A New Rare Mutation (691delCC/insAAA) in Exon 17 of the PYGM Gene Causing McArdle Disease

Quintáns, Beatriz; Sánchez-Andrade, A; Teijeira, Susana; Fernandez-Hojas, Roberto; Rivas, Eloy; López, María José; Navarro, Carmen

doi:10.1001/archneur.61.7.1108

Cited by 12 publications

(4 citation statements)

References 23 publications

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“…The latter has been shown to blunt cAMP activation of glycogen phosphorylase in skeletal muscle (20), in addition to having direct cardiac effects. The marked impairment of exercise capacity in McArdle's disease (21-23), due to heterogeneous nonsense mutations in the PYGM gene (24), also supports the contention that impaired carbohydrate flux can limit skeletal muscle function.…”

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confidence: 74%

Glycogen Phosphorylase Inhibition in Type 2 Diabetes Therapy

2005

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Inhibition of hepatic glycogen phosphorylase is a promising treatment strategy for attenuating hyperglycemia in type 2 diabetes. Crystallographic studies indicate, however, that selectivity between glycogen phosphorylase in skeletal muscle and liver is unlikely to be achieved. Furthermore, glycogen phosphorylase activity is critical for normal skeletal muscle function, and thus fatigue may represent a major development hurdle for this therapeutic strategy. We have carried out the first systematic evaluation of this important issue. The rat gastrocnemius-plantaris-soleus (GPS) muscle was isolated and perfused with a red cell suspension, containing 3 mol/l glycogen phosphorylase inhibitor (GPi) or vehicle (control). After 60 min, the GPS muscle was snap-frozen (rest, n ‫؍‬ 11 per group) or underwent 20 s of maximal contraction (n ‫؍‬ 8, control; n ‫؍‬ 9, GPi) or 10 min of submaximal contraction (n ‫؍‬ 10 per group). GPi pretreatment reduced the activation of the glycogen phosphorylase a form by 16% at rest, 25% after 20 s, and 44% after 10 min of contraction compared with the corresponding control. AMP-mediated glycogen phosphorylase activation was impaired only at 10 min (by 21%). GPi transiently reduced muscle lactate production during contraction, but other than this, muscle energy metabolism and function remained unaffected at both contraction intensities. These data indicate that glycogen phosphorylase inhibition aimed at attenuating hyperglycaemia is unlikely to negatively impact muscle metabolic and functional capacity. Diabetes 54: 2453-2459, 2005 G lycogen phosphorylase catalyzes the breakdown of glycogen to glucose-1-phosphate in liver and tissues with high and fluctuating energy demands. Glycogen phosphorylase exists in two interconvertible forms (a and b); the proportion that exists in each form is regulated by phosphorylation. The less active b form is transformed by phosphorylation to the more active a form. In skeletal muscle, the transformation from b to a is regulated by changes in intracellular concentrations of AMP, inosine monophosphate (IMP), and inorganic phosphate and by glycogen phosphorylase kinase activation, all of which increase during contraction. Glycogen phosphorylase kinase also exists in two forms, glycogen phosphorylase kinase a and glycogen phosphorylase kinase b. Glycogen phosphorylase kinase b activity is increased in the presence of elevated intracellular calcium (Ca ϩ2 ) and cAMP, mediated by contraction (1-4) and adrenaline (5-7), respectively, which then phosphorylates and activates glycogen phosphorylase kinase a. Phosphorylated glycogen phosphorylase kinase a then phosphorylates and transforms glycogen phosphorylase b to its more active a form. On cessation of contraction, calcium is sequestered back into the sarcoplasmic reticulum, and the elevated concentrations of ADP, AMP, and inorganic phosphate are used to regenerate muscle ATP and phosphocreatine (PCr) stores. Glycogen phosphorylase a form is subsequently dephosphorylated by the action of protein phosphatases, wher...

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confidence: 74%

Glycogen Phosphorylase Inhibition in Type 2 Diabetes Therapy

2005

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“…Additionally, more than 40 rare mutations are known [4,9,11]. However, there is little information about the frequency and distribution of these less common mutations among different ethnic groups.…”

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confidence: 99%

Analysis of spectrum and frequencies of mutations in McArdle disease

et al. 2007

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The study further extends the genetic heterogeneity of myophosphorylase gene mutations showing no mutational hotspot and no genotype-phenotype correlation. Most novel missense mutations were located in secondary structures or active sites of the enzyme. Some of the less common mutations are recurrent with different frequencies within Europe. Ethnic origin and frequency of less common mutations must be considered to establish efficient strategies in molecular genetic testing. Performing molecular testing can avoid muscle biopsy.

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“…As far as December 2005, 46 different PYGM mutations, 21 residing in the N-terminal and 25 in the C-terminal of the gene, have been identified in GSD-V patients (Deschauer et a. 2001, Mancuso et al 2003, Quintans et al 2004, Isackson et al 2005, Paradas et al 2005) (see also the Human Gene Mutation Database http://www.hgmd.cf.ac.uk/), making the diagnosis more accurate by DNA testing. In addition, muscle RNA studies demonstrated that a silent mutation leads to a severe alteration in mRNA splicing .…”

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confidence: 99%

McArdle disease: the mutation spectrum ofPYGMin a large Italian cohort

et al. 2006

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Deficiency of the muscle isozyme of glycogen phosphorylase is causative of McArdle disease or Glycogen storage disease type V (GSD-V), the most common autosomal recessive disorder of glycogen metabolism. The typical clinical presentation is characterized by exercise intolerance with cramps, and recurrent myoglobinuria. To date, 46 mutations in the PYGM gene have been detected in GSD-V patients. We report the mutational spectrum in 68 Italian patients. We identified 30 different mutations in the PYGM gene, including 19 mutations that have not been reported previously. The novel mutations include: eight missense mutations (c.475G>A, p.G159R; c.689C>G, p.P230R; c.1094C>T, p.A365E; c.1151C>A, p.A384D; c.1182C>T, p.R428C; c.1471C>T, p.R491C; c.2444A>C, p.D815A; c.2477G>C, p.W826S), two nonsense mutations (c.1475G>A, p.W492X; c.1627A>T, p.K543X), five splice site mutations (c.855 +1G>C; c.1092 +1G>A; c. 1093-1G>T; c.1239 +1G>A; c.2380 +1G>A), and four deletions (c.715_717delGTC, p.V239del; c.304delA, p.N102DfsX4; c.1970_2177del, p.V657_G726; c.2113_2114delGG, p.G705RfsX16). Whereas we confirmed lack of direct correlation between the clinical phenotype and the genotype, we also found that the so-called 'common mutation' (p.R50X) accounted for about 43% of alleles in our cohort and that no population-related mutations are clearly identified in Italian patients.

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A New Rare Mutation (691delCC/insAAA) in Exon 17 of the PYGM Gene Causing McArdle Disease

Cited by 12 publications

References 23 publications

Glycogen Phosphorylase Inhibition in Type 2 Diabetes Therapy

Glycogen Phosphorylase Inhibition in Type 2 Diabetes Therapy

Analysis of spectrum and frequencies of mutations in McArdle disease

McArdle disease: the mutation spectrum ofPYGMin a large Italian cohort

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