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K Tanji

Publications and source records attributed to K Tanji.

At least 55 records · Page 3Linked to original sources
PubMed1999

Exercise intolerance due to a nonsense mutation in the mtDNA ND4 gene.

We report the first molecular defect in an NADH-dehydrogenase gene presenting as isolated myopathy. The proband had lifelong exercise intolerance but no weakness. A muscle biopsy showed cytochrome c oxidase (COX)-positive ragged-red fibers (RRFs), and analysis of the mitochondrial enzymes revealed complex I deficiency. Sequence analysis of the mitochondrial genes encoding the seven NADH-dehydrogenase subunits showed a G-to-A transition at nucleotide 11832 in the subunit 4 (ND4) gene, which changed an encoded tryptophan to a stop codon. The mutation was heteroplasmic (54%) in muscle DNA. Defects in mitochondrially encoded complex I subunits should be added to the differential diagnosis of mitochondrial myopathies.

Adult↗
PubMed1999

Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.

Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane. Mitochondrial DNA (mtDNA) encodes three COX subunits (I-III) and nuclear DNA (nDNA) encodes ten. In addition, ancillary proteins are required for the correct assembly and function of COX (refs 2, 3, 4, 5, 6). Although pathogenic mutations in mtDNA-encoded COX subunits have been described, no mutations in the nDNA-encoded subunits have been uncovered in any mendelian-inherited COX deficiency disorder. In yeast, two related COX assembly genes, SCO1 and SCO2 (for synthesis of cytochrome c oxidase), enable subunits I and II to be incorporated into the holoprotein. Here we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits. The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome.

Amino Acid Sequence↗
PubMed1998

Study of mitochondrial DNA depletion in muscle by single-fiber polymerase chain reaction.

We studied muscle biopsies from 3 children with a mitochondrial myopathy characterized histochemically by the presence of ragged-red fibers (RRF) and various numbers of cytochrome c oxidase (COX)-negative fibers. We quantitated the absolute amounts of total mitochondrial DNA (mtDNA) in isolated normal COX-positive muscle fibers and in COX-negative RRF. There was severe mtDNA depletion in all fibers from the two most severe cases. In the third case mtDNA depletion could not be established with conventional diagnostic tools, but it was documented in single COX-negative fibers; COX-positive fibers showed the same amounts of mtDNA as fibers from aged-matched controls. Our observations indicate that mtDNA single-fiber PCR quantitation is a highly sensitive and specific method for diagnosing cases with focal mtDNA depletion. This method also allows one to correlate amounts of mtDNA with histochemical phenotypes in individual fibers from patients and age-matched controls, thereby providing important information about the functional role of residual mtDNA.

Biopsy↗
PubMed1998

The mitochondrial DNA A8344G mutation in Leigh syndrome revealed by analysis in paraffin-embedded sections: revisiting the past.

In 1975, we presented the results of a study on a family with a constellation of features that included a chronic spinocerebellar syndrome, neuropathologically proven Leigh syndrome, and sudden death in infancy or childhood affecting several members over three generations. Inheritance was thought to be autosomal dominant. Twenty years later, we reinterpreted the inheritance pattern as maternal. Mitochondrial DNA (mtDNA) extracted from paraffin-embedded brain samples from the proband revealed the A8344G myoclonic epilepsy and ragged-red fiber (MERRF) mutation as the molecular basis for this multifaceted neurological syndrome. This re-evaluation of archival material is an instructive example of "medical archeopathology."

Adolescent↗
PubMed1998

Clinical manifestations of mitochondrial DNA depletion.

OBJECTIVE: We studied five new patients with mitochondrial DNA (mtDNA) depletion to better define the clinical spectrum of this disorder. BACKGROUND: mtDNA depletion has been associated with myopathy or hepatopathy, or both, in infants and young children. Involvement of the CNS and peripheral nervous system has not been clearly established. METHODS: We reviewed the clinical course and performed morphologic, biochemical, and genetic analyses of muscle samples from five patients. RESULTS: Age at onset ranged from 3 months to 5 years, and one patient survived until age 10 1/2 years. Two patients had laboratory and clinical features reminiscent of dystrophinopathy, two had evidence of brain involvement, and two had peripheral neuropathy. Muscle biopsy specimens in all patients showed abundant ragged-red fibers. Biochemistry showed cytochrome c oxidase deficiency in all patients tested and decreased activities of other respiratory chain complexes in some. CONCLUSIONS: Inheritance appeared to be autosomal recessive, suggesting that mutations in nuclear DNA are responsible for mtDNA depletion. mtDNA depletion should be considered in children with mitochondrial disorders of uncertain etiology, and criteria for diagnosis are proposed.

Blotting, Southern↗
PubMed1998

Mitochondrial DNA depletion in a patient with long survival.

We studied a 29-year-old woman with myopathy since childhood with evidence of mitochondrial DNA (mtDNA) depletion. Muscle biopsy sample showed cytochrome c oxidase (COX)-negative fibers. Biochemistry showed COX deficiency. Southern blot analysis showed 76% depletion of mtDNA as compared with controls. This patient's clinical course suggests that long survival is possible in some patients with mtDNA depletion.

Adult↗
PubMed1997

Identification of a novel mutation in the mtDNA ND5 gene associated with MELAS.

We report a novel G13513A mutation in the mitochondrial ND5 gene in a patient who had morphologically and biochemically abnormal muscle mitochondria and died at age 45 with a diagnosis of MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). The mutation affects an evolutionarily conserved nucleotide and was heteroplasmic in muscle, leukocytes, and several autopsy tissues, including brain. The mutation was less abundant (<5%) in leukocytes from an asymptomatic sister and was not found in over 100 controls, thus satisfying accepted criteria for pathogenicity. Our report reinforces the concept of genetic heterogeneity in MELAS and confirms that MELAS can be due to mutations in polypeptide-coding mtDNA genes.

Amino Acid Sequence↗
PubMed1997

Maternally inherited encephalopathy associated with a single-base insertion in the mitochondrial tRNATrp gene.

We identified a single thymidine insertion at nucleotide position 5537 (T5537i) in the mitochondrial DNA transfer RNA gene for tryptophan in a family in which the proband had a progressive neurological disorder and his brother died in infancy of Leigh syndrome. Muscle biopsy from the proband showed subsarcolemmal proliferation of mitochondria and decreased activities of oxidative metabolism enzymes, in particular complex IV. Complex IV was also severely reduced in autopsy tissues, including heart and brain tissues, from the Leigh syndrome infant. The novel T5537i mutation was very abundant in tissues from the proband and the infant (>92%) and less abundant (range, 42-89%) in blood, hair follicles, and skin fibroblasts from 4 maternal relatives, 3 of whom showed a neuropsychiatric disturbance. The mutation was not found in more than 100 control subjects. The degree of heteroplasmy in blood correlated well with the severity of the clinical presentation, suggesting specific segregation with the disease.

Adult↗
PubMed1997

Ciliary neurotrophic factor immunoreactivity in rat intramuscular nerve during reinnervation through a silicone tube after severing of the rat sciatic nerve.

The immunoreactivity of ciliary neurotrophic factor (CNTF) and S100 was studied in the degenerating and regenerating intramuscular nerves after the sciatic nerve was severed. The sciatic nerves of male Wistar rats were transected at the midpoint of the thigh, and silicone tubing was used to obtain effective reinnervation. The strong immunoreactivity of CNTF and S100 was observed in the Schwann cell cytoplasm of intramuscular nerves (IMN) and at the neuromuscular junction (NMJ) on the control sections. The CNTF immunoreactivity gradually became weak and indistinct in the Schwann cell cytoplasm after the operation. However, it was recognized again in the IMN at 4 weeks after the operation. On the other hand, the S100 immunoreactivity was continuously observed except at the NMJ through the denervating and reinnervating period. At 12 weeks after the operation, the strong immunoreactivity of both CNTF and S100 was observed again. These findings suggest that the amount of CNTF protein decreased in Schwann cells of the IMN and NMJ during the denervating period and increased during the reinnervating period in proportion to the number of remyelinated Schwann cells after severing of the sciatic nerve. They also suggest that CNTF was more highly correlated than the S100 protein with the reinnervation activity of Schwann cells.

Animals↗
PubMed1997

Mitochondrial disorders.

In this minireview, we attempt to survey the three main group of mitochondrial disorders, defects of nuclear DNA, defects of mitochondrial DNA, and defects of intergenomic signaling, with emphasis on recent contributions and pathogenetic mechanisms. In so doing, we have tried to point out some of the numerous unsolved problems in genotype/phenotype correlation and to indicate future directions of research.

Central Nervous System Diseases↗
PubMed1997

Heterogeneous clinical presentation of the mtDNA NARP/T8993G mutation.

To obtain a better molecular definition of patients with syndromic retinitis pigmentosa, we screened for mitochondrial DNA (mtDNA) alterations of the two ATPase genes and 22 tRNA-coding sequences in 10 patients whose features resembled NARP (neuropathy, ataxia, and retinitis pigmentosa) syndrome. In two patients, one of whom showed features mimicking Kearns-Sayre syndrome, we identified a heteroplasmic T8993G mutation (average 80%) in the mitochondrial ATPase 6 gene. There was no mutated mtDNA in muscle and leukocytes from the mother of one patient or in leukocytes from his brother, suggesting a rapid segregation of the mutated nucleotide. MtDNA analysis should be considered in the differential diagnosis of patients with syndromic retinitis pigmentosa.

Adult↗
PubMed1996

Multiple mitochondrial DNA deletions in sporadic inclusion body myositis: a study of 56 patients.

Inclusion body myositis, a chronic inflammatory disorder, is the most common cause of myopathy in adults over the age of 50. Diagnosis is based on clinical features and distinctive morphological findings by both light and electron microscopy. The causes of inclusion body myositis are still unknown. Ultrastructural mitochondrial changes and ragged-red fibers are common in patients with sporadic inclusion body myositis, and multiple [correction of mutiple] mitochondrial DNA (mtDNA) deletions have been reported in 3 such patients, suggesting that mtDNA mutations may have a pathogenetic role. We studied 56 patients with sporadic inclusion body myositis, using a combination of clinical, morphological, biochemical, and molecular genetic analyses to determine the frequency and the distribution of mtDNA deletions. Using the polymerase chain reaction, we found multiple mtDNA deletions in 73% of patients, compared to 40% of normal age-matched control subjects and 47% of disease control subjects. The presence of deletions correlated with morphological evidence of ragged-red, cytochrome c oxidase-negative fibers, and with defects of complexes I and IV of the electron transport chain. Although aging may account for a proportion of mtDNA deletions in patients with sporadic inclusion body myositis and control subjects, mtDNA alterations may be accelerated in sporadic inclusion body myositis.

Adult↗
PubMed1996

A case of malignant transformation in thoracic vertebral hemangioma following repetitive irradiation and extraction.

We report a rare case of thoracic vertebral hemangioma which developed into angiosarcoma during the course of repetitive operations and irradiation. A 44 year old female was operated on for hemangioma of the first thoracic vertebra. The diagnosis of hemangioma was confirmed histopathologically with the specimen from the first operation. The tumor developed multiple lesions later in the clinical course after the first operation, these lesions were removed in four consecutive operations and each histological diagnosis was that of hemangioma. Throughout the period of these operations, the patient was treated with steroid, and with radiotherapy simultaneously. The patient underwent the fifth operation for the recurrence of the tumor on 26 March 1990, and the histopathological diagnosis was not hemangioma but hemangiosarcoma which was considered a malignant transformation. The tumor cells immunohistochemically revealed positive staining with UEA-I, Factor-VIII, as the tumor immunohistochemically showed a vascular endothelioid nature.

Adult↗
PubMed1996

Multiple mitochondrial DNA deletions associated with autosomal recessive ophthalmoplegia and severe cardiomyopathy.

Six patients in two unrelated families from the eastern Arabian peninsula presented with childhood-onset progressive external ophthalmoplegia (PEO), mild facial and proximal limb weakness, and severe cardiomyopathy requiring cardiac transplantation. Muscle biopsies showed ragged-red and cytochrome c oxidase-negative fibers. The activities of several complexes in the electron-transport chain were decreased and Southern blot analysis showed multiple mtDNA deletions. The apparent autosomal-recessive inheritance and the association with cardiomyopathy distinguish this syndrome from autosomal-dominant PEO with multiple mtDNA deletions. The combination of autosomal-recessive PEO, cardiomyopathy, and multiple mtDNA deletions appears to be another disease due to a defect of communication between the nuclear and mitochondrial genomes.

Adolescent↗
PubMed1995

Analysis of PrPc mRNA by in situ hybridization in brain, placenta, uterus and testis of rats.

An amyloid-like isoform of a 33- to 34-kD glycoprotein, termed as the scrapie prion protein (PrPsc), plays a critical role in transmissible spongiform encephalopathies of animals and humans. It has even been suggested to present the responsible infectious agent. This protein is a posttranslationally modified form of the cellular isoform of prion protein (PrPc). Hitherto, little has been known about the functions of PrPc. In order to examine the localization of PrPc mRNA in rat tissues, the in situ hybridization technique was performed. In rat brain, PrPc mRNA was predominantly localized within pyramidal cells of the hippocampus, large neurons of the thalamus and neocortex, and Purkinje cells of the cerebellum. In the placenta, not only PrPc mRNA was localized to a subpopulation of decidual cells at the highest levels, it was also expressed in the amnion and mesodermal layer of the yolk sac. Furthermore, PrPc mRNA was also expressed in the myometrium of the uterus and seminiferous tubule in the testis. However, signals were not obtained in the lung, spleen, liver of prenatals and other fetus tissues. The distribution of rat PrPc mRNA portrayed the levels which were different among the various types of cells, suggesting that its expression may be regulated in a tissue-specific manner.

Animals↗