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K Arahata

Publications and source records attributed to K Arahata.

At least 55 records · Page 3Linked to original sources
PubMed1998

Dysferlin, a novel skeletal muscle gene, is mutated in Miyoshi myopathy and limb girdle muscular dystrophy.

Miyoshi myopathy (MM) is an adult onset, recessive inherited distal muscular dystrophy that we have mapped to human chromosome 2p13. We recently constructed a 3-Mb P1-derived artificial chromosome (PAC) contig spanning the MM candidate region. This clarified the order of genetic markers across the MM locus, provided five new polymorphic markers within it and narrowed the locus to approximately 2 Mb. Five skeletal muscle expressed sequence tags (ESTs) map in this region. We report that one of these is located in a novel, full-length 6.9-kb muscle cDNA, and we designate the corresponding protein 'dysferlin'. We describe nine mutations in the dysferlin gene in nine families; five are predicted to prevent dysferlin expression. Identical mutations in the dysferlin gene can produce more than one myopathy phenotype (MM, limb girdle dystrophy, distal myopathy with anterior tibial onset).

Adult↗
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

Two cases of chromosome 4q35-linked early onset facioscapulohumeral muscular dystrophy with mental retardation and epilepsy.

Two cases of early onset facioscapulohumeral muscular dystrophy (FSHD) with mental retardation and epilepsy are reported. They were sporadic, unrelated, severely affected females. In both cases, Southern blot analysis of the EcoRI-digested genomic DNA, using probes p13E-11 and pFR-1, detected the shortest 10 kb EcoRI fragments reported to date. Patient 1 showed infantile spasms at the age of 4 months and localization-related epilepsy at the age of 2.5 years. Muscular atrophy in the face, shoulder girdle and upper arms was observed from the age of 4 years. In Patient 2, lack of facial expression was noticed since the age of 1 year, and at 4 years she was noted to have a loss of bilateral upward gaze. She developed localization-related epilepsy at the age of 9 years. From the age of 10 years, weakness of the lower limbs progressed and she became wheelchair-bound at the age of 14 years and 8 months. She had moderate sensorineural hearing loss, a loss of bilateral upward gaze and tongue atrophy. Their IQs were 33 and 45, respectively. The two patients suggest that mental retardation and epilepsy may be part of the clinical spectrum of FSHD, especially in very early onset patients with large deletions.

Adolescent↗
PubMed1998

Epilepsy and mental retardation in a subset of early onset 4q35-facioscapulohumeral muscular dystrophy.

The gene for facioscapulohumeral muscular dystrophy (FSHD) has been mapped to chromosome 4q35. In most patients with FSHD, a deletion of 3.3 kb tandemly repeated units within the EcoRI fragment that can be detected by probe p13E-11 is associated with the disease. To elucidate the relation between the phenotype and the genotype in FSHD, we examined 91 Japanese unrelated families with a clinical diagnosis of FSHD (140 patients, 205 healthy individuals). Of these, 78 families (86%) had 4q35-FSHD (127 patients), in which 20 patients (20/127, 16%) were classified as early onset FSHD. We found that all nine patients with the smallest EcoRI fragments (10 to 11 kb) were classified among the early onset group (9/20, 45%), and these patients showed a high frequency of both epilepsy (4/9, 44%) and mental retardation (8/9, 89%). In contrast, none of the remaining patients with 4q35-FSHD had epilepsy or mental retardation. We conclude that FSHD patients with a large gene deletion in the FSHD gene region tend to have a higher chance of showing severe clinical phenotypes with CNS abnormalities. This finding may have practical implications for genetic counseling, although the molecular genetic background remains unclear.

Adolescent↗
PubMed1997

Integrins (alpha7beta1) in muscle function and survival. Disrupted expression in merosin-deficient congenital muscular dystrophy.

Mutations in genes coding for dystrophin, for alpha, beta, gamma, and delta-sarcoglycans, or for the alpha2 chain of the basement membrane component merosin (laminin-2/4) cause various forms of muscular dystrophy. Analyses of integrins showed an abnormal expression and localization of alpha7beta1 isoforms in myofibers of merosin-deficient human patients and mice, but not in dystrophin-deficient or sarcoglycan-deficient humans and animals. It was shown previously that skeletal muscle fibers require merosin for survival and function (Vachon, P.H., F. Loechel, H. Xu, U.M. Wewer, and E. Engvall. 1996. J. Cell Biol. 134:1483-1497). Correction of merosin deficiency in vitro through cell transfection with the merosin alpha2 chain restored the normal localization of alpha7beta1D integrins as well as myotube survival. Overexpression of the apoptosis-suppressing molecule Bcl-2 also promoted the survival of merosin-deficient myotubes, but did not restore a normal expression of alpha7beta1D integrins. Blocking of beta1 integrins in normal myotubes induced apoptosis and severely reduced their survival. These findings (a) identify alpha7beta1D integrins as the de facto receptors for merosin in skeletal muscle; (b) indicate a merosin dependence for the accurate expression and membrane localization of alpha7beta1D integrins in myofibers; (c) provide a molecular basis for the critical role of merosin in myofiber survival; and (d) add new insights to the pathogenesis of neuromuscular disorders.

Animals↗
PubMed1997

Laminin alpha2 chain-null mutant mice by targeted disruption of the Lama2 gene: a new model of merosin (laminin 2)-deficient congenital muscular dystrophy.

Using the gene targeting technique, we have generated a new mouse model of congenital muscular dystrophy (CMD), a null mutant for the laminin alpha2 chain. These homozygous mice, designated dy3Kldy3K, are characterized by growth retardation and severe muscular dystrophic symptoms and die by 5 weeks of age. Light microscopy revealed that muscle fiber degeneration in these mice begins no later than postnatal day 9. In degenerating muscles, considerable amounts of TUNEL positive nuclei were detected as well as DNA laddering, suggesting increased apoptotic cell death was involved in the process of muscle fiber degeneration.

Animals↗
PubMed1997

Emerin, deficiency of which causes Emery-Dreifuss muscular dystrophy, is localized at the inner nuclear membrane.

X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscle disorder characterized by the clinical triad of progressive wasting of humero-peroneal muscles, early contractures of the elbows, Achilles tendons and postcervical muscles, and cardiac conduction block with a high risk of sudden death. The gene for EDMD on Xq28 encodes a novel protein named emerin that localizes at the nuclear membrane of skeletal, cardiac and smooth muscles and some other non-muscle tissues. To investigate a possible physiological role for emerin, we examined the ultrastructural localization of the protein in human skeletal muscle and HeLa cells, using ultrathin cryosections. We found that the immune-labeled colloidal gold particles were localized on the nucleoplasmic surface of the inner nuclear membrane, but not on the nuclear pore. Emerin stayed on the cytoplasmic surface of the nuclear lamina, even after detergent treatment that solubilizes membrane lipids and washes out membrane proteins. These results suggest that emerin anchors at the inner nuclear membrane through the hydrophobic stretch, and protrudes from the hydrophilic region to the nucleoplasm where it interacts with the nuclear lamina. We speculate that emerin contributes to maintain the nuclear structure and stability, as well as nuclear functions, particularly in muscle tissues that have severe stress with rigorous contraction-relaxation movements and calcium flux.

Cell Nucleus↗
PubMed1997

Electron microscopic examination of basal lamina in Fukuyama congenital muscular dystrophy.

By light microscopy we previously obtained immunocytochemical evidence for basal lamina (BL) abnormality of skeletal muscle in Fukuyama congenital muscular dystrophy (FCMD). To further elucidate the pathological involvement of the BL in FCMD, we examined by electron microscopy the skeletal muscle in 12 cases of FCMD, nine cases of age-matched neuromuscular diseases unrelated to FCMD, and a case of merosin-negative CMD (MCMD). We found that the BL of skeletal muscle fibres in all patients with FCMD and the MCMD patient had a thin, deranged and often disrupted appearance. These features were more prominent in large calibre (> 15 microns) fibres than in small calibre (approximately 8 microns) fibres. Replication of the BL was not observed in 11 of the 12 FCMD patients. Although the BL over the intact plasma membrane had occasional gaps, the plasma membrane under the disrupted BL was normal in some case. Our results indicate the presence of fragile BL which may precede plasma membrane damage in FCMD skeletal muscle.

Basement Membrane↗
PubMed1997

Emery-Dreifuss syndrome.

Emery-Dreifuss syndrome is a heterogeneous entity characterized by the following clinical triad: early contracture of the elbows. Achilles tendons and postcervical muscles; slowly progressive muscle wasting and weakness with a humeroperoneal distribution early in the course of disease; and a cardiomyopathy usually presenting as an atrioventricular block ranging from sinus bradycardia to complete heart block. As the heart block is the major problem, insertion of a cardiac pacemaker can be life saving. Recent advances through genetic and immunochemical studies have provided valuable clues to the understanding and the early diagnosis of this disease.

Cardiomyopathies↗
PubMed1997

Altered expression of the alpha7beta1 integrin in human and murine muscular dystrophies.

The alpha7beta1 integrin is the primary laminin receptor on skeletal myoblasts and adult myofibers. It has distinct functions during muscle development and contributes to muscle structural integrity. We have studied this integrin in cases where expression of dystrophin or laminin are compromised. Immunofluorescence demonstrates an increase in alpha7beta1 in patients with Duchenne muscular dystrophy and in mdx mice that lack dystrophin. Analysis of RNA from mdx mice and from patients with Duchenne and Becker muscular dystrophies indicates that the increase in the alpha7beta1 integrin is regulated at the level of alpha7 gene transcription. In contrast, the levels of alpha7beta1 integrin are severely diminished in patients with laminin alpha2 chain congenital dystrophy muscular dystrophy and in dy/dy mice that also do not make the alpha2 laminin chain. Analysis of RNA from the hindlimbs of dy/dy mice demonstrated that in the absence of laminin alpha7 gene transcription is inhibited and limited to specific alternatively spliced isoforms. We suggest that the increased expression of alpha7beta1 integrin in the absence of dystrophin compensates for the reduced dystrophin-mediated linkage of fibers with the basal lamina and modulates the development of pathology associated with these diseases. The decrease in alpha7beta1 integrin and its transcripts in the absence of laminin likely contributes to the severe myopathy that results from laminin alpha2 chain deficiency and suggests that laminin-2 regulates expression of the alpha7 integrin gene. The role of the alpha7beta1 integrin in muscle integrity also suggests that compromised expression of this receptor may underlie as yet undefined myopathies.

Adult↗
PubMed1997

[Changes in patterns of morbidity over 10 years among elderly patients with stroke who were treated in a rehabilitation unit].

We examined changes in outcomes among elderly patients with stroke who were admitted to the rehabilitation unit of our hospital from April, 1985 to March, 1995. During that period, 933 patients (489 men and 444 women, average age 71.3 years) were admitted and received physical therapy. During those 10 years, the average age of the patients increased, functional status with regard to sitting up and walking worsened, and the incidence of urinary incontinence at the time of discharge increased. In contrast, the percentage of patients discharged to home (50 to approximately 60%), the degree of impairment of lower extremities, and the onset-to-admission interval (3 to 4 months) did not change.

Aged↗
PubMed1997

[The frequency of patients with adhalin deficiency in a muscular dystrophy patient population].

Immunocytochemical deficiency of alpha-sarcoglycan (adhalin) in the skeletal muscle that is associated with normal dystrophin expression has been called adhalinopathy. However, recent molecular biological and genetic studies revealed that alpha-sarcoglycan is one of four subunits of sarcoglycans (alpha-delta) or sarcoglycan complex. Mutations of any one of the genes of these subunits cause loss of sarcoglycan complex, and therefore they are now called sarcoglycanopathy or limb-girdle muscular dystrophy (LGMD) 2C-2F. The frequency of sarcoglycanopathy is about 5-10% of dystrophin-normal muscular dystrophy. Mutation of alpha-sarcoglycan gene is most frequent (34%) among the four sarcoglycan genes as shown in the tables. However, 38% of the patients with sarcoglycanopathy have no mutation, implying the presence of yet unknown sarcoglycan(s) and/or interacting protein(s) with sarcoglycan complex.

Cytoskeletal Proteins↗
PubMed1997

[Facioscapulohumeral muscular dystrophy (FSHD)].

Facioscapulohumeral muscular dystrophy (FSHD; MIM 158900) is one of the major forms of muscular dystrophy, and is inherited in an autosomal dominant fashion. In most patients with FSHD, deletion of 3.3 kb tandemly repeated units within the EcoRI fragment, as detected by p13E-11 (D4F104S1) on chromosome 4q35, is associated with the disease (FSHD1A or 4q35-FSHD). Rare (< 5%) 4q35-unlinked FSHD (FSHD1B) is also known, and therefore genetic heterogeneity exists among FSHD. Recent studies based on the distinction of 4q35 EcoRI fragments from those of 10q26 improved the reliability of molecular diagnosis of the disease (> 95% accuracy). However, gene for FSHD1A has not been identified yet. Identification of the FSHD gene and characterization of the gene product are waited on tiptoe with expectation.

Chromosomes, Human, Pair 4↗
PubMed1997

[Emery-Dreifuss muscular dystrophy].

Emery-Dreifuss muscular dystrophy (EDMD) is an inherited muscular disorder characterized by the triad of progressive weakness in humero-peroneal muscles, early onset contractures and cardiomyopathy with conduction block that shows a high risk of sudden death. In 1994, the gene responsible for X-linked EDMD has been identified to Xq28 (designated as STA), that encodes a serine-rich protein of 254 amino acids, named emerin. In 1996, we discovered a nuclear membrane localization of emerin in the normal skeletal, cardiac and smooth muscles, but not in the tissues from patients with X-linked EDMD who had a nonsense mutation in the gene. In conclusion, molecular and genetic analyses of emerin are essential for accurate diagnosis of patients with EDMD.

Cardiomyopathies↗
PubMed1997

[Clinical and molecular genetic analyses of congenital myotonic dystrophy].

Myotonic dystrophy (DM) results from the amplification of an unstable CTG repeat in the 3' untranslated region of a transcript encoding an MtPK. Infants with congenital DM are shown to have on average a greater amplification of the CTG repeat than is seen in the noncongenital DM patients. The major clinical features of congenital DM are bilateral facial weakness, hypotonia, feeding difficulties, respiratory distress, delayed motor development and mental retardation. We present 6 patients, aged 11-35 years, from unrelated 5 families with clinical symptoms of congenital DM. The four of the patients were inherited paternally and only one showed a reduction in the CTG repeat size.

Gene Amplification↗
PubMed1996

Enhancement of CPP32-like activity in the TNF-treated U937 cells by the proteasome inhibitors.

CPP32, which is most closely related to CED-3 in the apoptotic protease in C. elegance, is activated during apoptosis induced by anti-Fas and TNF. Since processing of CPP32 is important for the activation, we examined the effects of protease inhibitors on CPP32-like activity in the TNF-treated U937 cells. Unexpectedly, proteasome inhibitors (at 5 microM) such as Z-LLnV, Z-LLL, and lactacystin enhanced CPP32-like activity, Ac-DEVD-MCA degrading activity, in the TNF-treated U937 cells in 3 hr, but E64d, cysteine protease inhibitor, did not. These proteasome inhibitors alone did not enhance CPP32-like activity in the untreated U937 cells under the condition used. The proteasome seems to protect the cells from apoptosis by degrading CPP32-like protease or its processing enzyme.

Caspase 3↗