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PubMed1990

A very small frame-shifting deletion within exon 19 of the Duchenne muscular dystrophy gene.

We report the molecular characterization of a Japanese Duchenne muscular dystrophy (DMD) patient. The analysis of genomic gene by polymerase chain reaction indicates that the individuals have a limited deletion within an amplified region, which encompasses exon 19 of DMD gene. The amplified region was sequenced. Comparison of the deletion joint sequence with the normal amplified region sequence indicates that both 5' and 3' deletion end points are present within exon 19 and the deletion removes total 52 bp out of 88 bp of exon 19. Both his mother and sister are carriers of the deletion-containing allele. The mutation introduces a termination codon at residue 791 in exon 20, and is predicted to result in the production of a severely truncated protein. This sort of deletion (designated as DMD-Kobe) might be classified as a new type of DMD gene abnormality.

Adolescent↗

PubMed1978

Muscle transketolase in normal foetuses and Duchenne dystrophy.

The activity of the enzyme transketolase (EC 2.2.1.1) or the pentose phosphate metabolizing enzyme (PPME) was investigated in the quadriceps muscles of patients with Duchenne muscular dystrophy (DMD), polymyositis and spinal muscular atrophy (SMA) and in normal foetuses. The enzyme activity was significantly elevated in these muscle disorders with highest and lowest levels seen in DMD and SMA groups, respectively. The enzyme activity was increased early in DMD muscle and appeared to increase with progression of the disease. Normal foetal muscle contained high transketolase activity which is comparable to that seen in DMD patients.

Adolescent↗

PubMed1980

Altered erythrocyte spectrin extractability in Duchenne muscular dystrophy.

Spectrin extractability was measured in the erythrocyte membranes obtained from patients with Duchenne muscular dystrophy (DMD) and normal matched controls. After the extraction of spectrin by adding deionized water, an aliquot of the pellet was applied to 6% SDS-polyacrylamide gels. Spectrin-Band 3 ratio on the gels was used as an indicator of spectrin extractability. Our data disclosed that spectrin extractability is significantly reduced in DMD patients when compared with that of controls and these results suggest that spectrin from DMD patients is more tightly bound to the membranes. Our data may also be applicable to the discussion of the relationship of spectrin to other membrane properties as well as to previously described membrane abnormalities in DMD erythrocytes.

Electrophoresis, Polyacrylamide Gel↗

PubMed1983

Is erythrocyte membrane phospholipid organisation abnormal in Duchenne muscular dystrophy?

Many of the abnormalities reported in erythrocytes from Duchenne muscular dystrophy (DMD) patients, including alterations in the physical state of the membrane as determined by electron spin resonance, could arise from changes in the lipid components. Although several investigators have shown there to be no compositional differences between normal and DMD erythrocytes, there still exists the hitherto unexplored possibility that the normal asymmetric organisation of the lipids may be deranged in the disease. This report is concerned with the probing of the asymmetric transbilayer distribution of the glycerophospholipids using phospholipase A2 from bee venom. Our results suggest that more phosphatidyl choline (PC) is available for attack by the enzyme in the outer leaflet of the bilayer in DMD erythrocytes than in normals. This may be due to a greater than normal proportion of the PC being present in the outer leaflet or to enhanced transbilayer movement of PC molecules from the inner leaflet. Whichever the explanation, these findings indicate an organisational abnormality in DMD erythrocyte membranes.

Adolescent↗

PubMed1987

Systemic membrane defect and the inhibition of lymphocyte capping in Duchenne muscular dystrophy.

Eight reversible inhibitors were used to study decreases in lymphocyte capping in patients with Duchenne Muscular Dystrophy (DMD) when compared to controls. The inhibitors included hydrocortisone, chlorpromazine, calcium ionophore, Cytochalasin D, propranolol, dibucaine, fluoride and azide. All of these inhibitors disrupt cap formation. Mononuclear leukocytes from DMD patients and controls were isolated from whole blood, incubated with fluorescein-conjugated polyvalent antisera and inhibitor, induced to form caps, and the caps counted using a fluorescent microscope. Cell viabilities and morphology were assessed. After removal of inhibitor, the cells were recounted. All of the inhibitors significantly lowered capping in controls (p less than 0.001), but this effect was seen with only four out of the eight inhibitors in DMD patients. Dibucaine and azide were less inhibitory in patients (p less than 0.005, p greater than 0.05, and p greater than 0.05 respectively) while capping in patients was not inhibited by fluoride and hydrocortisone (p greater than 0.5). The lack of hydrocortisone inhibition suggests that the differences in capping between DMD patients and controls may lie within the membrane itself, rather than its associated components (i.e. cytoskeletal network), and that the defect occurs toward the beginning of the capping sequence.

Cell Membrane↗

PubMed1983

Differentiation properties of pure populations of human dystrophic muscle cells.

The interpretation of the majority of studies of Duchenne muscular dystrophy (DMD) has been complicated by the heterogeneous composition of the cultures used. In addition to muscle cells, muscle tissue contains adipocytes and fibroblasts and the proportion of these cell types varies, especially in disease states. To overcome this problem we developed culture conditions which permitted isolation and characterization of pure populations of clonally derived human muscle cells [1, 2]. Here we report the successful application of these methods to muscle cells from biopsies of individuals with diagnosed DMD. The normal and mutant human muscle cells were used in experiments of muscle differentiation in the same manner as cell lines. Frozen-stored cells were thawed, plated in a series of replicate plates, and allowed to differentiate under similar culture conditions. Yet, in contrast with cell lines, the cells were karyotypically normal, not altered by adaptation to long-term culture, and had a finite lifespan. We have systematically analysed specific properties of the normal and DMD muscle cells which differentiated in culture. The kinetics and extent of myoblast fusion, myotube morphology, and the accumulation and distribution of membrane acetylcholine receptors were monitored. In addition, the isozyme composition of creatine kinase and its intracellular and extracellular distribution were determined. Our results indicate that DMD muscle cells are fully capable of initiating myogenesis in culture and do not differ from normal muscle in several important parameters of differentiation.

Cell Differentiation↗

PubMed1987

Increased chloride efflux in fibroblasts from X-linked muscular dystrophies and clones from Duchenne carriers.

Previous studies have suggested an increased chloride membrane permeability in Duchenne muscular dystrophy (DMD) fibroblasts. We report that an increased chloride efflux with respect to controls is present not only in fibroblasts from DMD, but also from two other X-linked muscular dystrophies, Becker and Emery-Dreifuss, as well as in clones from DMD carrier females. The latter observation suggests that, at least in DMD, the increased chloride efflux phenotype might be subject to lyonization.

Cells, Cultured↗

PubMed1976

Increased phosphorylated components of erythrocyte membrane spectrin band II with reference to Duchenne muscular dystrophy.

Increased erythrocyte band II phosphorylation has been demonstrated in patients with Duchenne muscular dystrophy (DMD). Band II has been purified by preparative sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis. Isoelectric focusing of purified band II from which SDS has been removed reveals heterogeneity. Band II migrates as multiple bands on isoelectric focusing gels and as a single band on SDS-polyacrylamide gels. The increased phosphorylation in DMD does not occur uniformly in all components of band II. Highly phosphorylated components of band II are present in DMD in which only minimal phosphorylation occurs in controls. These results suggest the presence of an abnormal band II substrate in erythrocyte membranes from DMD patients.

Adult↗

PubMed1981

Oral kinesthesia in patients with Duchenne muscular dystrophy.

In trials on normal subjects and patients with Duchenne muscular dystrophy (DMD), interdental dimension discrimination (IDD) was tested by assessing the ability of subjects to discriminate between pairs of sticks of different dimensions held between the upper and lower teeth. The IDD ability of the DMD patients was significantly inferior to that of the normal subjects. Further, DMD patients tended to overestimate the dimension of the first stick of each pair even more than did normal subjects. Vibration applied to the mandible seemed to lessen such inaccuracies of oral kinesthesia in the DMD patients. These results are compatible with the idea that muscle receptors, especially muscle spindles in jaw closing muscles, are mainly responsible for IDD.

Adolescent↗

PubMed1981

Calcium flux of erythrocytes in Duchenne muscular dystrophy.

The calcium flux of erythrocytes from patients with Duchenne muscular dystrophy (DMD) was measured. Passive influx was determined using erythrocytes incubated with lanthanum chloride as a specific inhibitor to calcium transport. There was no significant difference in calcium influx into cytosol and into membrane fractions between DMD and control age-matched boys. Influx of calcium was also determined using ATP-depleted erythrocytes incubated without the inhibitor. Again there was no significant difference between DMD and control values. Efflux of calcium was measured using erythrocytes loaded with calcium ionophore A23187. Calcium efflux speed was related to intracellular calcium concentration and the efflux reached a plateau at about 1 mM. There was no significant difference in calcium efflux rate as a function of intracellular calcium concentration between DMD and control.

Adenosine Triphosphate↗

PubMed1981

Alterations in lipid incorporation in Duchenne muscular dystrophy. Studies of fresh and cultured muscle.

The incorporation of [3H] glycerol into lipids of fresh and cultured skeletal muscle obtained from patients with Duchenne muscular dystrophy (DMD), patients with myotonic dystrophy (My Dyst), controls, and aborted fetuses (10-12 weeks old) was studied. A significant increase of specific incorporation of [3H] glycerol into phosphatidylcholine (PCh), phosphatidylserine (PS), phosphatidylinositol (PI), and triglycerides (TRI) was found in DMD and fetal muscle in both fresh and cultured muscle. No significant differences, however, were noted between the values of glycerol incorporation in DMD and fetal muscle. The ratio between phospholipids and TRI changed significantly for fresh muscle in DMD (3.5) and fetal muscle (4.9) versus controls (24). The incorporation of glycerol into these lipids in My Dyst fresh and cultured muscle showed the same value as controls when expressed both as incorporation/mg protein and ratio between phospholipids and TRI.

Adolescent↗

PubMed1984

Altered binding of Ricinus communis I lectin by muscle membranes in Duchenne muscular dystrophy.

Recently, it has become clear that a structural or functional abnormality of the plasma membrane may be involved in the pathogenesis of Duchenne muscular dystrophy (DMD). We have used a D-galactose specific lectin, that binds strongly to the muscle cell surface, to search for differences in sarcolemmal staining in biopsies from 5 normal and 7 DMD individuals. Electron optical studies revealed a dramatic and consistent decrease in lectin binding by the muscle plasma membrane in DMD. Although unable at this stage to identify the specific molecular abnormality responsible for this decreased staining, the results provide good evidence that a basic structural change within the plasma membrane may be intimately associated with DMD.

Adolescent↗

PubMed1985

Ribosomal protein synthesis in cultured skin fibroblast cells obtained from patients with Duchenne muscular dystrophy.

Ribosomes and ribosomal subunits were extracted from cultured skin fibroblasts from patients with Duchenne muscular dystrophy (DMD). A poly(U)-directed polyphenylalanine synthesis system was used to test 80S ribosomes from DMD cells and normal controls as well as hybrid 80S couples of subunits from DMD cells and control cells. The activity of ribosomes extracted from the patients was 38-62% lower than that of normal controls. Of the 80S hybrid ribosomes, only those consisting of 40S subunits from DMD cells and 60S subunits from the control cells, showed a similar decrease in activity. That means that the defect is exclusively based on an alteration in the small ribosomal subunit.

Adolescent↗

PubMed1987

A qualitative and quantitative study of the ultrastructure of regenerating muscle fibres in Duchenne muscular dystrophy and polymyositis.

Quantitative and qualitative ultrastructural analyses were made of selected small muscle fibres from muscle biopsies from 23 patients with Duchenne muscular dystrophy (DMD) and 10 with polymyositis. It is argued that the fibres selected were regenerating. The myofibrillar content of the fibres was similar in both samples. In both there was considerable misalignment of the myofibrils but their orientation tended to improve as the content increased. The mitochondrial content was similar in the two samples but there were more ultrastructural abnormalities in the DMD population. The concentration of glycogen was elevated and the sarcoplasmic reticulum (SR) was much more commonly dilated in the DMD patients. Dilated SR is the prenecrotic change seen most frequently in mature muscle fibres in DMD and seems to be the first ultrastructural manifestation of the disease process. Its occurrence in the regenerating fibres suggest that the primary genetic lesion is being recapitulated in successive generations of fibres.

Biopsy↗

PubMed1987

Collagen synthesis in cultured myoblasts and myotubes from patients with Duchenne muscular dystrophy.

Collagen synthesis was studied in cultured myoblasts and myotubes from 4 patients with Duchenne muscular dystrophy (DMD) and 4 control persons. Incorporation of [3H]proline into collagen of DMD cells and control cells was not significantly different. The same types of collagen, i.e., type I and type III were synthesized by myogenic cells from DMD patients and controls. In contrast to others, we could not obtain evidence for an increase in the degree of prolyl hydroxylation in collagen of the DMD muscle cells.

Biopsy↗

PubMed1988

Binding of Ricinus communis I lectin to developing dystrophic muscle in human fetus.

In previous studies it was shown that a D-galactose-specific lectin, Ricinus communis I (RCA I), does not bind to the plasma membrane of muscle fibres from patients with Duchenne muscular dystrophy (DMD) in contrast to normal muscle. We have now studied RCA I binding to the membranes of developing human fetal muscle in fetuses at 95% risk of DMD (n = 6) and normal controls (n = 5) with a developmental range of 12-20 weeks of gestation. The results were compared to the membrane appearance with conventional ultrastructure. Binding of RCA I to the muscle basement membrane was consistently strong from the early stages of myogenesis, such as in fusing myoblasts/myocytes. RCA I binding to the plasma membrane was weak but detectable in both DMD and normal fetuses at 12-14 weeks of gestation. Both the normal and diseased condition showed an increase of RCA I labelling of the muscle plasma membrane at 15-17 weeks and strong labelling at 18-20 weeks of gestation. No difference was observed in the RCA I localization of normal and diseased human fetal muscle plasma membrane. It is concluded that (a) the plasma membrane in developing fetal muscle undergoes a maturation process between 12 and 20 weeks gestational age leading to an increase in expression of RCA I binding carbohydrate moieties; and (b) that the absence of RCA I binding glycoprotein in mature DMD muscle plasma membrane reflects a change acquired during the course of disease.

Cell Membrane↗

PubMed1989

Distribution of dystrophin, nebulin and Ricinus communis I (RCA-I)-binding glycoprotein in tissues of normal and mdx mice.

Dystrophin, the protein product of the Duchenne muscular dystrophy (DMD) gene locus, appeared as an immunoreactive triplet of polypeptides in striated muscle tissues from normal mice on Western blot analysis. In smooth muscle tissues, an immunoreactive doublet of corresponding molecular weight was detected. No dystrophin was found in normal mouse brain, not even after enrichment for the Triton X-100 insoluble fraction. Dystrophin was absent from all corresponding tissues from the mdx mutant mouse strain which is known to lack dystrophin. The possibility that these immunoreactive bands represent isoforms is discussed. We have also investigated two other high molecular weight proteins which show secondary abnormalities in DMD muscle, namely nebulin and the 370 kDa Ricinus communis I lectin (RCA I)-binding glycoprotein. Nebulin levels were reduced in skeletal muscle from 6-week-old mdx mice but not in oesophagus from the same animals. By contrast, the RCA I-binding 370 kDa glycoprotein which is greatly reduced in DMD skeletal muscle was present in normal amounts in mdx skeletal muscle. These findings show, for the first time, that mdx myopathy differs from DMD myopathy not only morphologically, but also in its secondary biochemical abnormalities.

Animals↗

PubMed1989

Dystrophin immunostaining and freeze-fracture studies of muscles of patients with early stage amyotrophic lateral sclerosis and Duchenne muscular dystrophy.

We used polyclonal antibodies against dystrophin for the immunohistochemical localization of this protein in human skeletal muscle. Dystrophin was localized in the sarcolemma of the myofibers in 8 infantile and 11 adult normal control muscles and in 10 early stage patient muscles with amyotrophic lateral sclerosis (ALS). The protein was absent or markedly decreased in 8 early stage patients with Duchenne muscular dystrophy (DMD). Moreover the densities of sarcolemmal plasma membrane assemblies, orthogonal arrays and their pits were estimated by freeze-fracture electron microscopy studies in the same number of muscle samples in each disease and control case. The group median densities of orthogonal arrays and their pits in the ALS group and adult control group were 4.8 with a midrange of 1.1-13.5 (25-75%) and 7.5 with a midrange of 2.3-12.9, respectively (P greater than 0.1, Wilcoxon rank-sum test), whereas those of the DMD group and child control group were 0 with a midrange of 0-1.1 and 10.8 with a midrange of 5.4-16.7 respectively (P less than 0.01). The skeletal muscles of mdx mice and their controls were also investigated by the same techniques. In mdx mice, the absence or marked deficiency of dystrophin was also noted; however, the decrease of orthogonal arrays was not as severe as in DMD, which might relate to the milder clinical features in mdx mice as compared with those in DMD.

Adult↗