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Biomedical subjects

I Nonaka

Publications and source records attributed to I Nonaka.

At least 127 records · Page 7Linked to original sources
PubMed1998

Single muscle fiber analysis in patients with 3243 mutation in mitochondrial DNA: comparison with the phenotype and the proportion of mutant genome.

An A-to-G point mutation at nucleotide pair (np) 3243 (3243 mutation) in mitochondrial DNA (mtDNA) is a well-known pathogenic mutation, which has been found in approximately 80% of patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). It has been reported that the 3243 mutation also occurs in individuals with non-MELAS phenotypes. The reasons for the phenotypic heterogeneity of the 3243 mutation have not been clarified, although it may be closely related with mtDNA heteroplasmy and their differing proportions in different tissues. We examined the proportion of mutant DNA in muscle specimens at the cellular level using single fiber analysis in five patients with the 3243 mutation: three were diagnosed clinically as having MELAS and two had mitochondrial diabetes mellitus (MDM). In both phenotypes, ragged-red fibers (RRF) contained a higher percentage of mutant DNA (average 89.8%) than non-RRF (average 42.4%). On the other hand, the proportion of mutant DNA in non-RRF revealed a wider range than in RRF and the average was higher in MELAS patients (58.5+/-27.3%) than that in MDM patients (26.3+/-27.9%), which correlated with biochemical and morphological mitochondrial abnormalities in muscle. These findings may reflect the underlying mechanisms of tissue specificity in each phenotype.

Adolescent↗
PubMed1998

An ancient retrotransposal insertion causes Fukuyama-type congenital muscular dystrophy.

Fukuyama-type congenital muscular dystrophy (FCMD), one of the most common autosomal recessive disorders in Japan (incidence is 0.7-1.2 per 10,000 births), is characterized by congenital muscular dystrophy associated with brain malformation (micropolygria) due to a defect in the migration of neurons. We previously mapped the FCMD gene to a region of less than 100 kilobases which included the marker locus D9S2107 on chromosome 9q31. We have also described a haplotype that is shared by more than 80% of FCMD chromosomes, indicating that most chromosomes bearing the FCMD mutation could be derived from a single ancestor. Here we report that there is a retrotransposal insertion of tandemly repeated sequences within this candidate-gene interval in all FCMD chromosomes carrying the founder haplotype (87%). The inserted sequence is about 3 kilobases long and is located in the 3' untranslated region of a gene encoding a new 461-amino-acid protein. This gene is expressed in various tissues in normal individuals, but not in FCMD patients who carry the insertion. Two independent point mutations confirm that mutation of this gene is responsible for FCMD. The predicted protein, which we term fukutin, contains an amino-terminal signal sequence, which together with results from transfection experiments suggests that fukutin is a secreted protein. To our knowledge, FCMD is the first human disease to be caused by an ancient retrotransposal integration.

Amino Acid Sequence↗
PubMed1998

Tissue-specific involvement of multiple mitochondrial DNA deletions in familial mitochondrial myopathy.

It is still uncertain how deleted mitochondrial DNA (mtDNA) is distributed to each tissue during development, although deletions of mtDNA have been extensively observed in various pathologic conditions. This paper presents two Japanese siblings with progressive external ophthalmoplegia exhibiting multiple mtDNA deletions. In one patient, similar multiple mtDNA deletions were found in skeletal muscle specimens as well as in the spinal cord but not in the myocardium, liver or leukocytes. A similar deletion pattern was found in the skeletal muscle but not in the leukocytes of the other patient. The results suggest the complex mechanism to generate, expand and eliminate the deleted mtDNA in humans.

Adult↗
PubMed1998

MKBP, a novel member of the small heat shock protein family, binds and activates the myotonic dystrophy protein kinase.

Muscle cells are frequently subjected to severe conditions caused by heat, oxidative, and mechanical stresses. The small heat shock proteins (sHSPs) such as alphaB-crystallin and HSP27, which are highly expressed in muscle cells, have been suggested to play roles in maintaining myofibrillar integrity against such stresses. Here, we identified a novel member of the sHSP family that associates specifically with myotonic dystrophy protein kinase (DMPK). This DMPK-binding protein, MKBP, shows a unique nature compared with other known sHSPs: (a) In muscle cytosol, MKBP exists as an oligomeric complex separate from the complex formed by alphaB-crystallin and HSP27. (b) The expression of MKBP is not induced by heat shock, although it shows the characteristic early response of redistribution to the insoluble fraction like other sHSPs. Immunohistochemical analysis of skeletal muscle cells shows that MKBP localizes to the cross sections of individual myofibrils at the Z-membrane as well as the neuromuscular junction, where DMPK has been suggested to be concentrated. In vitro, MKBP enhances the kinase activity of DMPK and protects it from heat-induced inactivation. These results suggest that MKBP constitutes a novel stress-responsive system independent of other known sHSPs in muscle cells and that DMPK may be involved in this system by being activated by MKBP. Importantly, since the amount of MKBP protein, but not that of other sHSP family member proteins, is selectively upregulated in skeletal muscle from DM patients, an interaction between DMPK and MKBP may be involved in the pathogenesis of DM.

Amino Acid Sequence↗
PubMed1998

Muscular dystrophy associated with extra-abdominal desmoid tumor showing aberrant chromosome 1 [46,XX,add(1)(p36)].

We report on a 2-year-old girl with probable limb-girdle muscular dystrophy associated with an extra-abdominal desmoid tumor of the right mandible. This association is previously undescribed. The tumor was totally removed. Cytogenetic analysis of the tumor showed a clonal karyotypic abnormality: 46,XX,add(1)(p36) in 3 of 20 cells analyzed. Since an association of a neoplasm with limb-girdle muscular dystrophy has previously been reported in 3 cases, the two abnormalities are likely related causally. The chromosome abnormality in our patient may play a role in the occurrence of her desmoid tumor.

Child, Preschool↗
PubMed1998

A new congenital muscular dystrophy with mitochondrial structural abnormalities.

We report a new form of congenital muscular dystrophy (CMD) in 4 patients from three unrelated families with probable autosomal-recessive inheritance. All patients had the clinical characteristics of merosin-positive congenital muscular dystrophy, but had marked mental retardation. The disease was slowly progressive and 1 patient died from dilated cardiomyopathy at the age of 13 years. In addition to dystrophic changes with necrosis and regeneration in muscle, the most striking finding was mitochondrial depletion in the center of the sarcoplasm. Mitochondria at the periphery of fibers were markedly enlarged ("megaconial" appearance) with complicated cristae, and contained a normal amount of mitochondrial DNA by in situ hybridization. Mitochondrial enlargement may represent functional compensation for mitochondrial depletion in the central sarcoplasm, where myofibrillar degeneration occurred.

Adolescent↗
PubMed1998

Mitochondrial abnormalities in selenium-deficient myopathy.

We report a man who developed selenium-deficient myopathy during long-term parenteral nutrition. Muscle biopsy showed marked mitochondrial depletion in the deep sarcoplasm and enlarged mitochondria at the periphery mainly in type 2 fibers. Muscle weakness improved gradually after the second course of selenium supplementation. The peculiar mitochondrial abnormalities in muscle fibers appear to play a key role in the pathogenesis of selenium-deficient myopathy.

Adult↗
PubMed1998

Fiber-type-dependent expression of adenovirus-mediated transgene in mouse skeletal muscle fibers.

We show the efficient transduction and expression of the lacZ gene in the skeletal muscle of adult C57BL/10ScSn mice after adenovirus-mediated gene transfer. Of the myofibers in the tibialis anterior muscle 62% were beta-galactosidase positive after injection of the lacZ gene under the control of the chicken beta-actin promoter and the cytomegalovirus enhancer. The transduced gene was preferentially expressed in type IIA and IIX fibers, which were richer in oxidative enzymes than type IIB fibers.

Actins↗
PubMed1998

Founder-haplotype analysis in Fukuyama-type congenital muscular dystrophy (FCMD).

Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive, severe muscular dystrophy associated with brain anomalies. After our initial mapping of the FCMD locus to 9q31-33, we performed linkage disequilibrium analysis, which led us to suspect that the FCMD gene lay within a region of less than 100 kb containing D9S2107. In the present study, we developed two new microsatellites (D9S2170 and D9S2171) in close vicinity to D9S2107 and examined haplotypes of FCMD chromosomes by using four markers (cen-D9S2105-D9S2170-D9S2171-D9S2107-tel). As 82% of the FCMD chromosomes that we examined shared the founder haplotype (138-192-147-183) and 94% of the FCMD patients in our panel carried founder haplotypes on one or both chromosomes, the data supported the hypothesis of a single founder of this disease in the Japanese population. Eight haplotypes different from the founder's were observed in FCMD chromosomes, indicating that eight different FCMD mutations in addition to the founder's have occurred in Japan. Moreover, we have detected several historical recombinations that have disrupted the founder haplotype at D9S2105 or D9S2170 and conclude that the FCMD gene is probably located just centromeric to D9S2170.

Chromosomes, Human, Pair 9↗
PubMed1998

Severe infantile congenital myopathy with nemaline and cytoplasmic bodies: a case report.

A Japanese boy had marked generalized hypotonia and weakness and progressive respiratory failure since birth. Left biceps brachii muscle biopsy at 47 days of age showed marked variation in muscle fiber size, and nemaline and/or cytoplasmic bodies in approximately 10% of the muscle fibers. To our knowledge, the presence of nemaline and cytoplasmic bodies in the same muscle has not been previously reported. The severity of his respiratory failure and muscle weakness were thought to be related to muscle immaturity since there were many undifferentiated type 2C fibers.

Biopsy↗
PubMed1998

Dystrophin gene analysis on 130 patients with Duchenne muscular dystrophy with a special reference to muscle mRNA analysis.

On dystrophin gene analysis by multiplex polymerase chain reaction (PCR), 76 of 130 (58.5%) Japanese patients with Duchenne muscular dystrophy had a deletion or duplication in genomic DNA. Of the remaining 54 patients who had no identifiable gene mutations, muscle biopsy tissue was available in 16 for RNA extraction. The full length of the coding regions of dystrophin cDNA was amplified in 10 fragments by reverse transcription nested PCR (RT-PCR). Five of 16 patients (31%) had dystrophin cDNA of abnormal size. One patient had a deletion, and two duplications that were not covered by multiplex PCR, one an exon-skipping of exon 51 caused by a 5' consensus splice site mutation of intron 51, and one 172 bp or 202 bp insertion in the cDNA between exon 25 and 26. Nested RT-PCR from the total RNA extracted from muscle biopsy was useful for screening patients who had no identifiable gene abnormality by multiplex PCR.

Adolescent↗
PubMed1998

Confirmation that a T-to-C mutation at 9176 in mitochondrial DNA is an additional candidate mutation for Leigh's syndrome.

Among 80 patients with the clinical and brain imaging characteristics of Leigh's syndrome, 11 patients had a well-known mutation at nucleotide position (nt) 8993 in mitochondrial DNA. In addition, three patients had a T-to-C mutation at nt 9176 which had been described previously in only two brothers with bilateral striatal necrosis and one patient with Leigh's syndrome. In our three patients, one had the typical clinical characteristics of Leigh's syndrome from early infancy, and two had the later onset of neurological deficits. All had a slowly progressive course and basal ganglia abnormalities by neuroimaging. As nt 8993 and 9176 are located in the ATPase 6 coding region, altered ATPase function may be one of the enzyme abnormalities in Leigh's syndrome and other similar conditions with bilateral striatal necrosis.

Adolescent↗
PubMed1998

Distal myopathy with rimmed vacuoles.

Distal myopathy with rimmed vacuoles is an autosomal recessively inherited disorder with preferential involvement of the anterior tibial muscle. Recently the gene was discovered to be mapped to chromosome 9, the same region as in familial inclusion body myopathy (rimmed vacuole myopathy sparing the quadriceps). The onset of the disease was in young adults 20-40 years of age, averaging 26 years. The disease was progressive and most of the patients became non-ambulant within 12 years after the onset. The striking and common pathologic finding was the presence of rimmed vacuoles in muscle fibers with little evidence of necrotic or regenerative processes. Nuclear change with tubulofilamentous inclusions probably induces focal myofibrillar degeneration which activates the lysosomal system, resulting in active autophagocytosis and myelin body formation, i.e. rimmed vacuole formation.

Adolescent↗
PubMed1998

Presence of emerinopathy in cases of rigid spine syndrome.

Rigid spine syndrome (RSS) shows clinical similarities to Emery-Dreifuss muscular dystrophy (EDMD). Differential diagnosis between EDMD and RSS is essential because EDMD is often associated with life-threatening cardiomyopathy that can be cured by an implantation of a cardiac pacemaker. To determine if any of the patients with RSS had mutations of the emerin gene (responsible gene for X-linked EDMD or emerinopathy), we screened the patients for mutations. We found seven patients with a clinical picture consistent with RSS in the 6500 diagnostic muscle biopsies in our National Center over the last 19 years. We identified a novel mutation in the gene (1-bp frame-shift deletion in the exon 1) in one of the seven patients with RSS. This mutation created a premature termination at codon 12 and was expected to produce a severely truncated emerin. Emerin was not detected in the skeletal muscle. The unaffected mother of the patient was a heterozygous carrier for the mutation. The remaining six patients with RSS had no mutation in the gene and showed normal expression of emerin in the skeletal muscle. Our results emphasize the presence of clinical overlap between possible RSS and EDMD, and reinforce the necessity of molecular genetic diagnosis of emerin to exclude emerinopathy in a patient population that has a clinical diagnosis of RSS.

Adolescent↗
PubMed1998

MTM1 gene mutations in Japanese patients with the severe infantile form of myotubular myopathy.

The severe infantile form of myotubular myopathy is a fatal muscle disease that predominantly affects male infants and is characterized by severe weakness and hypotonia from birth. X-linked myotubular myopathy was found to be associated with mutations in the MTM1 gene in Xq28 encoding the putative tyrosine phosphatase, myotubularin. We screened the MTM1 gene for mutations in seven Japanese patients (six males and one female) who had the diagnosis of severe infantile form of myotubular myopathy. We found five mutations, including three novel mutations based on sequence analysis of RT-PCR fragments covering the entire open reading frame. Two patients (one male and one female), who had similar clinicopathologic features, did not have any mutation in the MTM1 gene open reading frame, suggesting that they may have had an autosomal recessive disease.

Child, Preschool↗
PubMed1998

Mutations in the integrin alpha7 gene cause congenital myopathy.

The basal lamina of muscle fibers plays a crucial role in the development and function of skeletal muscle. An important laminin receptor in muscle is integrin alpha7beta1D. Integrin beta1 is expressed throughout the body, while integrin alpha7 is more muscle-specific. To address the role of integrin alpha7 in human muscle disease, we determined alpha7 protein expression in muscle biopsies from 117 patients with unclassified congenital myopathy and congenital muscular dystrophy by immunocytochemistry. We found three unrelated patients with integrin alpha7 deficiency and normal laminin alpha2 chain expression. To determine if any of these three patients had mutations of the integrin alpha7 gene, ITGA7, we cloned and sequenced the full-length human ITGA7 cDNA, and screened the patients for mutations. One patient had splice mutations on both alleles; one causing a 21-bp insertion in the conserved cysteine-rich region, and the other causing a 98-bp deletion. A second patient was a compound heterozygote for the same 98-bp deletion, and had a 1-bp frame-shift deletion on the other allele. A third showed marked deficiency of ITGA7 mRNA. Clinically, these patients showed congenital myopathy with delayed motor milestones. Our results demonstrate that mutations in ITGA7 are involved in a form of congenital myopathy.

Antigens, CD↗
PubMed1998

Accumulation of tau in autophagic vacuoles in chloroquine myopathy.

Long-term administration of chloroquine to rats induces a vacuolar myopathy, which is specifically termed chloroquine myopathy (CM). In CM, tau mRNA levels were transiently upregulated in the early phase, while tau itself slowly accumulated in the late phase. The temporal profiles of tau mRNA levels and its accumulation were very similar to those of beta-amyloid protein precursor (APP) and its carboxyl-terminal fragments, both of which have been known to be degraded in lysosomes. Immunocytochemistry showed that tau progressively accumulated in the rimmed vacuoles exhibiting increased acid phosphatase activities, and immunoelectron microscopy demonstrated that tau was located within autophagic vacuoles. These results suggest that the accumulation of tau in CM is due to defective tau degradation in the lysosomal compartment in the muscle.

Acid Phosphatase↗