[Schwartz-Jampel syndrome(chondrodystrophic myotonia)].
Explore the source record for details and available documents.
Diagnosis, Differential↗
Biomedical subjects
Y Sunada
Publications and source records attributed to Y Sunada.
[Steinert myotonic dystrophy syndrome].
Explore the source record for details and available documents.
Diagnosis, Differential↗
[Dysgenesis of the corpus callosum].
Explore the source record for details and available documents.
Abnormalities, Multiple↗
[Myotonic dystrophy].
Explore the source record for details and available documents.
Agammaglobulinemia↗
Characterization of the transmembrane molecular architecture of the dystroglycan complex in schwann cells.
We have demonstrated previously 1) that the dystroglycan complex, but not the sarcoglycan complex, is expressed in peripheral nerve, and 2) that alpha-dystroglycan is an extracellular laminin-2-binding protein anchored to beta-dystroglycan in the Schwann cell membrane. In the present study, we investigated the transmembrane molecular architecture of the dystroglycan complex in Schwann cells. The cytoplasmic domain of beta-dystroglycan was co-localized with Dp116, the Schwann cell-specific isoform of dystrophin, in the abaxonal Schwann cell cytoplasm adjacent to the outer membrane. beta-dystroglycan bound to Dp116 mainly via the 15 C-terminal amino acids of its cytoplasmic domain, but these amino acids were not solely responsible for the interaction of these two proteins. Interestingly, the beta-dystroglycan-precipitating antibody precipitated only a small fraction of alpha-dystroglycan and did not precipitate laminin and Dp116 from the peripheral nerve extracts. Our results indicate 1) that Dp116 is a component of the submembranous cytoskeletal system that anchors the dystroglycan complex in Schwann cells, and 2) that the dystroglycan complex in Schwann cells is fragile compared with that in striated muscle cells. We propose that this fragility may be attributable to the absence of the sarcoglycan complex in Schwann cells.
Animals↗
Dietary effect of tocopherols and tocotrienols on the immune function of spleen and mesenteric lymph node lymphocytes in Brown Norway rats.
The immunoregulatory effects of dietary alpha-tocopherol (Toc) and tocotrienols (T-3) on humoral and cell-mediated immunity and cytokine productions were examined in Brown Norway rats. We found that the IgA and IgG productivity of spleen and mesenteric lymph node (MLN) lymphocytes was significantly enhanced in the rats fed on Toc or T-3, irrespective of concanavalin A (Con A) stimulation of the lymphocytes. On the contrary, the IgE productivity of lymphocytes from the rats fed on Toc or T-3 was less without Con A stimulation, but was greater in the presence of Con A, especially in the T-3 group. Toc or T-3 feeding significantly decreased the proportion of CD4+ T cells and the ratio of CD4+/CD8+ in both spleen and MLN lymphocytes of the rats fed on Toc or T-3. The interferon-gamma productivity of MLN lymphocytes was higher in the rats fed on Toc or T-3 than in those fed on a control diet in the presence of Con A, while that of spleen lymphocytes was lower in the rats fed on Toc or T-3. In addition, T-3 feeding decreased the productivity of tumor necrosis factor-alpha of spleen lymphocytes, while it enhanced the productivity of MLN lymphocytes. These results suggest that oral administration of Toc and T-3 affects the proliferation and function of spleen and MLN lymphocytes.
Animals↗
Sarcoglycan complex: a muscular supporter of dystroglycan-dystrophin interplay?
In striated muscle, the cytoskeletal protein dystrophin, the protein product of the Duchenne muscular dystrophy gene, is associated with a number of sarcolemmal glycoproteins to form a large oligomeric complex, the dystrophin-glycoprotein complex (DGC). Over the last 10 years, four of these sarcolemmal glycoproteins, alpha-, beta-, gamma- and delta-sarcoglycans, have been shown to form a distinct subcomplex, the sarcoglycan complex, in the DGC. Furthermore, the genetic defects of alpha-, beta-, gamma- and delta-sarcoglycans have been identified as the causes of four distinct forms of muscular dystrophies, which are now collectively called sarcoglycanopathy. Current studies are beginning to focus on the biological functions of the sarcoglycan complex and the molecular mechanism by which its dysfunction leads to muscle cell degeneration.
Animals↗
Differential expression of the parkin gene in the human brain and peripheral leukocytes.
Molecular cloning of the responsible gene on chromosome 6q25.2-27 for autosomal recessive juvenile parkinsonism (AR-JP) identified a novel protein of unknown function, named parkin. In patients with AR-JP, deletions most commonly involve exons 3-5 in the parkin gene. For mutation screening we tried to analyze the parkin transcript amplified by RT-PCR. Based on the assumption that illegitimate transcription of the parkin gene may occur in every cell type, we successfully amplified the parkin message from human peripheral leukocytes using RT-PCR. The parkin transcript in leukocytes was smaller in size than the full-length transcript in the brain. DNA sequencing determined that exons 3-5 were spliced out in the normal human leukocyte transcript. Our results demonstrate that alternative splicing produces distinct parkin transcripts in different tissues. Moreover, physiological splicing of deletion-prone exons may provide an important clue to understanding the pathogenesis of AR-JP.
Brain↗
Beta-sarcoglycan: genomic analysis and identification of a novel missense mutation in the LGMD2E Amish isolate.
The sarcoglycan complex is involved in the etiology of four autosomal recessive limb-girdle muscular dystrophies (LGMD2C-F). A missense mutation (T151R) in the beta-sarcoglycan gene on chromosome 4q12 has been shown to cause a mild form of LGMD2E in 11 families from a Southern Indiana Amish community sharing a common haplotype. We now report that two sibs from another Amish family with mild LGMD2E are compound heterozygotes for chromosome 4q12 markers. In order to characterize the genetic defect in this new family, we determined the genomic organization of the beta-sarcoglycan gene. A second missense mutation (R91C) has now been identified in this LGMD2E Amish family. This mutation is also present in the homozygous state in another family of probable Amish ancestry. Finally, analysis of all the components of the dystrophin-glycoprotein complex was performed for the first time on a biopsy from a patient homozygous for the beta-sarcoglycan mutation (T151R). Interestingly, in addition to the loss of the entire sarcoglycan complex, we detected a reduction of alpha-dystroglycan which suggests a role for the sarcoglycan complex in stabilizing alpha-dystroglycan at the sarcolemma.
Adolescent↗
Biological activities of C3 beta c, a novel neutrophil chemoattractant derived from the beta-chain of rat complement C3.
Biological activities of C3 beta c, which is a C-terminal fragment of the beta-chain of rat complement C3, have been studied by in vivo and in vitro experiments. C3 beta c was purified as a novel neutrophil chemoattractant from the exudate of the chronic phase of rat carrageenin-induced inflammation. The purified C3 beta c induced neutrophil chemotaxis in vivo when C3 beta c was injected into the preformed air-pouch on the back of rats. C3 beta c transiently increased the intracellular free Ca2+ concentration of neutrophils and enhanced the adhesion of neutrophils to fibrinogen in vitro, suggesting that C3 beta c has the ability to express an adhesion molecule of rat neutrophils. In addition, C3 beta c at low concentrations (10(-10)-10(-11) M) stimulated rat macrophages to produce cytokine-induced neutrophil chemoattractant-2, a member of the interleukin-8 family. Furthermore, C3 beta c enhanced vascular permeability in vivo, which is suppressed by cyproheptadine, suggesting that C3 beta c may have the characteristics of an anaphylatoxin. Our results suggest that C3 beta c contributes to oedema formation and neutrophil accumulation at inflammatory sites in rats.
Animals↗
Differential production of chemokines and their role in neutrophil infiltration in rat allergic inflammation.
BACKGROUND: Recently we demonstrated that activated rat macrophages produced neutrophil chemotactic factors (chemokines) including cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2alpha, CINC-2beta, CINC-3/rat macrophage inflammatory protein (MIP)-2 and rat MIP-1alpha (rMIP-1alpha). METHODS: In the present study, by using an enzyme-linked immunosorbent assay specific for each chemokine, we determined the levels of the chemokines in the pouch fluid (inflammatory site) of the fluorescein isothiocyanate-labeled ovalbumin (FITC-OVA)-induced allergic inflammation in rats. Effects of anti-chemokine antibodies on neutrophil chemotaxis were determined in vivo and in vitro. RESULTS: CINC-1 was the major chemokine which rapidly increased after challenge with FITC-OVA, whereas CINC-3 was a minor one, and CINC-2, CINC-3 and rMIP-1alpha increased slowly with a lag time of about 2 h. Anti-CINC-1/CINC-2 antibodies, which inhibited all the CINCs, suppressed both neutrophil infiltration in vivo and neutrophil chemotactic activity of the 8-hour pouch fluid in vitro, whereas anti-rMIP-1alpha antibody slightly suppressed the chemotaxis in vivo and in vitro. CONCLUSION: Our results suggest that CINCs, especially CINC-1 and CINC-2, play an important role in the infiltration of neutrophils into the inflammatory site of FITC-OVA-induced allergic inflammation in rats.
Animals↗
Characterization of a 30-kDa peripheral nerve glycoprotein that binds laminin and heparin.
We have shown previously that a bovine peripheral nerve protein with a molecular mass of about 30 kDa binds laminin in blot overlay assay. In this paper, we have characterized this 30-kDa laminin-binding protein (LBP30). LBP30 was extracted from the crude bovine peripheral nerve membranes at pH 12 or by 0.5 M NaCl but not by 2% Triton X-100. LBP30 bound to heparin-Sepharose in the presence of 0.5 M NaCl. The results of lectin staining indicated that LBP30 contained both terminally sialylated and nonsialylated Ser/Thr-linked oligosaccharides. LBP30 bound laminin-2 as well as laminin-1 but not fibronectin or collagen type IV. When immobilized LBP30 was incubated with the crude peripheral nerve membrane extracts, all of the endogenous peripheral nerve laminin chain isoforms, the alpha1, alpha2, beta1, beta2, and gamma1 chains, were detected bound to LBP30. The binding of LBP30 to laminin was inhibited by heparin, heparan sulfate, dextran sulfate, or NaCl but was not affected significantly by chondroitin sulfate, dextran, or EDTA. Although LBP30 bound to laminin-1 denatured with SDS in a nonreducing condition, the binding was reduced drastically when laminin-1 was denatured with SDS in a reducing condition, suggesting that the binding of LBP30 is somewhat dependent on the high order structure of laminin-1. Immunohistochemical analysis demonstrated the broad distribution of LBP30 in the perineurium and endoneurium of bovine peripheral nerve. These results indicate that LBP30 is a laminin- and heparin-binding glycoprotein localized in the perineurium and endoneurium of bovine peripheral nerve.
Animals↗
Peripheral nerve involvement in merosin-deficient congenital muscular dystrophy and dy mouse.
Merosin, also called laminin-2, is an isoform of laminin comprised of the alpha 2, beta 1 and gamma 1 chains. Deficiency of merosin alpha 2 chain was recently identified as the primary cause of the classical form of congenital muscular dystrophy (CMD), an autosomal recessive neuromuscular disorder characterised by muscular dystrophy and brain white matter abnormalities. Interestingly, merosin-deficient CMD and its animal model dy mouse are also accompanied by dysmyelination of peripheral motor nerves. In peripheral nerve, merosin is expressed in the endoneurium surrounding the Schwann cell/myelin sheath, while the putative merosin receptors dystroglycan and alpha 6 beta 4 integrin are expressed in the outer membrane of Schwann cell/myelin sheath. Together with the well known fact that the deposition of laminin in the basement membrane is essential for Schwann cell myelination, these findings indicate that the interaction of merosin with dystroglycan and/or alpha 6 beta 4 integrin plays an important role in peripheral myelinogenesis and that the disturbance of this interaction leads to peripheral dysmyelination in merosin deficiency. The clinical significance of peripheral dysmyelination in merosin deficiency is also discussed.
Animals↗
Mild congenital muscular dystrophy in two patients with an internally deleted laminin alpha2-chain.
Congenital muscular dystrophy (CMD) is a group of clinically and genetically heterogeneous disorders inherited in an autosomal recessive mode. The alpha2-chain of laminin-2 (previously called merosin) has been shown by immunohistochemical and genetic analyses to be implicated in the pathogenesis of the 'classic' form of CMD. In the 'merosin-deficient' subgroup, which represents about half of the cases, more definite evidence of the involvement of the laminin alpha2-chain has recently been reported with the identification of mutations in the gene encoding the alpha2-chain of laminin 2 (LAMA2) in CMD patients. Here we report on two siblings from a consanguineous family expressing an internally deleted laminin alpha2-chain as a result of a splice site mutation in the LAMA2 gene which causes the splicing of exon 25. The predicted protein lacks 63 amino acids in domain IVa which forms a globular structure on the short arm of the alpha2-chain. Interestingly, these patients appear mildly affected compared to others who completely lack this protein. This situation presents a striking analogy with Becker muscular dystrophy, where in-frame deletions in the dystrophin gene result in the expression of a semi-functional protein and lead to a mild phenotype.
Amino Acid Sequence↗
Dystroglycan is essential for early embryonic development: disruption of Reichert's membrane in Dag1-null mice.
Dystroglycan is a central component of the dystrophin-glycoprotein complex (DGC), a protein assembly that plays a critical role in a variety of muscular dystrophies. In order to better understand the function of dystroglycan in development and disease, we have generated a null allele of dystroglycan (Dag1neo2) in mice. Heterozygous Dag1neo2 mice are viable and fertile. In contrast, homozygous Dag1neo2 embryos exhibit gross developmental abnormalities beginning around 6.5 days of gestation. Analysis of the mutant phenotype indicates that an early defect in the development of homozygous Dag1neo2 embryos is a disruption of Reichert's membrane, an extra-embryonic basement membrane. Consistent with the functional defects observed in Reichert's membrane, dystroglycan protein is localized in apposition to this structure in normal egg cylinder stage embryos. We also show that the localization of two critical structural elements of Reichert's membrane--laminin and collagen IV--are specifically disrupted in the homozygous Dag1neo2 embryos. Taken together, the data indicate that dystroglycan is required for the development of Reichert's membrane. Furthermore, these results suggest that disruption of basement membrane organization might be a common feature of muscular dystrophies linked to the DGC.
Amino Acid Sequence↗
Mutational diversity and hot spots in the alpha-sarcoglycan gene in autosomal recessive muscular dystrophy (LGMD2D).
Sarcoglycanopathies are a genetically heterogeneous group of autosomal recessive muscular dystrophies in which the primary defect may reside in any of the genes coding for the different partners of the sarcolemmal sarcoglycan (SG) complex: the alpha-SG (LGMD2D at 17q21.2), the beta-SG (LGMD2E at 4q12), the gamma-SG (LGMD2C at 13q12), and the delta-SG (LGMD2F at 5q33). We report a series of 20 new unrelated families with 14 different mutations in the alpha-SG gene. Along with the mutations that we previously reported this brings our cohort of patients with alpha-sarcoglycanopathy to a total of 31 unrelated patients, carrying 25 different mutations. The missense mutations reside in the extracellular domain of the protein. Five of 15 missense mutations, carried by unrelated subjects on different haplotype backgrounds and of widespread geographical origins, account for 58% of the mutated chromosomes, with a striking prevalence of the R77C substitution (32%). The severity of the disease varies strikingly and correlates at least in part with the amount of residual protein and the type of mutation. The recurrent R284C substitution is associated with a benign disease course.
Base Sequence↗
The role of dystroglycan, a novel receptor of laminin and agrin, in cell differentiation.
Dystroglycan was originally identified as the extracellular and transmembrane constituents of a large oligomeric complex of sarcolemmal proteins associated with dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene. During the last few years, dystroglycan has been demonstrated to be a novel receptor of not only laminin but also agrin, two major proteins of the extracellular matrix having distinct biological effects. The fact that the drastic reduction of dystroglycan in the sarcolemma, caused by the absence of dystrophin, leads to muscle cell death in DMD patients and mdx mice indicates that, as a laminin receptor, dystroglycan contributes to sarcolemmal stabilization during contraction and stretch of striated muscle cells. Dystroglycan is also expressed in the neuromuscular junction and non-muscle tissues such as kidney, brain and peripheral nerve, and, as a receptor of laminin/agrin, has been implicated in such diverse and specific developmental processes as epithelial morphogenesis, synaptogenesis and myelinogenesis. These findings point to the fundamental role of dystroglycan in the cellular differentiation process shared by many different cell types. In this paper, we review the recent publications on the biological functions of dystroglycan and discuss its roles in cell differentiation.
Animals↗
Characterization of delta-sarcoglycan, a novel component of the oligomeric sarcoglycan complex involved in limb-girdle muscular dystrophy.
The sarcoglycan complex is known to be involved in limb-girdle muscular dystrophy (LGMD) and is composed of at least three proteins: alpha-, beta-, and gamma-sarcoglycan. delta-Sarcoglycan has now been identified as a second 35-kDa sarcolemmal transmembrane glycoprotein that shares high homology with gamma-sarcoglycan and is expressed mainly in skeletal and cardiac muscle. Biochemical analysis has demonstrated that gamma- and delta-sarcoglycan are separate entities within the sarcoglycan complex and that all four sarcoglycans exist in the complex on a stoichiometrically equal basis. Immunohistochemical analysis of skeletal muscle biopsies from patients with LGMD2C, LGMD2D, and LGMD2E demonstrated a reduction of the entire sarcoglycan complex in these muscular dystrophies. Furthermore, we have mapped the human delta-sarcoglycan gene to chromosome 5q33-q34 in a region overlapping the recently linked autosomal recessive LGMD2F locus.
Amino Acid Sequence↗