McArdle's disease-muscle glycogen phosphorylase deficiency.
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Amino Acid Sequence↗
Biomedical subjects
R H Edwards
Publications and source records attributed to R H Edwards.
McArdle's disease: molecular genetics and metabolic consequences of the phenotype.
McArdle's disease is defined as a lack of functional muscle glycogen phosphorylase. Analysis of the myophosphorylase gene has demonstrated substantial heterogeneity in the mutations that cause the disease, but in almost all individuals, the molecular phenotype is the absence of the protein in skeletal muscle. Muscle glycogen phosphorylase is a major repository of vitamin B6 in the body, accounting for at least 80% of the total body pool. In McArdle's patients, this pool is therefore missing, introducing the possibility that vitamin B6 metabolism might be altered in these individuals. Preliminary data have shown that McArdle's patients show signs of a subclinical vitamin B6 deficiency, and that oral vitamin B6 supplementation can improve vitamin B6 status and enhance fatigue resistance in muscle.
Base Sequence↗
Historical perspective: a framework for interpreting pathobiological ideas on human muscle fatigue.
The flow of ideas on the causes of human muscle fatigue appear to have been established in the literature during the last century. Critical analysis had to await innovative experimental designs or techniques. Progress has come particularly from the recognition of inconsistencies, particularly in clinical conditions in which there are alterations in the supply of energy or contractile function. While there is a continuing search for a unique cause of fatigue, much evidence points to there being different causes according to the type of muscular activity or clinical condition. "Nature's experiments" (patients exhibiting isolated defects of function or metabolism) offer unique opportunities for understanding the relative importance of particular levels of metabolic organization or physiological control. Theories of limiting biochemical processes and the Ca- kinetic basis of electromechanical coupling defects are both essentially "single-cell" models of fatigue. Functional requirements appear to determine the diversity of structure and organization of motor units. This would suggest that a "muscle cell population" approach would take into account the consequences of disease altering the number, type of functioning fibers or intrinsic strength of individual fibers. A graphical model is offered to allow a possible interpretation of the cause of fatigue in different forms of exercise and clinical conditions.
History, 18th Century↗
The pathology of the lower leg muscles in pure forefoot pes cavus.
Enlargement of the peroneus longus muscle is a common occurrence in patients with forefoot pes cavus, and may contribute to the cavus deformity. The present study compares the morphology of up to five lower leg muscles from 17 patients with forefoot pes cavus with those of normal muscles. Eight cases had an identifiable neurogenic cause for the cavus. In four cases of hereditary motor-sensory neuropathy, the tibialis anterior showed more severe damage than the peroneus longus. In two cases of cerebral palsy, fibre atrophy and increased oxidative enzyme activity were observed. In nine clinically idiopathic cases, the histological appearances ranged from normal to generalised fibre atrophy or hypertrophy in individual muscles. There was a trend for the mean fibre area to be greater in peroneus longus than in tibialis anterior in six of the idiopathic group of patients. The muscle cross-sectional area on magnetic resonance imaging was correlated closely with the mean fibre area measured on tissue sections. In idiopathic forefoot pes cavus, fibre hypertrophy in peroneus longus (relative to tibialis anterior) may contribute to the cavus deformity. Muscle fibre hyperplasia may contribute to the peroneal muscle enlargement in Friedreich's ataxia. In none of the cases was peroneus longus enlargement due to fat or fibrous tissue replacement.
Adolescent↗
Transport of histamine by vesicular monoamine transporter-2.
Histamine mediates signalling by a wide range of neural and non-neural cells including mast cells. Like other biogenic amines, histamine is released from specialized secretory vesicles and requires transport from the cytoplasm into these vesicles. Of the two vesicular monoamine transporters, histamine potently inhibits 3H-serotonin transport by one (VMAT2) but not the other (VMAT1). In addition, histamine-containing cells in both neural and non-neural cells express VMAT2. However, histamine lacks the hydroxyl groups generally considered necessary for recognition as a substrate by the vesicular monoamine transporters. Using a heterologous expression system, we now report that VMAT2 not only shows inhibition by histamine but also transports 3H-histamine. Interestingly, histamine differs from other monoamine transmitters and does not inhibit 3H-reserpine binding to VMAT2, indicating interaction at a distinct site. Surprisingly, reserpine inhibits histamine transport with much less potency than serotonin transport, suggesting a different transport mechanism. However, replacement of serines in the third transmembrane domain of VMAT2 that have been shown to be essential for recognition of other monoamines also eliminate 3H-histamine transport, suggesting that these serine residues may do more than simply recognize the hydroxyl groups on a monoamine substrate.
Biological Transport↗
Muscle imaging in health and disease.
Muscle imaging has been used largely as an adjunct in the assessment of patients with muscle disease and has been reported in descriptive terms only. Developments in computer-based image analysis techniques applied to muscle have enabled the quantification of muscle images using ultrasonography, computed tomography and magnetic resonance techniques. In conjunction with physiological measurements of muscle force, accurate determinations of muscle section area have allowed the determination of force per unit of cross-sectional area. This important measurement is essential if therapeutic approaches in muscle disease are to be adequately assessed. In this review the uses and merits of different imaging techniques are described with reference to new developments in quantitative analysis of muscle images and the possible utilisation of these techniques in neuromuscular disease is discussed.
Humans↗
How does dystrophin deficiency lead to muscle degeneration?--evidence from the mdx mouse.
The mdx mouse has a defect in the same gene as boys with Duchenne muscular dystrophy, which results in the absence of the protein product, dystrophin. A large number of recent studies have used the mdx mouse model to examine the potential role of dystrophy in normal muscle and the mechanisms by which dystrophin-deficiency leads to myopathy. This review discusses critically the results of these studies and their relevance to understanding the mechanisms by which dystrophin-deficiency leads to muscle necrosis.
Animals↗
The transport of neurotransmitters into synaptic vesicles.
Using selection in the neurotoxin MPP+, we have isolated a cDNA encoding vesicular amine transport. The transporter protects against MPP+ by sequestering the toxin in vesicles, away from its primary site of action in mitochondria. Unexpectedly, two distinct but highly related genes encode vesicular amine transport in the adrenal gland and the central nervous system. The sequence of both predicts twelve transmembrane domains and weak homology to a class of bacterial antibiotic resistance proteins. The two human genes occur on different chromosomes. In addition, the two transporters show a number of differences in function, including substrate specificity and the interaction with one inhibitor and the amphetamines.
1-Methyl-4-phenylpyridinium↗
Sequence polymorphism in the Epstein-Barr virus latent membrane protein (LMP)-2 gene.
Latent membrane protein 2A (LMP-2A) is expressed in Epstein-Barr virus transformed B lymphocytes in vitro and has been detected in various types of EBV-associated malignancies. LMP-2A interferes with membrane signal transduction through phosphorylation of its hydrophilic N-terminal domain and binding of the cellular tyrosine kinases encoded by fyn and lyn. In vitro, the domain can block calcium influx and participate in signal transduction inducing cytokine production. These two activities are differently affected by site-directed mutagenesis of potentially phosphorylated amino acid residues. Several potential tyrosine protein kinase recognition motifs have been identified including an antigen recognition motif (ARAM). ARAMs are activated by tyrosine phosphorylation that enables binding of tyrosine protein kinases such as lyn and fyn. To assess the importance of potential sequence variation in natural EBV infection and in tumourigenesis, the sequence of the LMP-2A N-terminal domain was determined in 28 EBV isolates, including 14 fresh tumour isolates. Comparison of the corresponding sequences with the prototype B95 strain indicates that LMP-2 is generally conserved with a few base pair changes resulting in conservative amino acid changes in an occasional isolate. However, five single-base loci were frequently mutated, resulting in three patterns of sequence polymorphism in exon 1 of LMP-2A. The patterns did not segregate with EBV Type 1 or Type 2 and were detected in both lymphoid and epithelial tissues. Four of the most frequent mutations at loci 166627, 166750, 166796 and 166805 (codons 23, 63, 79 and 82) could potentially affect tyrosine protein kinase binding motifs. The pivotal tyrosines (codons 74 and 85) and leucines (codons 77 and 88) of the LMP-2 ARAM were not affected in any of the isolates, suggesting that ARAM function is important for EBV infection in vivo. However, the inter-spacing positions 79 and 82 were distinct in more than 50% of the isolates. These prevalent polymorphisms could influence interaction of the LMP-2 cytoplasmic domain with specific cellular ligand proteins.
Amino Acid Sequence↗
Differential expression of two vesicular monoamine transporters.
Specific transport proteins package classical neurotransmitters into vesicles so that their release can be regulated by neural activity. Previous studies have suggested that a single activity mediates the vesicular transport of monoamines in the adrenal gland, brain, and other tissues such as mast cells and platelets. However, molecular cloning has recently identified two vesicular transporters for monoamines. Although the predicted proteins are closely related in sequence, they show a range of differences in their physiologic and pharmacologic properties. To clarify further the biological significance of the observed functional differences, we have generated anti-peptide antibodies to the C-termini of the two transporters and used them to determine the distribution and localization of the proteins in the rat. We have detected expression of vesicular monoamine transporter 1 (VMAT1) in adrenal chromaffin cells but not in neural cells. Interestingly, some adrenal chromaffin cells also express VMAT2 but the amount of VMAT2 relative to VMAT1 appears much lower than in the bovine adrenal gland. In contrast, sympathetic ganglion cells express only VMAT2, as do enteric neurons and enterochromaffin-like cells of the stomach. Thus, although adrenal chromaffin cells, sympathetic and enteric neurons derive from the neural crest, they express different vesicular amine transporters. In the CNS, dopamine, norepinephrine, epinephrine, 5-HT, and histamine cell groups all express VMAT2. These findings are consistent with the functional characteristics of VMAT1 and VMAT2 and help to explain several classic pharmacological observations. VMAT2-immunoreactivity is generally stronger in cell bodies, proximal dendrites and axonal processes, indicating the potential for monoamine storage at each of these sites. Surprisingly, dopaminergic interneurons in the olfactory bulb show no detectable immunoreactivity for either VMAT1 or VMAT2.
Adrenal Glands↗
Molecular cloning of a putative vesicular transporter for acetylcholine.
Classical neurotransmitters such as acetylcholine (ACh) require transport into synaptic vesicles for regulated exocytotic release. The Caenorhabditis elegans gene unc-17 encodes a protein with homology to mammalian transporters that concentrate monoamine neurotransmitters into synaptic vesicles. Mutations in unc-17 protect against organophosphorus toxicity, indicating a role in cholinergic neurotransmission. Using the relationship of unc-17 to the vesicular amine transporters, we first isolated a related sequence from the electric ray Torpedo californica [Torpedo vesicular ACh transporter (TorVAChT)] that is expressed by the electric lobe but not by peripheral tissues. Using the relationship of the Torpedo sequence to unc-17, we then isolated the cDNA for a rat homologue (rVAChT). Northern blot analysis shows expression of these sequences in the basal forebrain, basal ganglia, and spinal cord but not cerebellum or peripheral tissues. In situ hybridization shows expression of rVAChT mRNA in all cholinergic cell groups, including those in the basal forebrain, brainstem, and spinal cord that previously have been shown to express choline acetyltransferase mRNA. The human VAChT gene also localizes to chromosome 10 near the gene for choline acetyltransferase. Taken together, these observations support a role for rVAChT in vesicular ACh transport and indicate its potential as a novel marker for cholinergic neurons.
Acetylcholine↗
McArdle's disease: a rare frameshift mutation in exon 1 of the muscle glycogen phosphorylase gene.
We have previously discovered a common nonsense mutation in exon 1 of the myophosphosphorylase gene in patients with McArdle's disease, but this failed to explain all cases. We now report a second mutation (G-->TT) in one patient, also in exon 1. This mutation causes a shift in the reading frame which results in the replacement of Val15 by Phe. A further 10 amino acids of mis-sense protein are synthesised before a stop codon is reached.
Amino Acid Sequence↗
The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors.
Classical studies using bovine chromaffin granules have defined the physiologic and pharmacologic properties of the vesicular amine transporter that packages monoamine transmitters into intracellular vesicles for subsequent regulated release. The recent isolation of two distinct but closely related cDNA clones encoding vesicular amine transport suggests that the activity expressed in the brain (synaptic vesicle amine transporter or SVAT) may differ significantly from the previously described adrenal gland activity (chromaffin granule amine transporter or CGAT). A direct comparison of the two transporters now shows that SVAT has a higher affinity than CGAT for monoamine substrates, in particular for histamine. In addition, SVAT shows approximately 10-fold greater sensitivity to tetrabenazine than CGAT. [3H]Dihydrotetrabenazine shows no detectable binding to CGAT but does bind to SVAT, accounting for the differential sensitivity. Furthermore, methamphetamine preferentially inhibits transport by SVAT relative to CGAT, apparently by competing at the site of amine recognition rather than by disrupting the vesicular pH gradient. These previously unsuspected differences in the storage of monoamine transmitter in the central nervous system and the adrenal gland may help to account for several classic pharmacological observations.
1-Methyl-4-phenylpyridinium↗
Cloning of the cellular receptor for amphotropic murine retroviruses reveals homology to that for gibbon ape leukemia virus.
The host and tissue specificity of retrovirus infection is largely determined by specific cellular receptors that mediate virus entry. Genes encoding these receptors are widely distributed in the genome, and the receptors identified to date show no sequence similarity. We have identified the cellular receptor for amphotropic murine retroviruses, Ram-1, by screening a rat cDNA expression library introduced into amphotropic virus-resistant hamster cells. The 656-amino acid receptor is homologous to the gibbon ape leukemia virus receptor at both hydrophobic termini but is highly divergent in the central hydrophilic region. Both receptors appear to be integral membrane proteins having multiple membrane-spanning regions. Identification of this family of receptors will help define the evolutionary relationship between retroviruses and their cellular receptors.
Amino Acid Sequence↗
Time course of changes in plasma membrane permeability in the dystrophin-deficient mdx mouse.
Control C57Bl/10 and mutant, dystrophin-deficient mdx mice of different ages were used to study the permeability of the plasma membrane to cytosolic components, to a vital stain (procion orange) and to extracellular 45calcium. Prenecrotic, 14 +/- 2-day-old mdx mice had normal serum activities of creatine kinase (CK) and pyruvate kinase (PK). Muscles from these animals also had no increased permeability to procion orange or extracellular 45calcium. Serum activities of CK and PK had risen acutely in the 21-day-old mdx mouse compared with control and remained elevated up to 6 months of age. The influx of procion orange and 45calcium content were abnormally elevated in the 40 +/- 4-day-old mdx mouse. These data provide no evidence for an increase in muscle plasma membrane permeability as a primary pathogenic effect of a lack of dystrophin, but results suggest that some factor expressed or de-expressed during mouse development may be necessary for the full expression of the dystrophic process.
Aging↗
Neural-targeted gene therapy for rodent and primate hemiparkinsonism.
Expression of the rate-limiting enzyme for catecholamine biosynthesis, tyrosine hydroxylase (TH), via retroviral and plasmid expression vectors improved the efficacy of conditionally immortalized nigral neural cells in ameliorating rodent and nonhuman primate models of Parkinson's disease through neural transplantation. No improvement in rotational behavior occurred when sham transplants or nondopaminergic transplants were performed. Transplantation of the temperature-sensitive immortalized parental nigral neural line with a TH expression vector resulted in improvement for at least 2 months. Improvement was accompanied by HPLC evidence of increased L-DOPA production and immunocytochemical evidence of TH in the transfected cells increased over that of the parental line. No tumor formation was detected. These results suggest that: (1) temperature-sensitive immortalized neural cells may be genetically engineered successfully to improve their efficacy for the treatment of parkinsonism; and (2) a change in L-DOPA production, as opposed to growth factor production or other factors, is likely to account for the observed improvement, since the parental and derived lines differ by a single gene.
Animals↗
Operations research survey and computer simulation of waiting times in two medical outpatient clinic structures.
Outpatient services are increasingly recognised as an important component of health care provision and may be improved through the application of modern management techniques. We have performed a time and role audit of consultation and waiting times in two medical clinics using different queuing systems: namely, a serial processing clinic where patients wait in a single queue and a quasi-parallel processing clinic where patients are directed to the shortest queue to maintain clinic flow. Data collected were used to construct a computer simulation of patient flows in clinic. Assessment of patient satisfaction in the clinic process was determined using a self-administered questionnaire. Mean waiting time was shorter in the quasi-parallel processing clinic: 26 (SD 17) minutes compared with 36(24) minutes in the serial processing clinic. In the serial processing clinic 61% of patients waited more than 30 minutes compared with 41% in the quasi-parallel processing clinic. In the serial processing clinic 8% of 142 patients surveyed complained of the time spent waiting. The computer simulation we produced was able to determine waiting times with different clinic structures. The simulation showed that reductions in waiting time up to 30% might be achieved by changing our serial processing clinic to a quasi-parallel processing one. Performance of medical outpatient clinics can be improved by examining and changing clinic management. Computer simulation of outpatient clinics offers a means of assessing the impact of such changes on waiting time in clinic and on waiting lists.
Algorithms↗
Hereditary distal myopathy with granulo-filamentous cytoplasmic inclusions containing desmin, dystrophin and vimentin.
A 56-year-old female and her 34-year-old daughter presented with a predominantly distal myopathy affecting the peroneal and calf muscles, neck flexors and hand muscles. Both patients and two other daughters had cardiac arrhythmias, three requiring the insertion of cardiac pacemakers. Skeletal muscle biopsies revealed a complex myopathic process with granular degeneration, rimmed vacuoles and eosinophilic cytoplasmic inclusions. Ultrastructurally, the inclusions were composed of electron dense granular material and filaments forming linear masses beneath the sarcolemma and rounded masses within the cytoplasm of the fibres. Immunohistochemistry revealed labelling of the inclusions for desmin, dystrophin and vimentin, but not for alpha-actinin, spectrin, utrophin or myosin heavy chains. This family shows a hereditary distal myopathy with some features in common with previously-reported cases in which biopsies showed cytoplasmic inclusion bodies containing desmin. This group of diseases is clinically and pathologically heterogeneous. In the present cases, the accumulation of cytoplasmic filaments may reflect a generalised disturbance of filamentous protein metabolism rather than a specific disorder of desmin.
Adult↗