chinese family. An in vivo mitochondrial protein labeling analysis showed ∼53% reduction in the rate of mitochondrial translation in mutant cells. The impaired mitochondrial protein synthesis leads to defects in overall respiratory capacity or malate/glutamate-promoted respiration or succinate/glycerol-3-phosphate-promoted respiration, or N,N,N',N'-tetramethyl-pphenylenediamine/ascorbate-promoted respiration in mutant cells. An increasing production of reactive oxygen species was observed in the mutant cells carrying the 15927G>A mutation. These results provide the direct evidence that the tRNA(Thr) 15927G>A mutation is associated with CHD. Our findings may provide new insights into pathophysiology and intervention targets of this disorder.

Asunto(s)

Enfermedad Coronaria/genética , Mitocondrias/genética , Mitocondrias/metabolismo , Mutación Puntual , ARN de Transferencia de Treonina/genética , ARN/genética , Adulto , Anciano , Anciano de 80 o más Años , Pueblo Asiatico/genética , Línea Celular , Respiración de la Célula , Enfermedad Coronaria/fisiopatología , Femenino , Genes Mitocondriales , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Proteínas Mitocondriales/biosíntesis , Proteínas Mitocondriales/genética , Consumo de Oxígeno , Linaje , ARN/metabolismo , ARN Mitocondrial , ARN de Transferencia de Treonina/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Aminoacilación de ARN de Transferencia , Adulto Joven

RESUMEN

We reported here clinical, genetic evaluations and molecular analysis of mitochondrial DNA (mtDNA) in two Han Chinese families carrying the known mitochondrial 12S rRNA A1555G mutation. In contrast with the previous data that hearing loss as a sole phenotype was present in the maternal lineage of other families carrying the A1555G mutation, matrilineal relatives among these two Chinese families exhibited both hearing loss and hypertension. Of 21 matrilineal relatives, 9 subjects exhibited both hearing loss and hypertension, 2 individuals suffered from only hypertension and 1 member had only hearing loss. The average age at onset of hypertension in the affected matrilineal relatives of these families was 60 and 46 years, respectively, whereas those of hearing loss in these two families were 33 and 55 years, respectively. Molecular analysis of their mtDNA identified distinct sets of variants belonging to the Eastern Asian haplogroup D5a. In contrast, the A1555G mutation occurred among other mtDNA haplogroups D, B, R, F, G, Y, M and N, respectively. Our data further support that the A1555G mutation is necessary but by itself insufficient to produce the clinical phenotype. The other modifiers are responsible for the phenotypic variability of matrilineal relatives within and among these families carrying the A1555G mutation. Our investigation provides the first evidence that the 12S rRNA A1555G mutation leads to both of hearing loss and hypertension. Thus, our findings may provide the new insights into the understanding of pathophysiology and valuable information for management and treatment of maternally inherited hearing loss and hypertension.

Asunto(s)

Pérdida Auditiva/etnología , Pérdida Auditiva/genética , Hipertensión/etnología , Hipertensión/genética , Mitocondrias/metabolismo , Mutación , ARN Ribosómico/genética , Adulto , Anciano , Pueblo Asiatico/genética , Secuencia de Bases , ADN Mitocondrial/química , Femenino , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje , Fenotipo , Filogenia , ARN Ribosómico/metabolismo

RESUMEN

Mutations in mitochondrial DNA (mtDNA) are one of the molecular bases of hypertension. Among these, the tRNAMet A4435G, tRNAMet/tRNAGln A4401G, tRNAIle A4263G, T4291C and A4295G mutations have been reported to be associated with essential hypertension. These mutations alter the structure of the corresponding mitochondrial tRNAs and cause failures in tRNA metabolism. These shortages of these tRNAs lead to an impairment of mitochondrial protein synthesis and a failure in the oxidative phosphorylation function. These result in a deficit in ATP synthesis and an increase of generation of reactive oxygen species. As a result, these mitochondrial dysfunctions may contribute to the development of hypertension. Furthermore, the tissue specificity of these pathogenic mtDNA mutations might be associated with tRNA metabolism and nuclear modifier genes. These mtDNA mutations should be considered as inherited risk factors for future molecular diagnosis. Thus, these findings provide new insights into the molecular mechanism, management and treatment of maternally inherited hypertension. This review summarized the association between mtDNA mutations and hypertension.

Asunto(s)

ADN Mitocondrial/genética , Hipertensión/genética , Secuencia de Bases , Humanos , Mutación , Conformación de Ácido Nucleico , ARN de Transferencia/genética

RESUMEN

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.

Asunto(s)

ADN Mitocondrial/química , Hipertensión/genética , Mutación , ARN de Transferencia de Metionina/genética , Adulto , Anciano , Pueblo Asiatico/genética , Secuencia de Bases , China , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Linaje

RESUMEN

We report here the clinical, genetic, and molecular evaluations of four Han Chinese families with Leber's hereditary optic neuropathy. Thirty-one (20 males/11 females) of 83 matrilineal relatives in these families exhibited the variable severity and age-at-onset in visual impairment. The average age-of-onset of vision loss was 22years old. Strikingly, these penetrances of visual impairment in these Chinese families were higher than those in other 11 Chinese pedigrees carrying the only ND4 G11778A mutation. Molecular analysis identified the known G11778A mutation and distinct sets of variants belonging to the Asian haplogroups M10a and M7c2. Of these, the T14502C mutation caused the substitution of a highly conserved isoleucine for valine at position 58 in ND6. This mutation has been associated with LHON in other Chinese families with very low penetrance of LHON. Thus, the deficient activities of complex I, caused by G11778A mutation, would be worsened by the T14502C mutation in these four Chinese families. As a result, mitochondrial dysfunctions would lead to the high penetrance and expressivity of visual loss in these Chinese families carrying both G11778A and T14502C mutations than other 11 Chinese families carrying only G11778A mutation. These data suggested that the T14502C variant may modulate the phenotypic manifestation of the G11778A mutation in these Chinese pedigrees.

Asunto(s)

NADH Deshidrogenasa/genética , Atrofia Óptica Hereditaria de Leber/genética , Atrofia Óptica Hereditaria de Leber/fisiopatología , Adulto , Pueblo Asiatico/genética , China , Femenino , Humanos , Masculino , Mutación , Linaje , Adulto Joven

RESUMEN

Mitochondrial 12S rRNA 1555A>G mutation is one of the important causes of aminoglycoside-induced and nonsyndromic deafness. Our previous investigations showed that the A1555G mutation was a primary factor underlying the development of deafness but was insufficient to produce deafness phenotype. However, it has been proposed that mitochondrial haplotypes modulate the phenotypic manifestation of the 1555A>G mutation. Here, we performed systematic and extended mutational screening of 12S rRNA gene in a cohort of 1742 hearing-impaired Han Chinese pediatric subjects from Zhejiang Province, China. Among these, 69 subjects with aminoglycoside-induced and nonsyndromic deafness harbored the homoplasmic 1555A>G mutation. These translated to a frequency of approximately 3.96% for the 1555A>G mutation in this hearing-impaired population. Clinical and genetic characterizations of 69 Chinese families carrying the 1555A>G mutation exhibited a wide range of penetrance and expressivity of hearing impairment. The average penetrances of deafness were 29.5% and 17.6%, respectively, when aminoglycoside-induced hearing loss was included or excluded. Furthermore, the average age-of-onset for deafness without aminoglycoside exposure ranged from 5 and 30years old, with the average of 14.5years. Their mitochondrial genomes exhibited distinct sets of polymorphisms belonging to ten Eastern Asian haplogroups A, B, C, D, F, G, M, N, R and Y, respectively. These indicated that the 1555A>G mutation occurred through recurrent origins and founder events. The haplogroup D accounted for 40.6% of the patient's mtDNA samples but only 25.8% of the Chinese control mtDNA samples. Strikingly, these Chinese families carrying mitochondrial haplogroup B exhibited higher penetrance and expressivity of hearing loss. In addition, the mitochondrial haplogroup specific variants: 15927G>A of haplogroup B5b, 12338T>C of haplogroup F2, 7444G>A of haplogroup B4, 5802T>C, 10454T>C, 12224C>T and 11696G>A of D4 haplogroup, 5821G>A of haplogroup C, 14693A>G of haplogroups Y2 and F, and 15908T>C of Y2 may enhance the penetrace of hearing loss in these Chinese families. Moreover, the absence of mutation in nuclear modifier gene TRMU suggested that TRMU may not be a modifier for the phenotypic expression of the 1555A>G mutation in these Chinese families. These observations suggested that mitochondrial haplotypes modulate the variable penetrance and expressivity of deafness among these Chinese families.

Asunto(s)

ADN Mitocondrial/genética , Sordera/genética , Sordera/fisiopatología , Haplotipos/genética , Mutación , ARN Ribosómico/genética , Adolescente , Aminoglicósidos/efectos adversos , Secuencia de Bases , Niño , Preescolar , China , Sordera/inducido químicamente , Pérdida Auditiva/inducido químicamente , Pérdida Auditiva/genética , Pérdida Auditiva/fisiopatología , Humanos , Mitocondrias/genética , Datos de Secuencia Molecular , Fenotipo , Filogenia