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Biomedical subjects

I Nonaka

Publications and source records attributed to I Nonaka.

At least 109 records · Page 6Linked to original sources
PubMed1999

alpha1-syntrophin gene disruption results in the absence of neuronal-type nitric-oxide synthase at the sarcolemma but does not induce muscle degeneration.

alpha1-Syntrophin is a member of the family of dystrophin-associated proteins and is strongly expressed in the sarcolemma and the neuromuscular junctions. All three syntrophin isoforms have a PDZ domain that appears to participate in protein-protein interactions at the plasma membrane. alpha1-Syntrophin has additionally been shown to associate with neuronal nitric-oxide synthase (nNOS) through PDZ domains in vitro. These observations suggest that alpha1-syntrophin may work as a modular adaptor protein that can link nNOS or other signaling enzyme to the sarcolemmal dystrophin complex. In the sarcolemma, nNOS regulates the homeostasis of reactive free radical species and may contribute to the oxidative damage to muscle protein in muscle disease such as Duchenne muscular dystrophy. In this study, we generated alpha1-syntrophin knock-out mice to clarify the interaction between alpha1-syntrophin and nNOS in the skeletal muscle. We observed that nNOS, normally expressed in the sarcolemma, was largely absent from the sarcolemma, but considerably remained in the cytosol of the knock-out mice. Even though the distribution of nNOS was altered, the knock-out mice displayed no gross histological changes in the skeletal muscle. We also discovered that muscle contractile properties have not been influenced in the knock-out mice.

Animals↗
PubMed1999

Effective adenovirus-mediated gene expression in adult murine skeletal muscle.

We established an efficient method for obtaining expression of a foreign marker gene transferred in vitro into myoblasts and in vivo into adult mouse skeletal muscles using adenovirus vector. After infection of the C2 myoblasts with the adenovirus vector containing the beta-actin promoter with cytomegalovirus (CMV) enhancer (CAG promoter) AxCALacZ, significantly greater number of cells express beta-galactosidase when compared with the adenovirus vector expressing the lacZ gene under the control of the SR alpha viral terminal repeat promoter (AxSRLacZL) or the myosin heavy chain (MHC) IIB promoter (AxMHCLacZ). We also injected AxCALacZ into the skeletal muscles of 5- to 6-week-old C57BL/10 mice and determined that more than 60% of their muscle fibers expressed the lacZ gene 7 days after injection. The CAG promoter may have application in the development of gene therapy for Duchenne muscular dystrophy (DMD) using adenovirus vector.

Adenoviridae↗
PubMed1999

Transforming growth factor-beta2 is elevated in skeletal muscle disorders.

The transforming growth factor betas (TGF-betas) are multifunctional growth factors that act on both fibroblasts and myosatellite cells. In rodent models of muscle diseases, high levels of TGF-beta2 are expressed by myogenic cells. We have examined whether the expression of TGF-beta2 is also elevated in diseased human muscles. The disorders examined were Duchenne muscular dystrophy, myotonic dystrophy, myotubular myopathy, spinal muscular atrophy, and amyotrophic lateral sclerosis. The levels of TGF-beta2 immunoreactivity were elevated in atrophic, necrotic, and regenerating fibers and in fibers with central nuclei or cytoplasmic masses, irrespective of whether fibrosis was present. We therefore suggest that TGF-beta2 is important for muscle repair and that the presence of a TGF-beta within a muscle only leads to fibrosis if certain other factors are present.

Amyotrophic Lateral Sclerosis↗
PubMed1999

A new three allele polymorphism at distal 21q22.3, a region relatively devoid of polymorphic markers. Mutations in brief no. 212. Online.

We amplified 305bp of the 3'UT region of COL18A1 from 62 healthy chromosomes from Caucasian individuals. SSCP analysis of these PCR products allowed us to identify 3 alleles which were confirmed through sequencing analysis and ASO. The heterozigosity found for this polymorphic region is 74.2%, and mendelian inheritance was demonstrated in 5 two/three generation families. This polymorphism, located in a region relatively devoid of microsatellites, will be very useful for linkage analysis, particularly for narrowing down candidate regions for genes mapped in this area.

3' Untranslated Regions↗
PubMed1999

Nebulin is normally expressed in nemaline myopathy.

Since the nebulin gene is located in the candidate gene locus of autosomal recessive nemaline myopathy, 2q21.2-q22, we examined five muscle biopsy specimens with monoclonal and polyclonal antibodies against nebulin in combination with the modified Gomori trichrome stain. We were able to demonstrate immunohistochemically that there was no abnormality in nebulin in the muscle fibers both with and without nemaline bodies. Although the molecular weight of nebulin was normal, it was slightly reduced in amount on immunoblotting.

Humans↗
PubMed1999

Early onset of X-linked Emery-Dreifuss muscular dystrophy in a boy with emerin gene deletion.

A boy developed contractures of the Achilles tendons at 3 years and of the postcervical muscles at 7 years, although neither contractures of the elbows nor cardiac abnormality were recognized by the age of 9 years. Muscle computed tomography scanning revealed changes characteristic of muscle involvement. Emerin was not detected in the biopsied muscle, and RT-PCR and PCR-based genomic DNA analyses of the emerin gene demonstrated no amplification product in the patient. These results confirmed the diagnosis of X-linked Emery-Dreifuss muscular dystrophy (EDMD), and reinforce the necessity of molecular genetic diagnosis of the membrane protein emerin in younger patients with possible EDMD before appearance of the typical symptoms, to avoid sudden cardiac death.

Child↗
PubMed1999

Circular dystrophin RNAs consisting of exons that were skipped by alternative splicing.

Exon skipping by alternative splicing and circular RNA formation are proposed to be interrelated events. Since multiple patterns of alternative splicing have been demonstrated in both the 5' and 3' regions of the dystrophin gene, the dystrophin transcript in skeletal muscle cells provides a model system in which this idea is tested. Nine circular RNAs that were expected to result from known exon skipping patterns in the 5' region of this gene were in fact identified, but three other circular RNAs expected to result from other known exon skipping reactions in this region could not be detected. The identification of two unexpected circular RNAs led to the discovery of two novel alternative splicing reactions. One circular RNA originating in the 3' region of the gene was identified but it lacked one small sized exon compared with the expected exon structure. Circular RNAs from the 5' region of the dystrophin gene could not be detected in Duchenne muscular dystrophy patients who have deletions of one or more exons in this segment of the gene, even though alternative splicing products were identified. These results showed that circular RNA formation is not necessarily linked to exon skipping and suggest that an undetermined factor regulates circular RNA formation.

Alternative Splicing↗
PubMed1999

Distal myopathies.

Among various previously described distal myopathies, several diseases have now been established as clinically and genetically distinct entities. The most representative diseases are dominantly inherited Welander distal myopathy and tibial muscular dystrophy, and the recessively inherited distal myopathy with rimmed vacuoles and distal muscular dystrophy (Miyoshi myopathy). Since the discovery of the gene loci for several distal myopathies, several diseases previously categorized as different disorders have now proven to be the same or allelic disorders (e.g. distal myopathy with rimmed vacuoles and hereditary inclusion body myopathy, Miyoshi myopathy and limb-girdle muscular dystrophy with gene locus at 2p13). Except for Miyoshi myopathy, which has the typical findings of muscular dystrophy, most of the distal myopathies share the common pathologic features of myopathic changes with rimmed vacuoles. The pathologic changes are somewhat similar to those seen in chronic muscular dystrophy, but necrotic and regenerative processes are less prominent and creatine kinase levels are either normal or only mildly elevated. Further study is necessary to determine why rimmed vacuoles are so common in the distal myopathies, and what role they play in the pathogenesis of muscle fibre atrophy and loss, predominantly in the distal portions of the extremities.

Genes, Recessive↗
PubMed1999

Myonuclear domain and myosin phenotype in human soleus after bed rest with or without loading.

After 2 or 4 mo of bed rest (6 degrees head-down tilt) and 1 mo of ambulation, there was a tendency toward a higher percentage of fibers expressing fast myosin heavy chain (MHC) isoforms and a de novo appearance of fibers coexpressing type I+IIa+IIx and IIa+IIx MHC in human soleus fibers. After 2 and 4 mo of bed rest, the mean size of type I fibers decreased by 12 (P > 0.05) and 39%, respectively. Because myonuclear number/mm of fiber length was unchanged, myonuclear domain was smaller after bed rest than before. The mean size and myonuclear domain of type I fibers were largest after 1 mo of recovery. The effects of wearing an antigravity device (Penguin suit), which had a modest but continuous resistance at the knee and ankle (Penguin-1) or knee resistance without loading on the ankle (Penguin-2), for 10 consecutive h/day were determined during 2 mo of bed rest. Mean fiber sizes in Penguin-1, but not Penguin-2, group were maintained at or above pre-bed-rest levels, whereas neither group showed phenotype changes. Myonuclear domain in type I fibers was larger in Penguin-1 and smaller in Penguin-2 group post- compared with pre-bed rest, indicating that a single daily 10-h bout of modest muscle loading can prevent bed-rest-induced soleus fiber atrophy but has minimal effect on myosin phenotype. The specific adaptive cellular strategies involved may be a function of the duration and magnitude of the adaptive stimulus as well as the immediate activity history of the fiber before the newly changed functional demands.

Adult↗
PubMed1999

[MELAS].

Explore the source record for details and available documents.

DNA, Mitochondrial↗
PubMed1999

[A patient of Walker-Warburg syndrome with a haplotype different from that in Fukuyama-type congenital muscular dystrophy].

A 3-month-old female baby was diagnosed as having Walker-Warburg syndrome (WWS), based on the following clinical findings: type II lissencephaly associated with marked ventricular dilatation, cerebellar malformation, retinal malformation, elevated serum creatine kinase level and abnormal muscle CT findings. She was a product of parents with consanguineous marriage. She presented with severe hypotonia and profound psychomotor retardation since birth. She developed infantile spasms at 8 months of age, and vitamin B6 was very effective. A genetic analysis revealed the absence of the founder haplotype commonly seen in Fukuyama-type congenital muscular dystrophy (FCMD), suggesting that the WWS gene is not always identical to the FCMD gene. When she was examined at the age of 4 years, she had no apparent further psychomotor development. Her clinical symptoms were more severe than those of the typical FCMD.

Abnormalities, Multiple↗
PubMed1999

[A sporadic case of Charcot-Marie-Tooth disease type 1 A associated with a duplication in chromosome 17 p11.2-p12].

Charcot-Marie-Tooth disease type 1A (CMT1A) is an autosomal dominant demyelinating peripheral neuropathy. Most patients with CMT1A including sporadic cases have been found to have a 1.5 megabase tandem DNA duplication in chromosome 17 p11.2-p12 (CMT1A duplication). We reported a 7-year-old girl with sporadic CMT 1 associated with the CMT1A duplication. The diagnosis of CMT 1 was based on the symmetrical distal muscle weakness, per cavus deformity, reduced motor and sensory nerve conduction velocities, and segmental de- and remyelinatin on sural nerve biopsy. To detect the CMT 1A duplication, peripheral myelin protein 22 (PMP-22) cDNA and a polymorphic marker in this region, VAW409 R3, were employed as probes for Southern blot analysis. Sporadic cases of autosomal dominant-CMT type 1 can not be clinically differentiated from recessive-CMT1. Testing for the CMT1A duplication is an important first step even in the molecular diagnosis of sporadic CMT1.

Charcot-Marie-Tooth Disease↗
PubMed1999

[Hepatic involvement in a case of lysosomal glycogen storage disease with normal acid maltase].

A 19-year-old man, who could run only slowly since childhood and who walked on his toes since 12 years of age, noted difficulty in climbing upstairs at 17 years of age. He was admitted to Kyushu University Hospital because of elevated AST, ALT and CK levels. On admission, the liver was palpable two fingerbreadths beneath the right costal margin. A neurological examination revealed a low IQ on WAIS-R, a decreased muscle tonus in his four limbs, moderate weakness of the neck flexor and bilateral tibialis anterior muscles, contracture of the ankle joints, and bilateral pes cavus. The serum CK was elevated to 1,124U/l. Hepatic enzymes, such as AST, ALT, LDH and gamma-GTP were also moderately increased in the sera. A needle EMG disclosed myogenic patterns in the limb muscles. Biopsied biceps brachii muscle showed a mild variation in the fiber size and multiple tiny vacuoles in 5-10% of the muscle fibers. PAS and acid phosphatase were strongly positive in some vacuoles. On electron microscopy, numerous autophagic vacuoles containing glycogen granules were observed. The acid maltase activities were, however, normal in the peripheral blood lymphocytes, the biopsied muscle, and the cultured skin fibroblasts. He was thus diagnosed to have lysosomal glycogen storage disease with normal acid maltase. A histological examination of the biopsied liver revealed the portal and central veins to be slightly sclerotic. In addition, mild fatty changes and frequent nuclear vacuolization were present in the hepatocytes. On electron microscopy, enlarged mitochondria with irregular cristae were also observed. Due to the fact that the cardiac function was well preserved, these hepatic lesions were thought to result from the metabolic abnormalities underlying in this disorder.

Adult↗
PubMed1998

Four novel mutations of the connexin 32 gene in four Japanese families with Charcot-Marie-Tooth disease type 1.

DNA-based mutation analysis on the connexin 32 gene was performed in 49 families with Charcot-Marie-Tooth disease (CMT) type 1 but without duplication involving the chromosomal region, 17p12-p11.2. Mutations were identified in five of the 49 families, and four of the five mutations were hitherto undescribed: Va137Met, Glu57His, Arg142Glu, Val177Ala. X-linked CMT sometimes lacks evidence for X-linked transmission and cannot be differentiated from CMT type 2, especially in females with mildly decreased nerve conduction velocity. Therefore, molecular analysis is useful for molecular pathology of their disease.

Adolescent↗
PubMed1998

Up-regulation of glial cell line-derived neurotrophic factor (GDNF) expression in regenerating muscle fibers in neuromuscular diseases.

Glial cell line-derived neurotrophic factor (GDNF) has been shown to exert a target-derived trophic factor for motor neurons. Immunohistochemical analyses revealed that expression of GDNF in regeneration muscle fibers was up-regulated in polymyositis (PM) and Duchenne type muscular dystrophy (DMD). Reverse transcriptase polymerase chain reaction (RT-PCR) analyses showed that the full length GDNF was up-regulated in PM and DMD muscle; normal muscle exhibited mostly truncated GDNF. The results indicate that the GDNF expression is regulated in regeneration of human skeletal muscle.

Cells, Cultured↗
PubMed1998

Lysosomal glycogen storage disease with normal acid maltase with early fatal outcome.

In a male infant who had cardiomyopathy, generalized muscle weakness and increased serum creatine kinase levels, his muscle biopsy revealed myopathic changes with tiny intracytoplasmic vacuoles containing PAS-positive material and high acid phosphatase activity, but had normal acid maltase activity biochemically. These findings were consistent with those seen in lysosomal glycogen storage disease with normal acid maltase (Danon disease). Sarcolemmal indentations commonly seen in this disease were missing, but a complement membrane attack complex, C5b-9 was positive along the surface membrane of the muscle fibers as seen in X-linked vacuolar myopathy. The patient was on a respirator and died at 27 months of age from pneumonia and hypertrophic cardiomyopathy. Lysosomal glycogen storage disease with normal acid maltase may be manifested at birth with marked skeletal and cardiac involvement leading to death in early infancy.

Biomarkers↗