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Biomedical subjects

I Nonaka

Publications and source records attributed to I Nonaka.

At least 73 records · Page 4Linked to original sources
PubMed2000

Primary LAMP-2 deficiency causes X-linked vacuolar cardiomyopathy and myopathy (Danon disease).

"Lysosomal glycogen storage disease with normal acid maltase" which was originally described by Danon et al., is characterized clinically by cardiomyopathy, myopathy and variable mental retardation. The pathological hallmark of the disease is intracytoplasmic vacuoles containing autophagic material and glycogen in skeletal and cardiac muscle cells. Sarcolemmal proteins and basal lamina are associated with the vacuolar membranes. Here we report ten unrelated patients, including one of the patients from the original case report, who have primary deficiencies of LAMP-2, a principal lysosomal membrane protein. From these results and the finding that LAMP-2-deficient mice manifest a similar vacuolar cardioskeletal myopathy, we conclude that primary LAMP-2 deficiency is the cause of Danon disease. To our knowledge this is the first example of human cardiopathy-myopathy that is caused by mutations in a lysosomal structural protein rather than an enzymatic protein.

Antigens, CD↗
PubMed2000

Walker-Warburg syndrome is genetically distinct from Fukuyama type congenital muscular dystrophy.

A female patient who fulfilled the diagnostic criteria of Walker-Warburg syndrome had muscle biopsy finding of muscular dystrophy. There was normal expression of merosin (laminin alpha2 chain) and dystrophin and only slightly reduced dystrophin-associated glycoprotein expression. On genetic analysis, she had no specific haplotype, the common mutation of 3kb insertion, or point mutations in the Fukuyama-type congenital muscular dystrophy gene, suggesting that the two diseases are not genetically identical.

Alleles↗
PubMed2000

Haemopoietic biglycan produced by brain cells stimulates growth of microglial cells.

We have recently found that soluble biglycan purified from rat thymic myoid cells had haemopoietic activity capable of inducing preferential growth and differentiation of monocytic lineage cells from various haemopoietic sources, including brain microglial cells. In the present study, to understand developmental mechanisms of microglial/monocytic cells in the brain, we have attempted to identify haemopoietic activity of the brain biglycan. The mRNA and the immunological epitope of biglycan were detected in the rat brain homogenates and several rat glial cell lines. Immunohistochemical study showed that several different types of brain cells produced biglycan. During development biglycan synthesis in the brain appeared to be increased. The brain haemopoietic biglycan was easily separated by DEAE-Sepharose chromatography from the macrophage colony stimulating factor (M-CSF) which was concomitantly produced from the brain cells. The brain haemopoietic biglycan, purified through immunoaffinity column, indeed stimulated growth of primarily cultured microglial cells. Taken together, these results suggest that the haemopoietic biglycan plays an important role in generating brain-specific circumstances for development of microglial/monocytic cells.

Animals↗
PubMed2000

Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2A.

A defect of the gene for p94 (calpain 3), a skeletal muscle-specific calpain, is responsible for limb girdle muscular dystrophy type 2A (LGMD2A), or 'calpainopathy', which is an autosomal recessive and progressive neuromuscular disorder. To study the relationships between the physiological functions of p94 and the etiology of LGMD2A, we created transgenic mice that express an inactive mutant of p94, in which the active site Cys129 is replaced by Ser (p94:C129S). Three lines of transgenic mice expressing p94:C129S mRNA at various levels showed significantly decreased grip strength. Sections of soleus and extensor digitorum longus (EDL) muscles of the aged transgenic mice showed increased numbers of lobulated and split fibers, respectively, which are often observed in limb girdle muscular dystrophy muscles. Centrally placed nuclei were also frequently found in the EDL muscle of the transgenic mice, whereas wild-type mice of the same age had almost none. There was more p94 protein produced in aged transgenic mice muscles and it showed significantly less autolytic degradation activity than that of wild-type mice. Although no necrotic-regenerative fibers were observed, the age and p94:C129S expression dependence of the phenotypes strongly suggest that accumulation of p94:C129S protein causes these myopathy phenotypes. The p94:C129S transgenic mice could provide us with crucial information on the molecular mech-anism of LGMD2A.

Animals↗
PubMed2000

Expression of MyoD and myogenin in dystrophic mice, mdx and dy, during regeneration.

Expression of two myogenic regulatory factors, MyoD and myogenin, was studied in regenerating muscles of dystrophic mice and compared to a chemically induced regeneration process. First, the distribution of the two proteins was determined immunohistochemically at various time points after single administrations of a local anaesthetic, bupivacaine hydrochloride, which causes myonecrosis followed by regeneration. Detectable levels of MyoD appeared at 18 h and the expression reached their maximum levels at 48 h after the injection, which coincide with the stage when satellite cells are activated and start to proliferate. Myogenin became detectable in 24 h and its expression reached its highest level at 72 h after injection when newly formed myotubes appeared. The two genes were also expressed in the dystrophic muscles from dy and mdx mice which exhibit dystrophic pathological features but are associated with different phenotypes. In mdx mice the two genes were expressed at reasonably high levels in parallel with the active regenerating process, whereas in dy mice MyoD and myogenin expressions decreased as fibrosis progressed. However, MyoD was relatively more strongly expressed in the larger mature myotubes of dy mice than in those of mdx mice, suggesting prolonged regenerative activity. In dy and mdx mice, MyoD and myogenin were expressed in different quantities, indicating that these animals have distinct regenerating activities. Our findings confirm that expression of both MyoD and myogenin genes is necessary in the regenerative process for the proliferation of satellite cells (myoblasts) and for the development of early regenerating fibers (myotubes) even in dystrophic muscles.

Animals↗
PubMed2000

Mitochondrial DNA mutations in Leigh syndrome and their phylogenetic implications.

Of 100 patients with the clinical diagnosis of Leigh syndrome, 21 were found to have specific enzyme defects: 15 involving cytochrome c oxidase (COX); 4, pyruvate dehydrogenase complex (PDHC); one, complex I (reduced nicotinamide adenine dinucleotide [NADH]-coenzyme Q reductase) and one, complex II (succinate-ubiquinone reductase) deficiencies. In addition to the most common form of COX deficiency, mtDNA mutations in the adenosine triphosphatase (ATPase) 6 coding region were also commonly seen. Eighteen patients (18%) had mtDNA mutations at nucleotide position (np) 8993 or 9176. The mutated DNAs were present in a heteroplasmic state, comprising more than 90% of the DNA in muscle and/or blood samples from all patients. Patients with the T-to-G mutation at np 8993 usually had early onset of the disease with rapid progression, showing the typical clinical features of Leigh syndrome. On the other hand, those with the T-to-C 8993 mutation showed a milder and more chronic course. Patients with the mutation at np 9176 showed variable courses. Phylogenetic analysis of mtDNA D-loop sequences for the patients with the ATPase 6 mutations and normal Japanese subjects revealed that a T-to-G/C mutation at np 8993 and a T-to-C mutation at np 9176 occurred many times independently in the Japanese population.

Adenosine Triphosphatases↗
PubMed2000

Two pathogenic point mutations exist in the authentic mitochondrial genome, not in the nuclear pseudogene.

Technical advancements in molecular genetics have shown various mitochondrial DNA (mtDNA) abnormalities in patients with mitochondrial myopathies. Recently, it has been revealed that, in these patients, the nuclear DNA carries sequences similar to those of the mtDNA (nuclear pseudogene) and it has several point mutations previously reported to be pathogenic. We verified the existence of the T3250C and T3291C mutations, which we have found in patients with mitochondrial myopathy, in the authentic mitochondrial genome. A long polymerase chain reaction provides a powerful tool for avoiding nuclear pseudogene amplification and for ruling out ambiguity in the detection of the mutation for diagnosis.

DNA, Mitochondrial↗
PubMed2000

A patient with mitochondrial myopathy associated with isolated succinate dehydrogenase deficiency.

We report on a boy with normal mental development who had muscle hypotonia and congenital dislocation of the hip and knee joints. Histochemical and biochemical examinations of his muscle specimen revealed no succinate dehydrogenase (SDH) activity. Since the NADH cytochrome c reductase and cytochrome c oxidase activities were normal, we concluded that he had an isolated SDH deficiency. Our patient provides further evidence for the clinical variability of this disorder.

Biopsy↗
PubMed2000

Central core disease and congenital neuromuscular disease with uniform type 1 fibers in one family.

We report a family in which the father had central core disease and his son had congenital neuromuscular disease with uniform type 1 fibers. This is the first report of such a combination. Although they had no recognized mutation in the ryanodine receptor gene, it is highly likely that the son also had central core disease but without core structures. The absence of cores may be due to the muscle sample or the young age of the patient since core structures have been reported to increase with age. Although the prevalence of core structures in individual muscles is unknown, there is a possibility of sampling error. In some patients, congenital neuromuscular disease with uniform type 1 fibers is closely related to or identical with central core disease.

Adult↗
PubMed2000

A case of Walker-Warburg syndrome.

Walker-Warburg syndrome (WWS) is an autosomal recessive disorder characterized by type II lissencephaly, cerebellar and retinal anomalies, and congenital muscular dystrophy. We report a female diagnosed with WWS based on clinical criteria. This patient was found to have fetal hydrocephalus on ultrasonography at 29 weeks of gestation, and exhibited severe hypotonia, ocular malformations, and hydrocephalus at birth. MRI revealed type II lissencephaly, hydrocephalus, and other severe brain malformations. Genetic analysis was performed to distinguish WWS from severe Fukuyama-type congenital muscular dystrophy (FCMD), which has numerous findings in common. This revealed no expression of the founder haplotype or single-stranded conformation polymorphism (SSCP) abnormalities. Since the life expectancy of patients with FCMD is longer, differential diagnosis should be performed precisely.

Abnormalities, Multiple↗
PubMed2000

Siblings of Schwartz-Jampel syndrome with abnormal muscle computed tomographic findings.

Schwartz-Jampel syndrome (SJS) is a disorder characterized by myotonia, joint contractures, skeletal abnormalities, facial dysmorphism and growth retardation. We present two boys of ages 4 and 8 years with SJS. Their clinical, electromyographic and histopathological findings were similar to those described, except for computed tomography (CT) images that revealed diffuse high attenuation in sternocleidomastoid muscles and low attenuation in the paraspinal, quadriceps, sartorius, soleus and gastrocnemius muscles. This is the first report describing abnormal muscle CT findings associated with SJS. Additional studies of muscle CT might help to improve understanding of the pathogenesis of SJS.

Child↗
PubMed2000

Glycogen storage myopathies.

The glycogen storage myopathies are caused by enzyme defects in the glycogenolytic or in the glycolytic pathway affecting skeletal muscle alone or in conjunction with other tissues. The authors review recent findings in this area, including a new entity, aldolase deficiency, and the wealth of molecular genetic data that are rapidly accumulating. Despite this progress, genotype-phenotyp3 correlations are still murky in most glycogen storage myopathies.

Biopsy↗
PubMed2000

Frequent mutations in Japanese patients with acid maltase deficiency.

We screened 22 Japanese patients with acid maltase deficiency (seven with the infantile type, eight with the juvenile type and seven with the adult type) for three previously described mutations, D645E, S529V and R672Q, and a novel mutation, R600C. Although D645E has been reported to be common in Chinese patients with the infantile type, only three of 44 alleles (two of 14 infantile type alleles) from Japanese patients harbored the D645E mutation. The S529V mutation was identified in six of 14 alleles from adult-onset patients. None of the infantile or juvenile patients harbored the S529V mutation. Therefore, S529V apparently results in the adult type disease and is common in Japanese adult-onset patients. R672Q was identified in two pairs of siblings with the juvenile type. A novel mutation, R600C, was identified in eight of 22 patients (nine of 44 alleles). Therefore, R600C is another common Japanese mutation occurring at a CpG dinucleotide "hot spot". Homozygosity for this mutation apparently results in the infantile phenotype. Genetic diagnosis by detecting these four mutations might be feasible for most Japanese patients with acid maltase deficiency.

Adolescent↗
PubMed2000

Genetic heterogeneity in three Chinese children with Fukuyama congenital muscular dystrophy.

Three Chinese patients, two boys and one girl, were afflicted with the typical clinical, myopathological and neuroradiological findings of Fukuyama congenital muscular dystrophy (FCMD). Polymorphism analysis of our patients did not reveal the founder haplotype (138-192-147-183 in D9S2105-D9S2170-D9S2171-D9S2107) of Japanese FCMD, even though one patient was descended from Japanese ancestry. Full mutational analysis of the fukutin gene revealed that there is neither 3 kb insertion nor point mutation. These findings suggest genetic heterogeneity between Chinese and Japanese FCMD patients.

Child↗
PubMed2000

Oculopharyngeal muscular dystrophy in a Japanese family with a short GCG expansion (GCG)(11) in PABP2 gene.

Clinicopathological and molecular genetic findings on a new Japanese family with oculopharyngeal muscular dystrophy are reported. The family has 54 members, ten of whom are affected (seven male and three female), in 3 generations. Three affected males, one affected female and one unaffected female of seven living siblings in the third generation were examined. Bilateral ptosis developed in the 4th and 5th decades in the three male cases, and in the 7th decade in the female, and this was followed by diplopia, nasal voice, dysphagia and muscle weakness. In addition, severe external ophthalmoplegia, dysphonia, and proximal amyotrophy were prominent in this family. Electromyographs revealed myogenic/neurogenic changes, and computed tomography disclosed selective muscle wasting with fatty replacement, predominantly in the lower extremities. Muscle biopsy in the four affected patients showed variation in fiber size, and the presence of small angulated fibers and occasional rimmed vacuoles. Electron microscopic examination revealed an accumulation of filamentous inclusions in muscle fiber nuclei. DNA analysis identified that (GCG)(6) in the PABP2 gene was expanded to (GCG)(11) in the four affected cases examined. All studies were negative in the one unaffected. These results confirm that OPMD is caused by GCG short expansion and provides insights into the genetic mechanisms which may contribute to adult onset myopathy, confined to oculopharyngeal muscles.

Aged↗
PubMed2000

Generation of mice with mitochondrial dysfunction by introducing mouse mtDNA carrying a deletion into zygotes.

Mice carrying mitochondrial DNA (mtDNA) with pathogenic mutations would provide a system in which to study how mutant mtDNAs are transmitted and distributed in tissues, resulting in expression of mitochondrial diseases. However, no effective procedures are available for the generation of these mice. Isolation of mouse cells without mtDNA (rho0) enabled us to trap mutant mtDNA that had accumulated in somatic tissues into rho0 cells repopulated with mtDNA (cybrids). We isolated respiration-deficient cybrids with mtDNA carrying a deletion and introduced this mtDNA into fertilized eggs. The mutant mtDNA was transmitted maternally, and its accumulation induced mitochondrial dysfunction in various tissues. Moreover, most of these mice died because of renal failure, suggesting the involvement of mtDNA mutations in the pathogeneses of new diseases.

Animals↗