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Biomedical subjects

Y Sunada

Publications and source records attributed to Y Sunada.

At least 55 records · Page 3Linked to original sources
PubMed1996

Absence of gamma-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy linked to chromosome 13q12.

We have partially sequenced rabbit skeletal muscle gamma-sarcoglycan, an integral component of the dystrophin-glycoprotein complex. Specific antibodies were produced against a gamma-sarcoglycan peptide and used to examine the expression of gamma-sarcoglycan in skeletal muscle of patients with severe childhood autosomal muscular dystrophy linked to chromosome 13q12 (SCARMD). We show by immunofluorescence and Western blotting that in skeletal muscle from these patients gamma-sarcoglycan is completely absent and alpha- and beta-sarcoglycan are greatly reduced in abundance, whereas other components of the DGC are preserved. In addition, we show that in normal muscle alpha-, beta-, and gamma-sarcoglycan constitute a tightly associated sarcolemma complex which cannot be disrupted by SDS treatment.

Animals↗
PubMed1996

Clinical heterogeneity of adhalin deficiency.

We report adhalin deficiency in 8 patients with clinically diagnosed muscular dystrophy, dystrophic histopathological features, high plasma creatine kinase levels, normal expression of dystrophin, and marked variability of symptoms. Although the distribution of hyposthenia was similar in all 8 patients and predominantly involved muscles in the pelvic girdle, age at onset and rate of disease progression were highly variable: In 2 patients onset, at ages 24 and 25, was later than has been previously observed. We found no apparent relation between disease severity and the quantity of adhalin expressed. Two kinds of myopathy with adhalin deficiency have been reported: one caused by a mutation in the adhalin gene on chromosome 17 (primary adhalinopathy) and the other linked to chromosome 13. The product of the gene on chromosome 13 is probably associated with adhalin and its deficiency results in secondary adhalinopathy. The severity of clinical phenotypes in these adhalinopathies seems to relate more to the kind and site of the mutations than to the residual amount of the protein. We also detected a variable reduction in the laminin beta 1 subunit by immunohistochemistry in most patients, confirming that this is commonly associated with adhalin deficiency.

Adolescent↗
PubMed1996

Muscular dystrophy associated with beta-Dystroglycan deficiency.

beta-Dystroglycan, a 43-kd transmembrane dystrophin-associated glycoprotein, plays an important role in linking dystrophin to the laminin-binding alpha-dystroglycan. alpha-/beta-Dystroglycan is encoded by a single gene on chromosome 3p21 and ubiquitously expressed in muscle and nonmuscle tissues. No known human diseases have been mapped to this locus. Here, we describe the selective deficiency of beta-dystroglycan in a 4-year-old Saudi boy with muscular dystrophy. The patient had a borderline elevation of serum creatine kinase level and early-onset proximal symmetrical muscle weakness and wasting without calf hypertrophy. The milder phenotype may suggest a secondary deficiency of beta-dystroglycan; however, the unique immunofluorescence labeling suggests that the patient may present a novel form of muscular dystrophy.

Child, Preschool↗
PubMed1996

Lethal congenital muscular dystrophy in two sibs with arthrogryposis multiplex: new entity or variant of cobblestone lissencephaly syndrome?

We report on two sisters of first degree cousin parents who were born with severe hypotonia, arthrogryposis multiplex congenita (AMC) and dysmorphic features consistent with the fetal akinesia/hypokinesia sequence. They needed assisted ventilation and each died at the age of 5 months. Both had type II lissencephaly (cobblestone lissencephaly) which was visualized by magnetic resonance imaging (MRI) in the proband. Ophthalmic evaluation revealed no ocular malformations in either of them. Brain auditory evoked potentials (BAEP) revealed bilateral severe sensorineural hearing loss in the proband, whereas an MRI-guided open muscle biopsy of the sartorius muscle (the only remaining thigh muscle) showed features of muscular dystrophy. Immunohistochemistry revealed normal dystrophin, dystrophin-associated glycoproteins (DAG) and merosin. Certain clinical and pathological features distinguish the disease seen in these sisters from reported isolated cases where lethal AMC was associated with brain dysplasia and from the main syndromes of congenital muscular dystrophy/cobblestone lissencephaly. Differences from the Walker-Warburg syndrome, which simulates it in severity, included the absence of severe hydrocephalus, normal creatine kinase (for age) and minimal (mainly periventricular) white matter abnormalities. The findings suggest either an independent entity, in the studied family, or an allelic variation of the cobblestone lissencephaly (type II lissencephaly) syndrome.

Arthrogryposis↗
PubMed1996

In vivo muscle gene transfer of full-length dystrophin with an adenoviral vector that lacks all viral genes.

Duchenne muscular dystrophy (DMD) is an important target for gene transfer because of the disease's high frequency and devastating course. To date, adenoviral vector-mediated gene transfer for DMD has been unavailable because (1) adenoviral vectors were unable to accommodate the full-length dystrophin cDNA (14 kb); and (2) adenoviral vectors induced inflammatory reactions in the gene transfer recipient. We addressed both problems with a novel adenoviral vector that contains no viral genes and encodes 28.2 kb of foreign DNA including both the full-length dystrophin cDNA with the muscle creatine kinase promoter for transcriptional control and a lacZ marker gene. This report presents the in vivo expression of dystrophin and beta-galactosidase from this vector in skeletal muscle of the mdx mouse, a mutant mouse that lacks dystrophin. Somatic delivery of the vector by intramuscular injection in 6-day-old mice resulted in the expression of full-length, recombinant dystrophin at the muscle membrane. Dystrophin-associated proteins were restored in muscle fibers expressing recombinant dystrophin. Mdx muscle injected with our vector showed a decrease in the proportion of fibers with nuclei located centrally; centrally placed nuclei in muscle fibers are characteristic of cycles of degeneration and regeneration suffered by dystrophin-deficient muscle tissue. These results are strong evidence that adenoviral vector-mediated full-length dystrophin delivery provides substantial somatic function.

Adenoviridae↗
PubMed1995

Haplotype analysis in gelsolin-related amyloidosis reveals independent origin of identical mutation (G654A) of gelsolin in Finland and Japan.

Familial amyloidosis, Finnish type (FAF) (gelsolin-related amyloidosis) is an autosomal dominant form of systemic amyloidosis characterized by corneal lattice dystrophy and peripheral polyneuropathy. The accumulating protein in FAF consists of fragments of gelsolin, an actin-modulating protein. The gelsolin mutation G654A has been found in both Finnish and Japanese patients. To study the origin of the gelsolin mutation in these patients we performed haplotype analysis in 10 Finnish and 2 Japanese FAF families. Poymorphic DNA markers GSN, D9S103, AFMa061xd9, and AFMa139xb9 revealed a uniform disease haplotype in all the disease-associated chromosomes of the Finnish FAF families, which was different from the one observed in the Japanese families. The present results and the previously detected gelsolin mutation G654T in Czech and Danish FAF patients suggest that nucleotide 654 may represent a mutation hot spot in the gelsolin gene. The DNA markers studied here will be useful in future genealogical analyses of FAF.

Amyloid Neuropathies↗
PubMed1995

Three-dimensional MR imaging of brain surface anomalies in Fukuyama-type congenital muscular dystrophy.

Fukuyama-type congenital muscular dystrophy (FCMD), the second most common childhood muscular dystrophy in Japan, is characterized by the association with severe brain anomalies such as pachygyria and focal interhemispheric fusion. Conventional imaging techniques such as X-ray CT scan and MRI are ineffective for visualization of these brain surface anomalies. Here we investigated the efficacy of three-dimensional (3-D) reconstruction of brain surface MR images for the detection of brain anomalies in FCMD patients. 3-D brain surface MR images clearly visualized anomalies of cerebral gyrus such as pachygyria, as well as focal interhemispheric fusion. In addition, reconstructed horizontal images visualized structural derangement such as abnormal protrusion of white matter into gray matter. MR image abnormalities were confirmed by autopsy in 1 patient. These abnormalities were never observed in Duchenne muscular dystrophy (DMD) patients. Our results indicate the efficacy of the present method for the differential diagnosis between FCMD and DMD with severe mental retardation, which is essential for the genetic study to identify the causative gene of FCMD.

Adolescent↗
PubMed1995

Beta-sarcoglycan: characterization and role in limb-girdle muscular dystrophy linked to 4q12.

beta-Sarcoglycan, a 43 kDa dystrophin-associated glycoprotein, is an integral component of the dystrophin-glycoprotein complex. We have cloned human beta-sarcoglycan cDNA and mapped the beta-sarcoglycan gene to chromosome 4q12. Pericentromeric markers and an intragenic polymorphic CA repeat cosegregated perfectly with autosomal recessive limb-girdle muscular dystrophy in several Amish families. A Thr-to-Arg missense mutation was identified within the beta-sarcoglycan gene that leads to a dramatically reduced expression of beta-sarcoglycan in the sarcolemma and a concomitant loss of adhalin and 35 DAG, which may represent a disruption of a functional subcomplex within the dystrophin-glycoprotein complex. Thus, the beta-sarcoglycan gene is the fifth locus identified (LGMD2E) that is involved in autosomal recessive limb-girdle muscular dystrophy.

Amino Acid Sequence↗
PubMed1995

Identification of a novel mutant transcript of laminin alpha 2 chain gene responsible for muscular dystrophy and dysmyelination in dy2J mice.

Murine dystrophia muscularis-2J (dy2J) is an autosomal recessive disorder characterized by muscular dystrophy and dysmyelination of peripheral nerve. Biochemical characterization of dy2J mice revealed the expression of a mutant laminin alpha 2 chain with a smaller molecular weight in the basal lamina of striated muscle and peripheral nerve. DNA sequencing of the alpha 2 chain cDNA amplified by RT-PCR from dy2J mice identified a novel and predominant transcript with a 171 base in-frame deletion. We also confirmed an underlying splice donor site mutation in the alpha 2 chain gene of the dy2J mouse. Translation of this variant transcript would result in the expression of a truncated alpha 2 chain having a 57 amino acid deletion (residues 34-90) and a substitution of Gln91Glu in the N-terminal domain VI, which is presumed to be involved in self-aggregation of laminin heterotrimers. Thus, the mutant alpha 2 chain could disrupt the formation of the laminin network and lead to muscle cell degeneration. Our results provide a molecular basis of muscular dystrophy and dysmyelination of peripheral nerve.

Amino Acid Sequence↗
PubMed1995

Expression of human full-length and minidystrophin in transgenic mdx mice: implications for gene therapy of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a lethal X-linked recessive disorder with a high spontaneous mutation rate and no effective treatment, hence development of genetic based therapies is an important goal. We report that expression of a recombinant human minidystrophin cDNA, compatible with current viral vectors, can significantly reduce the myopathic phenotype in transgenic mdx mice, even when expressed at only 20-30% of endogenous dystrophin levels at the sarcolemma. To the extent that data obtained in mouse studies are applicable to DMD, the virtual elimination of morphological and biochemical abnormalities in the mdx mouse supports the use of this cDNA in somatic gene therapy protocols for DMD.

Animals↗
PubMed1995

Merosin-negative congenital muscular dystrophy associated with extensive brain abnormalities.

Congenital muscular dystrophies (CMDs) are autosomal recessive, heterogeneous disorders. The most frequent form in the Caucasian population is classic (occidental) CMD, characterized by exclusive muscle involvement, although abnormal brain white matter signals are occasionally observed on MRI. Recently, deficiency of merosin, the laminin isoform in skeletal muscle, has been identified in classic CMD patients. In skeletal muscle, merosin is a native ligand for dystroglycan linking the extracellular matrix and dystrophin. Thus, merosin deficiency could disrupt the attachment of muscle cell to the extracellular matrix and lead to muscle cell necrosis. Since merosin is also expressed in the nervous system and has biologic activities on neurite outgrowth and Schwann cell migration, deficiency of merosin could affect the development of the nervous system. We report here two patients with merosin-negative CMD presenting extensive brain abnormalities characterized by cortical anomaly, polymicrogyria, and abnormal white matter signals.

Brain↗
PubMed1995

Dystrophin-glycoprotein complex: molecular organization and critical roles in skeletal muscle.

Recent molecular and biochemical studies have disclosed the detailed molecular organization of the dystrophin-glycoprotein complex, which links the cytoskeleton to the extracellular matrix. Defects in several components of this complex cause different types of muscular dystrophy. This glycoprotein complex is also involved in clustering and anchoring acetylcholine receptors at the postsynaptic membrane.

Cytoskeletal Proteins↗
PubMed1994

Deficiency of merosin in dystrophic dy mice and genetic linkage of laminin M chain gene to dy locus.

Merosin is the predominant laminin isoform in the basal lamina of striated muscle and peripheral nerve, and consists of M, B1 or S, and B2 chains. Here we have demonstrated that merosin is a native ligand for alpha-dystroglycan, an extracellular component of the dystrophin-glycoprotein complex. We have also mapped the mouse M chain gene, Lamm, to the same region of mouse chromosome 10 to which the dystrophia muscularis (dy) locus has been mapped. The dy mutation represents a severe neuromuscular disease resembling human muscular dystrophy. Analysis of merosin expression of dystrophic dy mice revealed a specific deficiency of merosin in skeletal muscle, cardiac muscle, and peripheral nerve. Our results indicate that merosin deficiency may be the primary defect in dy mice and suggest that a disruption of the link between alpha-dystroglycan and merosin may be involved in the pathogenesis of muscle degeneration and peripheral neuropathy in dy mice.

Animals↗
PubMed1994

Cerebellar ataxia and polyneuropathy in a patient with IgM M-protein specific to the Gal(beta 1-3)GalNAc epitope.

A 79-year-old man with sensory dominant polyneuropathy, cerebellar ataxia, and palatal myoclonus had serum IgM M-protein that specifically bound to GM1, GD1b, and asialo-GM1. IgM with the same specificity was detected in his cerebrospinal fluid. Results of immunohistochemical studies showed specific binding of this monoclonal IgM to the cerebellar granular layer, dentate nucleus, inferior olive, and gray matter of the cerebrum and spinal cord. Monoclonal antibody GGR12, monospecific to GD1b, had an immunostaining distribution similar to that of the patient's IgM M-protein. The binding of M-protein may be associated with the development of cerebellar ataxia and palatal myoclonus in this patient.

Aged↗