Thymidine phosphorylase gene mutations cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).
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Gastrointestinal Diseases↗
Biomedical subjects
Yutaka Nishigaki
Publications and source records attributed to Yutaka Nishigaki.
Mitochondrial haplogroup N9b is protective against myocardial infarction in Japanese males.
Superoxide, which mitochondria mainly produce in vascular endothelial cells, plays an important role in the pathogenesis of atherosclerosis and coronary artery disease. Accordingly, mitochondrial functional differences are thought to be one of the most important factors for the risk of myocardial infarction among various individuals. In the present study, we surveyed mitochondrial haplogroups associated with myocardial infarction in Japanese subjects. The study population comprised 2,137 unrelated Japanese individuals, including 1,181 subjects with a first myocardial infarction (920 males, 261 females) and the control subjects (522 males, 434 females). Twenty-eight mitochondrial single nucleotide polymorphisms of 12 major mitochondrial haplogroups (A, B, D4, D5, F, G1, G2, M7a, M7b, M7c, N9a, and N9b) were determined by use of 28-plex PCR and fluorescent beads combined with sequence-specific oligonucleotide probes. After adjustment for age, sex, body mass index, and prevalence of smoking, hypertension, hypercholesterolemia, and type 2 diabetes, a significantly (P = 0.0019) lower prevalence of haplogroup N9b was detected in subjects with myocardial infarction than in the controls. Especially, the prevalence of this haplogroup was significantly lower (P = 0.0007) in the male subjects with the disease than in the male controls. In contrast, there were trends towards higher prevalence of the disease in haplogroup G1 for males (P < 0.05). No significant haplogroup-related associations were detected for females. Our data suggest that haplogroup N9b confers resistance against myocardial infarction in Japanese males.
Adult↗
Increased serum level of vascular endothelial growth factor in Mycobacterium avium complex infection.
OBJECTIVE: Pulmonary infection caused by Mycobacterium avium complex (MAC) is one of the granulomatous diseases which are associated with the expression of vascular endothelial growth factor (VEGF). The aim of the present study was to clarify the association of VEGF with the pathogenesis of MAC infection. METHODOLOGY: The serum VEGF levels in 46 patients with pulmonary MAC infection were compared with those in 16 normal control subjects. Pulmonary lesions were evaluated using chest CT. In 20 patients, after treatment, serum VEGF levels were measured and chest CT performed again to evaluate pulmonary response to treatment. RESULTS: Infected patients had higher serum VEGF levels than controls (435.2 +/- 29.1 vs. 167.0 +/- 10.6 pg/mL, P < 0.0001), and serum VEGF level correlated with the extent of disease. The serum VEGF levels in 14 patients who underwent treatment and exhibited an improvement in their pulmonary lesions decreased significantly compared with the results pretreatment (509.0 +/- 60.7 vs. 303.6 +/- 65.3 pg/mL, P = 0.0092). In infected patients, alveolar macrophages, epithelioid cells and multinucleated giant cells exhibited VEGF overexpression on immunohistochemical staining. CONCLUSIONS: This study suggests that VEGF may be associated with the pathogenesis of pulmonary MAC infection. Additionally, serum VEGF levels may be a useful surrogate marker for evaluating the extent of disease and of the response to treatment.
Adult↗
[Mitochondrial dysfunctions and age-associated diseases].
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Aged↗
Thymidine phosphorylase mutations cause instability of mitochondrial DNA.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder characterized by ptosis and progressive external ophthalmoplegia, peripheral neuropathy, severe gastrointestinal dysmotility, cachexia and leukoencephalopathy. Muscle biopsies of MNGIE patients have revealed morphologically abnormal mitochondria and defects of respiratory chain enzymes. In addition, patients harbor depletion, multiple deletions, and point mutations of mitochondrial DNA (mtDNA). This disorder is caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP) a cytosolic enzyme. In MNGIE patients, TP activity is very low or absent resulting in dramatically elevated levels of plasma thymidine and deoxyuridine. We have hypothesized that the increased levels of thymidine and deoxyuridine cause mitochondrial nucleotide pool imbalances that, in turn, generate mtDNA alterations.
DNA, Mitochondrial↗
Congenital or late-onset myopathy in patients with the T14709C mtDNA mutation.
Three patients with different clinical phenotypes harbored the same point mutation at nucleotide 14709 (T14709C) in the tRNAGlu gene of mitochondrial DNA (mtDNA). The first patient was a 21-month-old child with severe congenital myopathy, respiratory distress and mild mental retardation. Muscle biopsy showed about 12% cytochrome c oxidase (COX)-negative ragged-red fibers (RRFs), and markedly decreased activities of mitochondrial respiratory chain complexes I, III and IV. The other two patients were 51- and 55-year-old siblings with slowly progressive myopathy and diabetes mellitus. Muscle biopsy showed focal COX-negative RRFs and decreased activities of complexes I, III and IV. In all three patients, the T14709C mutation was abundant in muscle but present at lower levels in accessible tissues. Previously described patients with the same mutation also showed congenital or late-onset myopathy. Diabetes is frequently associated with both phenotypes and is a clinical clue to the molecular diagnosis.
Cysteine↗
[The improvement of the enforcement rate of the standard regimen (A) of tuberculosis chemotherapy by the introduction of common database system for tuberculosis].
OBJECTIVE: The purpose of this study was to improve the enforcement rate of the standard regimen (A) of tuberculosis chemotherapy. SUBJECTIVE AND METHODS: We introduced the common database system for tuberculosis in three national hospitals in Hokkaido. From January 2002 to December 2003, we collected the anonymous informations of the patients with tuberculosis at the start of treatment, at the discharge and at the end of treatment. Then, we reported the enforcement rate of the standard regimen (A) as a clinical indicator periodically to three hospitals. RESULTS: Four hundred and twenty-nine patients were registered. In patients below 80 years old, the enforcement rate of the standard regimen (A) was 48.5% in 2002. The enforcement rate rose significantly to 62.7% (p = 0.0126) in 2003. In elder smear-positive patients (> or =75) and in elder smear-negative patients (> or =70), the enforcement rate was low (29.1% and 25.0%, respectively). Furthermore in young smear-negative patients (< or =29), the enforcement rate was low (28.0%). As the extent of their disease was minimal, they were treated with other regimens. In patients treated with the standard regimen (A), there were no significant differences in the frequency of adverse effects between elder patients ( 70) and other patients (< or =69). There were also no significant differences in the frequency of changing the regimen between them. Median admission period of 2002 was 114 days. In 2003, it was shortened significantly to 110 days (p = 0.0487). CONCLUSION: By the introduction of the common database system for tuberculosis, the enforcement rate of the standard regimen (A) was improved. Low enforcement rate in young smear-negative patients in an important problem to be improved in the future. The clinical indicator based on the common database system between hospitals, is useful to clarify the problems, and then to improve the quality of medical performance.
Adult↗
[Human mitochondrial genome polymorphism database (mtSNP)].
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Asian People↗
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE): a disease of two genomes.
BACKGROUND: Mitochondrial encephalomyopathies are clinically and genetically heterogeneous because mitochondria are the products of 2 genomes: mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Among the mendelian-inherited mitochondrial diseases are defects of intergenomic communication, disorders due to nDNA mutations that cause depletion and multiple deletions of mtDNA. REVIEW SUMMARY: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder of intergenomic communication and is defined clinically by 1) severe gastrointestinal dysmotility; 2) cachexia; 3) ptosis, ophthalmoparesis, or both; 4) peripheral neuropathy; and 5) leukoencephalopathy. Skeletal muscle biopsies of patients have revealed abnormalities of mtDNA and mitochondrial respiratory chain enzymes. The disease is caused by mutations in the thymidine phosphorylase (TP) gene. TP protein catalyzes phosphorolysis of thymidine to thymine and deoxyribose 1-phosphate. In MNGIE patients, TP enzyme activity is reduced drastically, and plasma thymidine and deoxyuridine are elevated dramatically. We have hypothesized that alterations of nucleoside metabolism cause an imbalanced mitochondrial nucleotide pool that leads to depletion and deletions of mtDNA. CONCLUSIONS: MNGIE is a recognizable clinical syndrome caused by mutations in TP. The diagnosis can be confirmed by measuring TP activity in buffy coat or plasma levels of thymidine and deoxyuridine. Reduction of circulating thymidine and deoxyuridine in MNGIE patients may be therapeutic.
Adolescent↗
[Clinical analyses of Aspergillus infections in patients with underlying pulmonary disease].
To elucidate the clinical features of Aspergillus infections with underlying pulmonary disease, we analyzed 79 cases with positive results for anti-aspergillus antibody. The patients were 69 men and 10 women. Mean age at diagnosis was 68.0. Positive rates for isolation of Aspergillus spp. from the airways, and of galactomannan antigen and 1, 3-beta-D glucan in the serum were 44.3, 21.8, 26.5%, respectively. These findings did not show any differences according to underlying pulmonary disease. Twenty-nine patients died of the disease. Body mass indices, serum albumin levels and red blood cell counts were significantly lower in the patients who died. Extension of the lesion to the lower lobes or to 3 or more lobes was correlated significantly with poor survival. A specific diagnostic tool was required for early detection of the disease.
Aged↗
[Validity of measuring time to detect growth of M. tbc by BACTEC MGIT960 system for quantitation and prediction of mycobacterial growth].
STUDY DESIGN: Time to detect growth of M. tbc by BACTEC MGIT960 system was examined in sputum specimens collected from 114 patients with active pulmonary tuberculosis before and during antituberculosis therapy. By measuring TTD under chemotherapy, we tried to quantify mycobacterial growth and determine the sensitivity of MGIT system. RESULTS: The mean TTD significantly decreased in response to an increment in the range of the quantitation scale for solid media. Moreover, the TTD negatively correlated with colony counts (rho = - 0.636, P < 0.01). When automated monitoring continued until Day 28 after incubation, MGIT system had been capable of detecting 98% of Ogawa-positive specimens. The receiver operating characteristic (ROC) curve was plotted to determine the sensitivity and specificity in MGIT system, indicating the sensitivity of 98.3% corresponding cutoff level for TTD of Day 28. CONCLUSION: Measuring TTD in MGIT system could allow estimating the mycobacterial growth in similarly quantitative manner. The appropriate endpoint of monitoring could be decided as 4 weeks, accurately reflecting an outcome of cultivation with solid media.
Aged↗
Definitive diagnosis of mitochondrial neurogastrointestinal encephalomyopathy by biochemical assays.
BACKGROUND: Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the gene encoding thymidine phosphorylase (TP). The clinical manifestations of MNGIE are recognizable and homogeneous, but in the early stages, the disease is often misdiagnosed. This study assesses the reliability of biochemical assays to diagnose MNGIE. METHODS: We studied 180 patients with clinical features suggestive of MNGIE, 14 asymptomatic TP mutation carriers, and 20 controls. TP enzyme activity in the buffy coat was determined by a fixed-time method, and the plasma nucleosides thymidine (dThd) and deoxyuridine (dUrd) were assessed by a gradient-elution reversed phase HPLC method. TP was sequenced through standard procedures in patients who met the clinical criteria for MNGIE. RESULTS: Twenty-five of the 180 patients fulfilled the clinical criteria for MNGIE and had homozygous or compound heterozygous TP mutations. All had drastically decreased TP activity [mean (SD), 10 (15) nmol thymine formed. h(-1). (mg protein)(-1) vs 634 (217) nmol thymine formed. h(-1). (mg protein)(-1) for the controls]. Relative to the control mean, TP activities were reduced to 35% in mutation carriers and 65% in MNGIE-like patients. All 25 MNGIE patients had detectable plasma dThd [8.6 (3.4) micromol/L] and dUrd [14.2 (4.4) micromol/L]. Controls, carriers, and MNGIE-like patients showed no detectable plasma dThd and dUrd. CONCLUSIONS: We propose a diagnostic algorithm based on the determination of plasma dThd and dUrd, TP activity in buffy coat, or both to make a definitive diagnosis of MNGIE. Increased concentrations of dThd (>3 micromol/L) and dUrd (>5 micromol/L) in plasma or a decrease in buffy coat TP activity to </=8% relative to controls is sufficient to diagnose MNGIE.
Chromatography, High Pressure Liquid↗
ND5 is a hot-spot for multiple atypical mitochondrial DNA deletions in mitochondrial neurogastrointestinal encephalomyopathy.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive multisystem disorder associated with depletion, multiple deletions and site-specific point mutations of mitochondrial DNA (mtDNA). MNGIE is caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP; endothelial cell growth factor 1). Deficiency of TP leads to dramatically elevated levels of circulating thymidine and deoxyuridine. The alterations of pyrimidine nucleoside metabolism are hypothesized to cause imbalances of mitochondrial nucleotide pools that, in turn, may cause somatic alterations of mtDNA. We have now identified five major forms of mtDNA deletions in the skeletal muscle of MNGIE patients. While direct repeats and imperfectly homologous sequences appear to mediate the formation of mtDNA deletions, the nicotinamide adenine dinucleotide dehydrogenase 5 gene is a hot-spot for these rearrangements. A novel aspect of the mtDNA deletions in MNGIE is the presence of microdeletions at the imperfectly homologous breakpoints.
Base Sequence↗
The diagnostic and prognostic relevance of human telomerase reverse transcriptase mRNA expression detected in situ in patients with nonsmall cell lung carcinoma.
BACKGROUND: The objectives of this study were to evaluate the diagnostic and prognostic relevance of human telomerase reverse transcriptase (hTERT) detected in situ in patients with nonsmall cell lung carcinoma (NSCLC) and to investigate the possible correlations between hTERT mRNA in NSCLC and the patients' clinicopathologic features, including survival. METHODS: hTERT mRNA was detected by in situ hybridization in 146 samples from patients with NSCLC. The signal intensity of hTERT mRNA expression was evaluated by two independent observers. The expression level was defined subjectively as strong, moderate, or weak. RESULTS: hTERT mRNA was detected mainly in the cytoplasm of tumor cells. It was detected in the cytoplasm of 100% of samples from patients with NSCLC but was not detected in normal lung tissue, except in activated lymphocytes. There was a significant correlation between hTERT mRNA expression and pathologic tumor status, pathologic disease stage (pStage), and Ki-67 labeling index. There was no significant correlation between hTERT mRNA expression and age, gender, pathologic lymph node status (pN), histology, or tumor differentiation. The 5-year survival rates for patients with strong and moderate hTERT mRNA expression levels were 46.9% and 77.9%, respectively; the difference was statistically significant (P = 0.0001). A multivariate analysis of survival using a stepwise procedure revealed that hTERT mRNA expression, pN status, pStage, and age were statistically significant prognostic factors (P = 0.0029, P = 0.0012, P = 0.0237, and P = 0.0496, respectively). CONCLUSIONS: The findings suggested that hTERT mRNA expression may be useful for the diagnosis of NSCLC and also may be an independent prognostic factor for patients with NSCLC.
Adult↗
Elevated plasma deoxyuridine in patients with thymidine phosphorylase deficiency.
Mutations in the nuclear gene encoding thymidine phosphorylase (TP) cause mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), an autosomal recessive disease with mitochondrial dysfunction and mitochondrial DNA abnormalities. We have demonstrated alterations of thymidine (dThd) metabolism in MNGIE patients. Here, we report the accumulation of another substrate of TP, deoxyuridine (dUrd), whose circulating levels ranged from 5.5 to 24.4 microM (average 14.2) in MNGIE and were undetectable (<0.05 microM) in both TP mutation carriers and controls. The dramatic accumulation of dUrd may contribute to nucleotide pool imbalances and, together with the increased levels of dThd, is likely to contribute to the pathogenesis of MNGIE.
Base Sequence↗
Clinical and genetic heterogeneity in progressive external ophthalmoplegia due to mutations in polymerase gamma.
BACKGROUND: The mendelian forms of progressive external ophthalmoplegia (PEO) associated with multiple mitochondrial DNA deletions are clinically heterogeneous disorders transmitted as dominant or recessive traits. Autosomal dominant PEO is caused by mutations in at least 3 genes: adenine nucleotide translocator-1 (ANT1), encoding the muscle-specific adenine nucleotide translocator; chromosome 10 open reading frame 2 (C10orf2), encoding Twinkle helicase; and polymerase gamma (POLG), encoding the alpha subunit of polymerase gamma. Mutations in POLG can also cause autosomal recessive PEO, which is often associated with multisystemic disorders. OBJECTIVE AND METHODS: To further investigate the frequency and genotype-phenotype correlations of mutations in the POLG gene, we used single-stranded conformational polymorphism analysis and direct sequencing to screen 30 patients with familial or sporadic PEO and multiple mitochondrial DNA deletions in muscle but without mutations in ANT1 and C10orf2. RESULTS: Four unrelated patients had novel POLG mutations. A woman with PEO and mental retardation had a heterozygous Gly1076Val mutation. Two patients, one with PEO, exercise intolerance, and gastrointestinal dysmotility and the other with PEO, neuropathy, deafness, and hypogonadism, both had a Pro587Leu change. The fourth patient, who was compound heterozygous for Ala889Thr and Arg579Trp mutations, had PEO, gastrointestinal dysmotility, and neuropathy. These mutations were not detected in 120 healthy control alleles. CONCLUSIONS: Our results demonstrate that POLG mutations account for a substantial proportion of patients (13%) with PEO and multiple mitochondrial DNA deletions and cause both clinically and genetically heterogeneous disorders.
Adult↗
A novel mitochondrial tRNA(Leu(UUR)) mutation in a patient with features of MERRF and Kearns-Sayre syndrome.
In a patient with clinical features of both myoclonus epilepsy ragged-red fibers (MERRF) and Kearns-Sayre syndrome (KSS), we identified a novel guanine-to-adenine mitochondrial DNA (mtDNA) mutation at nucleotide 3255 (G3255A) of the tRNA(Leu(UUR)) gene. Approximately 5% of the skeletal muscle fibers had excessive mitochondria by succinate dehydrogenase histochemistry while a smaller proportion showed cytochrome c oxidase (COX) deficiency. In skeletal muscle, activities of mitochondrial respiratory chain complexes I, I + III, II + III, and IV were reduced. The G3255A transition was heteroplasmic in all tissues tested: muscle (53%), urine sediment (67%), peripheral leukocytes (22%), and cultured skin fibroblasts (< 2%). The mutation was absent in 50 control DNA samples. Single-fiber analysis revealed a higher proportion of mutation in COX-deficient RRF (94% +/- 5, n = 25) compared to COX-positive non-RRF (18% +/- 9, n = 21). The identification of yet another tRNA(Leu(UUR)) mutation reinforces the concept that this gene is a hot-spot for pathogenic mtDNA mutations.
Adenine↗
Site-specific somatic mitochondrial DNA point mutations in patients with thymidine phosphorylase deficiency.
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is an autosomal recessive disorder caused by loss-of-function mutations in the gene encoding thymidine phosphorylase (TP). This deficiency of TP leads to increased circulating levels of thymidine (deoxythymidine, dThd) and deoxyuridine (dUrd) and has been associated with multiple deletions and depletion of mitochondrial DNA (mtDNA). Here we describe 36 point mutations in mtDNA of tissues and cultured cells from MNGIE patients. Thirty-one mtDNA point mutations (86%) were T-to-C transitions, and of these, 25 were preceded by 5'-AA sequences. In addition, we identified a single base-pair mtDNA deletion and a TT-to-AA mutation. Next-nucleotide effects and dislocation mutagenesis may contribute to the formation of these mutations. These results provide the first demonstration that alterations of nucleoside metabolism can induce multiple sequence-specific point mutations in humans. We hypothesize that, in patients with TP deficiency, increased levels of dThd and dUrd cause mitochondrial nucleotide pool imbalances, which, in turn, lead to mtDNA abnormalities including site-specific point mutations.
Base Sequence↗