A new congenital myopathy in a Norwegian family.

UNLABELLED: A 6-y-old boy presented with a mild, and apparently non-progressive, congenital myopathy, primarily affecting explosive movements such as running and jumping. Five other cases, spanning four generations, were identified in his family. A dominant inheritance pattern was suggested. Quadriceps muscle histology showed a selective type II fibre atrophy, which is otherwise considered a non-specific change associated with a number of conditions. CONCLUSION: A Norwegian boy with an inherited muscle weakness is presented. Based on clinical and laboratory investigations, and in light of the inheritance pattern, a previously undescribed congenital myopathy is suggested.

Serum Gm allotype development during childhood.

Gm allotypes are genetic variants of the immunoglobulin heavy G chains (IGHG) of IgG molecules, coded from chromosome 14q32, characterized by differences in amino acid epitopes of the constant heavy G chains and inherited in the Mendelian manner. Gm allotypes have influence on IgG subclass levels, and serum Gm allotype levels have been given for different Gm genotypes in adults. Four hundred and thirty healthy children, aged 1-15 years, were examined for serum Gm allotypes and IgG subclasses from the six most common Gm genotypes and different age groups were measured using competitive enzyme-linked immunosorbant assay and radial immunodiffusion methods. Quantities (in g/l) of G1m(a) and G1m(f) of IgG1, G2m(n) and G2m(-n) of IgG2 and G3m(g), and G3m(b) of IgG3 are given. Different maturation rates of the alternative Gm allotypes within IgG1, IgG2 and IgG3 were shown. G2m(n) development was strikingly retarded compared with G2m(-n) from the gamma2 locus. This was found comparing IgG2 levels from homozygous G2m(-n-n) and G2m(nn) individuals, but was also seen in heterozygous G2m(n-n) genotypes. From the gamma1 locus G1m(f) levels dominated significantly, but inconstantly, over G1m(a) levels in heterozygous G1m(af) individuals. In homozygous G1m genotypes, G1m(aa) compared with G1m(ff) of the same age, one or the other dominated, sometimes significantly. Serum levels of G3m(b) from the gamma3 locus of homozygous G3m(bb) individuals were increased significantly compared with G3m(g) levels of homozygous G3m(gg) individuals, in ages over 3 years. However, in heterozygous G3m(gb) individuals G3m(b) dominance was not evident. There is a relatively rapid development of G1m(f) molecules and a retarded development of G2m(n) in the Gm(f;n;b) haplotype. In comparison, G1m(a) is retarded and G2m(-n) is enhanced in the Gm(a;-n;g) haplotype. The retarded serum G2m(n) development is comparable with serum IgA development during childhood. Different maturation rates of Gm allotypes within the same IgG subclass provide further explanation for the variation of the antibody response during childhood. Quantitative Gm allotype determinations give information of the activity from IGHG genes. The genetic variation constitutes an additional basis for evaluation of IgG antibodies in different diseases in childhood.

Alternative G1m, G2m and G3m allotypes of IGHG genes correlate with atopic and nonatopic pathways of immune regulation in children with bronchial asthma.

Most genetic studies of bronchial asthma deal with IgE responsiveness. The manner by which allergens trigger IgE production and activate mast cells suggests that several genetic loci may be involved. Several reports of candidate genes include chromosome 6 and HLA antigens, chromosome 14q11 and the alpha chain of the T cell receptor, chromosome 11q32 and the beta chain of the high-affinity IgE receptor and chromosome 5 and the gene cluster for IL-4, respectively. In addition, the immunoglobulin heavy chain G (IGHG) genes on chromosome 14q32 have been associated with both atopic and non atopic bronchial asthma in children. In order to further investigate the role of IGHG genes in asthmatic children, the phenotypes of patients with homozygous but alternative IGHG genes were investigated. IGHG gene expression of patients with childhood asthma was determined by serum Gm allotypes with a quantitative competitive indirect ELISA method. The groups consisted of 24 children with the homozygous G3m(b/b)-G1m(f/f)-G2m(n/n) and 16 with the alternative G3m(g/g)-G1m(a/a)-G2m(-n/-n) genes. The two different genotypes were investigated for serum IgE (PRIST), serum IgG subclass levels (radial immunodiffusion), Gm allotype levels (competitive ELISA), IgA and IgM levels (radial immunodiffusion), peripheral blood eosinophils, specific IgE antibodies (skin prick test, SPT, or radioallergosorbent test, RAST), number of peripheral blood CD lymphocyte markers (flow cytometry) and serum IL-4 and IFN-gamma levels (ELISA). Comparison of the two genotypes in children with bronchial asthma revealed significantly increased IgE (p < 0.001), increased specific IgE (p < 0.001), as investigated by SPT or RAST (n = 10 allergens tested), increased number of peripheral blood eosinophils (p < 0.01), increased serum IgG1(f/f)(p < 0.001), IgG2(n/n) (p < 0.001) and IgG3(b/b)(p < 0.01) levels, and decreased CD8 given in percent of the total number of peripheral lymphocytes, (p < 0.02) in the G3m(b/b)-G1m(f/f)-G2m(n/n) genotype. The asthmatic children with the G3m(g/g)-G1m(a/a)-G2m(-n/-n) genes instead showed low IgE levels, practically no specific IgE antibodies, a lower number of peripheral blood eosinophils, lower IgG1(a/a), IgG2(-n/-n) and IgG3(g/g) serum levels and higher CD8 lymphocyte numbers. The results show that the IGHG3(b/b)-IGHG1(f/f)-IGHG2(n/n) genes are in linkage disequilibrium with allergen-specific high-responding IGHE genes and present the atopic phenotype of bronchial asthma, while the IGHG3(g/g)-IGHG1(a/a)-IGHG2(-n/-n) genes present the nonatopic phenotype of childhood asthma. The two genotypes with different amino acid epitopes of their constant heavy gamma1, gamma2 and gamma3 chains presented qualitatively different IgG1, IgG2 and IgG3 molecules, respectively, and also different serum IgG1, IgG2 and IgG3 levels, together with different numbers of peripheral blood eosinophils and CD8 lymphocytes. The two IGHG genotypes represent different pathways of human immune regulation. An association of atopic IGHG genotype with other candidate genes for atopy could be suggested.

Ischemia-induced transplant arteriosclerosis in the rat. Induction of peptide growth factor expression.

Peptide growth factors have been reported to contribute to the atherogenic process, and they are known to mediate signals for vascular remodeling. Using syngeneic and allogeneic rat aorta transplant models, we analyzed the impact of cold ischemia time up to 24 hours and reperfusion injury on development of transplant arteriosclerosis during the first 2 months after transplantation. The expression of the transforming growth factor-beta (TGF-beta) family as well as the platelet-derived growth factor (PDGF) and its receptors was studied by use of immunohistochemistry, followed by semiquantitative evaluation and multivariate analysis. In the syngeneically transplanted aortas, the expression of TGF-beta 1, PDGF, and the two PDGF receptors in the neointima increased significantly with the extent of cold ischemia time. Furthermore, there was a significant induction of the latent TGF-beta binding protein in the neointima as well as TGF-beta 2 in the media, both correlating with the observation time after transplantation. In the allogeneic grafts, all examined proteins were already induced strongly 2 weeks after transplantation, even at the shortest ischemic period studied (1 hour). However, no positive correlation between growth factor expression and cold ischemia or observation time could be found. Double immunohistochemistry revealed that macrophages express PDGF and its receptors as well as TGF-beta 1. Smooth muscle cells express both types of PDGF receptors, and a few T cells express TGF-beta 1 as well as PDGF receptors. In summary, TGF-beta and PDGF are induced by allogeneic as well as ischemic stimuli in transplanted aortas, suggesting a role in the pathogenesis of transplant arteriosclerosis and representing a potential target for therapeutic intervention.

Effects of angiopeptin on transplant arteriosclerosis in the rat.

The influence of the somatostatin analogue angiopeptin on transplant arteriosclerosis was investigated using two aortic transplantation rat models. One was characterized by ischemia/reperfusion-induced changes in syngeneic transplants while immunologically induced changes dominated in the other allogeneic model. Angiopeptin, 100 micrograms/kg per day, was administered continuously until the sacrifice of the rats after 8 weeks. No additional immunosuppression was used in either model. An image analysis system was used to quantify the intimal and medial thicknesses of the grafts. In the syngeneic grafts, the intimal thickness was less than 50% of that of control grafts (P < 0.05), but no difference was seen in the allogeneic model. The expression of selected cells, TGF-beta s, and PDGF and PDGF alpha-receptors was detected immunohistochemically and displayed a similar picture in control and angiopeptin-treated grafts in both models. We conclude that angiopeptin has no clear immunosuppressive properties but may counteract ischemia-induced transplant arteriosclerosis.

C-CAM (Cell-CAM 105) is a calmodulin binding protein.

C-CAM (Cell-CAM 105) is a transmembrane cell adhesion molecule belonging to the immunoglobulin superfamily. It mediates intercellular adhesion of rat hepatocytes and occurs in various isoforms in several epithelia, vessel endothelia and leukocytes. We now report that purified liver C-CAM interacts specifically with calmodulin. Binding was observed both when 125I-labeled C-CAM was used in a dot-blot assay and when 125I-labeled calmodulin was used in a gel overlay assay. Experiments with protease-generated peptides indicated that calmodulin bound to the cytoplasmic domain of C-CAM. Analyses of whole liver membranes demonstrated that C-CAM is one of five major proteins that bind calmodulin in a calcium-dependent manner.

C-CAM (cell-CAM 105) is an adhesive cell surface glycoprotein with homophilic binding properties.

C-CAM (Cell-CAM 105) is a cell surface glycoprotein that is involved in cell-cell adhesion of rat hepatocytes in vitro. To elucidate the adhesion mechanism the binding properties of purified C-CAM were investigated. Using proteins immobilized on nitrocellulose it was found that radiolabeled C-CAM bound to C-CAM but not to a variety of other proteins. Partitioning in Triton X-114 showed that C-CAM has hydrophobic properties. In accordance with this, C-CAM was effectively incorporated into phosphatidylcholine liposomes by dialysis from octylglucoside-containing solutions. The C-CAM-containing liposomes bound specifically to isolated hepatocytes. This binding was blocked by Fab fragments of anti-C-CAM antibodies. Furthermore, preincubation of hepatocytes with anti-C-CAM antibodies followed by washing of the cells blocked binding of C-CAM-containing liposomes. At increasing C-CAM contents in the reconstituted liposomes a marked self-aggregation of the liposomes occurred. This aggregation was blocked by Fab fragments of anti-C-CAM antibodies and by alkaline pH. After neutralization a rapid reaggregation occurred. Neither C-CAM binding to C-CAM immobilized on nitrocellulose nor C-CAM-liposome aggregation required calcium ions. Liposomes reconstituted with C-CAM-depleted membrane glycoproteins did not self-aggregate or bind to hepatocytes. Thus, it is concluded that C-CAM can bind specifically to C-CAM in a homophilic binding reaction that does not require calcium. Accordingly, C-CAM has the potential of directly mediating cell-cell adhesion via C-CAM-C-CAM binding between adjacent cells.

The cell adhesion molecule Cell-CAM 105 is an ecto-ATPase and a member of the immunoglobulin superfamily.

Cell-CAM 105 (C-CAM), a cell adhesion molecule in rat hepatocytes, was digested with trypsin, and peptides were isolated and sequenced by Edman degradation. The sequences of 4 peptides agreed with different regions of rat liver ecto-ATPase. Detailed biochemical analyses confirmed the identity between C-CAM and the ecto-ATPase. C-CAM/ecto-ATPase is a transmembrane protein having 4 immunoglobulin-like domains in the extracellular portion, demonstrating membership of the immunoglobulin superfamily. The ATPase activity suggests that ATP might influence cell adhesion, which would explain the inhibitory effect of exogenously added ATP on adhesion of several cell types.