Alternative titles; symbols
HGNC Approved Gene Symbol: PYGM
SNOMEDCT: 55912009; ICD10CM: E74.04;
Cytogenetic location: 11q13.1 Genomic coordinates (GRCh38) : 11:64,746,389-64,760,715 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 11q13.1 | McArdle disease | 232600 | Autosomal recessive | 3 |
The PYGM gene encodes the muscle isoform of glycogen phosphorylase (EC 2.4.1.1), which catalyzes and regulates the breakdown of glycogen to glucose-1-phosphate during glycogenolysis. This metabolic pathway is necessary for the generation of ATP during physical activity (Gautron et al., 1987).
Gautron et al. (1987) isolated muscle phosphorylase cDNA clones from a human cDNA library. Northern blot experiments revealed 1 specific mRNA of 3.4 kb found uniquely in tissues expressing muscle phosphorylase. The muscle glycogen phosphorylase protein comprises 842 amino acids (Kubisch et al., 1998).
Burke et al. (1987) determined the intron/exon structure of the PYGM gene. Kubisch et al. (1998) provided a revised genomic structure for the PYGM gene, which contains 20 exons.
Lebo et al. (1984) used an improved method of chromosome sorting to assign the gene for skeletal muscle glycogen phosphorylase to chromosome 11. The method used a double laser system to sort chromosomes into 21 groups. A clone of the carboxy-terminal region of the myophosphorylase gene hybridized to a spot containing chromosomes 10, 11, and 12. Using chromosomes from cell lines with translocations of various ones of these 3 chromosomes, including a 4;11 reciprocal translocation, they assigned the gene to 11p13-qter. This location was confirmed by testing a series of Chinese hamster-human somatic cell hybrid DNAs that contained a single human chromosome 11 with various terminal deletions. Lebo et al. (1990) further sublocalized the PYGM gene to the proximal part of band 11q13 by fluorescence in situ hybridization.
Glaser et al. (1989) mapped the muscle, liver, and brain phosphorylases (Pygm, Pygl, and Pygb) to mouse chromosomes 19, 12, and 2, respectively, by comparing segregations patterns of RFLPs with those of previously mapped genetic markers in an interspecies backcross between Mus musculus domesticus and Mus spretus. A previously mapped 'muscle-deficient' mutation in the mouse (mdf) was found to be closely linked to the muscle phosphorylase gene. However, since muscle phosphorylase gene structure and expression appeared to be unaltered in homozygous mdf/mdf mice, this mutation was determined not to be a model of McArdle disease (232600), which is caused by mutation in the PYGM gene.
Courseaux et al. (1996) used a combination of methods to refine maps of the approximately 5-Mb region of 11q13 that includes multiple endocrine neoplasia type 1 (MEN1; 131100). They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel.
Among 94 enzyme-probe combinations, Lebo et al. (1990) identified a single MspI polymorphism in the PYGM gene region. This polymorphism and an insertion/deletion polymorphism more 3-prime to the gene were found to be informative in 75% of patients at risk for myophosphorylase deficiency, or McArdle disease (GSD5; 232600). Lebo et al. (1990) noted that the scarcity of polymorphic sites in the PYGM gene contrasted sharply with the situation with the liver phosphorylase gene (PYGL; 613741), the site of the mutation in glycogen storage disease VI (232700); in the case of PYGL, they found 6 polymorphic sites in 15 enzyme-probe combinations. Iwasaki et al. (1992) described highly informative minisatellite and microsatellite polymorphisms at the PYGM locus.
In a study of 40 patients with McArdle disease, Tsujino et al. (1993) identified 3 distinct point mutations in the PYGM gene (608455.0001-608455.0003). One of these mutations, arg50-to-ter (R50X; 608455.0001), was present in 75% of patients in heterozygous or homozygous state.
Andreu et al. (2007) provided an update of the molecular genetics of McArdle disease, noting that over 65 mutations in the PYGM gene had been identified.
Nogales-Gadea et al. (2008) found that 26 (92%) of 28 Spanish patients with McArdle disease showed nonsense-mediated decay (NMD) of their mutant PYGM mRNA transcript, corresponding mainly to mutations resulting in premature termination codons. R50X was the most common mutation in this cohort.
Garcia-Consuegra et al. (2009) used skeletal muscle mRNA and cDNA analysis to identify a second defect in the PYGM gene in 4 patients with McArdle disease in whom heterozygous PYGM mutations were initially detected by genomic DNA analysis. They identified a large deletion and splice site mutation in 1 patient each and a synonymous (K215K) substitution in exon 5 in 2 patients. Real-time PCR of muscle from 1 patient with the K215K substitution showed a drastic decrease in mRNA, implicating nonsense-mediated mRNA decay as a mechanism.
In 5 unrelated patients with McArdle disease, Wu et al. (2011) identified compound heterozygosity for the common R50X mutation and another pathogenic mutation in the PYGM gene (see, e.g., D51G, 608455.0020). A sixth patient was homozygous for a small deletion (608455.0021). All had typical features of the disorder, including exercise intolerance, decreased or absent PYGM activity and immunostaining in muscle samples, and increased serum creatine kinase. Three had rhabdomyolysis and myoglobinuria. Muscle biopsy of 5 patients showed glycogen accumulation. Although the median age at diagnosis was 29.5 years, most recalled having onset of symptoms in childhood or adolescence.
Vissing et al. (2009) reported 2 unrelated patients, aged 30 and 39 years, respectively, with a mild form of McArdle disease (232600) caused by compound heterozygosity for PYGM mutation. Each patient carried 1 typical mutation (R50X, 608455.0001; G205S, 608455.0002) and 1 splice site mutation (608455.0018 and 608455.0019). The splice site mutations were found to cause aberrant splicing and production of abnormally spliced proteins that were expressed in small amounts. Biochemical studies showed 1.0 to 2.5% residual PYGM activity, suggesting that the mutations were 'leaky' and allowed some normally spliced products to be generated. Both patients reported muscle cramps, pain, and episodes of rhabdomyolysis and myoglobinuria after exercise. One had 2 to 3 episodes, whereas the other had more than 10 with 1 episode of renal failure. Both also had increased serum creatine kinase, similar to patients with typical disease. However, both patients also had a high capacity for sustained exercise. Exercise testing showed an intermediate phenotype between controls and individuals with typical McArdle disease. The patients could complete 60 minutes of ischemic exercise before muscle cramping occurred, and peak oxidative capacity was about 2-fold higher compared to patients with typical McArdle disease. The findings indicated that very low levels of PYGM are sufficient to sustain glycogenolysis and muscle oxidative metabolism, and provided the first genotype/phenotype correlation at the molecular level.
Homozygosity for a common stop codon in the ACTN3 gene (R577X; 102574.0001) results in complete deficiency of the fast fiber muscle protein alpha-actinin-3. This ACTN3 genotype is associated with human athletic performance, and alpha-actinin-3-deficient mice (Actn3 knockout mice) have a shift in the properties of fast muscle fibers toward slower fiber properties, with increased activity of multiple enzymes in the aerobic metabolic pathway and slower contractile properties. Alpha-actinins have been shown to interact with a number of muscle proteins, including the key metabolic regulator glycogen phosphorylase (GPh). Quinlan et al. (2010) demonstrated a link between alpha-actinin-3 and glycogen metabolism. Actn3 knockout mice had higher muscle glycogen content and a 50% reduction in the activity of GPh. The reduction in enzyme activity was accompanied by altered posttranslational modification of GPh, suggesting that alpha-actinin-3 may regulate GPh activity by altering its level of phosphorylation. Quinlan et al. (2010) proposed that the changes in glycogen metabolism underlie the downstream metabolic consequences of alpha-actinin-3 deficiency.
In a study of 40 patients with McArdle disease (GSD5; 232600), Tsujino et al. (1993) identified 3 distinct point mutations in the PYGM gene. The most common mutation was a C-to-T change in exon 1, reported as an ARG49TER (R49X) substitution but now designated R50X. Eighteen patients were homozygous for the R49X mutation, while 12 were compound heterozygous for the R49X mutation and another mutation, thus accounting for 75% of all patients. The second mutation was a G-to-A change in exon 5, resulting in a gly205-to-ser (G205S; 608455.0002) substitution, reported as a GLY204SER (G204S) substitution. The third mutation was an A-to-C change in exon 14, resulting in a lys543-to-thr (L543T) substitution, reported as a LYS542THR (L542T) substitution. Six of the 40 patients had different mutations in the 2 alleles (i.e., were compound heterozygotes), and 11 were presumed to be compound heterozygotes for a known mutation and an unknown one. Only 5 patients had none of the 3 mutations. In 1 remarkable family, all 3 mutations were present in various combinations in 5 members of the family in which transmission appeared to be autosomal dominant. Thus, this was pseudodominance due to mating of a compound heterozygote with a person carrying a third mutation. Three children were all compound heterozygotes, but compound heterozygotes of 2 different compositions. The mother was a 204/49 compound; the father was a 542 carrier; 2 children were 542/204 compounds and 1 was a 542/49 compound. Presumed autosomal dominant inheritance was reported by Chui and Munsat (1976), and the occurrence of McArdle disease in 2 generations was attributed to manifestations in some heterozygotes by Schmidt et al. (1987) and Papadimitriou et al. (1990).
Bartram et al. (1993) found the R49X mutation in all 16 McArdle disease patients studied; 10 of the 16 were homozygous, and the remainder were heterozygous, with the other allele awaiting identification.
Vorgerd et al. (1998) performed mutation analysis in 9 patients from 8 unrelated German families with typical myophosphorylase deficiency. They found the R49X mutation in homozygous state in 4 patients as well as in compound heterozygous state in 3 others, suggesting that this is the most common mutation associated with myophosphorylase deficiency in Germans.
Martin et al. (2001) performed mutation analysis on DNA from 54 Spanish patients (40 families) with glycogen storage disease V and found the R49X mutation in 70% of patients and 55% of mutant alleles.
Martin et al. (2004) demonstrated that the R49X mutation is the most common among Dutch patients with McArdle disease.
Andreu et al. (2007) stated that the R49X mutation is now referred to as R50X. The highest frequency of R50X is in Great Britain and North America (81% and 63%, respectively), with approximately 50% frequency in other European countries.
For discussion of the gly205-to-ser (G205S) mutation in the PYGM gene that was found in compound heterozygous state in patients with McArdle disease (GSD5; 232600) by Tsujino et al. (1993), see 608455.0001.
Martin et al. (2001) performed mutation analysis on DNA from 54 Spanish patients (40 families) with GSD5 and found the G205S mutation in 14.8% of patients and 9% of mutant alleles.
For discussion of the lys543-to-thr (K543T) mutation in the PYGM gene that was found in compound heterozygous state in patients with McArdle disease (GSD5; 232600) by Tsujino et al. (1993), see 608455.0001.
In a 36-year-old woman who had been diagnosed with scleroderma at age 33 but who was also found to have myophosphorylase deficiency (GSD5; 232600), Tsujino et al. (1994) identified an A-to-C transversion (ATG to CTG), which abolished the translation initiation codon of the PYGM gene. The patient was a compound heterozygote with a common nonsense mutation, R50X (608455.0001).
In a 40-year-old man with McArdle disease (GSD5; 232600) who complained of myalgia and cramps after intense exercise but had no myoglobinuria, Tsujino et al. (1995) found compound heterozygosity for mutations in the in the PYGM gene: a G-to-A change, resulting in a glu654-to-lys (E654K) substitution and the common R50X mutation (608455.0001).
In a 22-year-old woman with McArdle disease (GSD5; 232600) who complained of exercise intolerance and cramps and had had 1 episode of myoglobinuria, Tsujino et al. (1995) identified a T-to-C change in the PYGM gene, resulting in a leu396-to-pro (L396P) substitution. Data from restriction analysis of the patient's PCR-amplified PYGM transcripts suggested that the mutation was in heterozygous state and that the myophosphorylase gene on the second allele was only faintly expressed. The nature of the mutation on the other allele was not found.
Iyengar et al. (1997) restudied the consanguineous Druze family with McArdle disease (GSD5; 232600) reported by Sarova-Pinhas and Sadeh (1989) and found all affected subjects to be homozygous for a G-to-A transition in the first nucleotide of intron 14 of the PYGM gene, a mutation previously reported by Tsujino et al. (1994). This mutation resulted in activation of an upstream cryptic splice site in exon 14, causing deletion of 67 basepairs from exon 14 and affecting the glucose binding domain of PYGM.
In a large Finnish kindred, Bruno et al. (1999) described the same mutation. The mutation at the 5-prime splice site of intron 14 was designated as 1844+G-A.
In 2 affected sibs with myophosphorylase deficiency (GSD5; 232600), Vorgerd et al. (1998) found compound heterozygosity for a gly685-to-arg (G685R) substitution and the nonsense mutation R50X (608455.0001).
In a patient with myophosphorylase deficiency (GSD5; 232600), Vorgerd et al. (1998) found compound heterozygosity for a nonsense mutation, arg575-to-ter (R575X), and a previously described missense mutation, G205S (608455.0002).
In a German patient with myophosphorylase deficiency (GSD5; 232600), Vorgerd et al. (1998) found compound heterozygosity for mutations in the PYGM gene: gln665-to-glu (Q665E) and a single base deletion (A) in lys753 (608455.0011).
For discussion of the 1-bp deletion (A) n lys753 of the PYGM gene that was found in compound heterozygous state in a patient with myophosphorylase deficiency (GSD5; 232600) by Vorgerd et al. (1998), see 608455.0010.
In a Turkish patient with McArdle disease (GSD5; 232600), Vorgerd et al. (1998) found homozygosity for an A-to-G transition within the initiation codon of the PYGM gene, resulting in a met1-to-val (M1V) substitution. (See also 608455.0004.)
In a large Finnish kindred with McArdle disease (GSD5; 232600), Bruno et al. (1999) identified a mutation in exon 14 of the PYGM gene, resulting in a glu540-to-ter substitution (E540X).
In 2 sibs with McArdle disease (GSD5; 232600), Martin et al. (2001) identified a micro-insertion/deletion in the PYGM gene in a compound heterozygous state: the previously described 1-bp deletion at codon 753 (608455.0011) in exon 18 and a novel insA/8-bp del mutation at codon 387 in exon 10. The novel mutation was predicted to result in premature termination of translation 33 amino acids downstream of the site of mutation, potentially encoding a severely truncated protein of 419 amino acids instead of 841 amino acids. Complete lack of myophosphorylase activity was observed in muscle. Martin et al. (2001) suggested that the underlying mechanism of mutagenesis may have been slipped mispairing mediated by the formation of a Moebius loop-like secondary intermediate.
Martin et al. (2001) performed mutation analysis on DNA from 54 Spanish patients (40 families) with glycogen storage disease V (GSD5; 232600) and found that 16.5% of patients and 13.7% of mutant alleles had the W797R substitution previously described by Fernandez et al. (2000).
In a patient with McArdle disease (GSD5; 232600), Fernandez-Cadenas et al. (2003) identified compound heterozygosity for mutations in the PYGM gene. One of the mutations, 1827G-A, was a silent mutation (lys608 to lys; K608K). cDNA studies showed that the change resulted in a severe mosaic alteration in mRNA splicing with multiple aberrant transcripts, including exon skipping, activation of cryptic splice sites, and exon-intron reorganization. The same mutation was identified in a second patient, supporting the idea that the K608K mutation has a primary pathogenic role. The second mutation was a 1722T-G transversion, resulting in a tyr573-to-ter (Y573X) (608455.0017) substitution.
For discussion of the tyr573-to-ter (Y573X) mutation in the PYGM gene that was found in compound heterozygous state in a patient with McArdle disease (GSD5; 232600) by Fernandez-Cadenas et al. (2003), see 608455.0016.
In a 30-year-old Swedish woman with a mild form of McArdle disease (GSD5; 232600), Vissing et al. (2009) identified compound heterozygosity for 2 mutations in the PYGM gene: R50X (608455.0001) and a G-to-A transition in intron 5, resulting in a splice site mutation and production of an abnormally spliced fragment in which 175 bp from intron 5 were spliced between exons 5 and 6. There were trace amounts of the aberrantly spliced product, and biochemical studies showed residual PYGM activity (1.0 to 2.5% of normal), suggesting that the splice site mutation was 'leaky' and allowed some normally spliced product to be generated. Although the patient had muscle cramps, pain, and episodes of rhabdomyolysis and myoglobinuria after exercise, she had a high capacity for sustained exercise. Exercise testing showed a phenotype that was intermediate between controls and individuals with typical McArdle disease. The patient could complete 60 minutes of ischemic exercise before muscle cramping occurred, and peak oxidative capacity was about 2-fold higher compared to patients with typical McArdle disease. The findings indicated that very low levels of PYGM are sufficient to sustain glycogenolysis and muscle oxidative metabolism.
In a 39-year-old North American man with a mild form of McArdle disease (GSD5; 232600), Vissing et al. (2009) identified compound heterozygosity for 2 mutations in the PYGM gene: an A-to-G transition in intron 3, resulting in a splice site mutation and production of an abnormally spliced protein lacking exon 4, and the G205S mutation (608455.0002). There were trace amounts of the aberrantly spliced product, and biochemical studies showed residual PYGM activity (1.0 to 2.5% of normal), suggesting that the splice site mutation was 'leaky' and allowed some normally spliced product to be generated. Although the patient had muscle cramps, pain, and episodes of rhabdomyolysis and myoglobinuria after exercise, he had a high capacity for sustained exercise. Exercise testing showed a phenotype that was intermediate between controls and individuals with typical McArdle disease. The patient could complete 60 minutes of ischemic exercise before muscle cramping occurred, and peak oxidative capacity was about 2-fold higher compared to patients with typical McArdle disease. The findings indicated that very low levels of PYGM are sufficient to sustain glycogenolysis and muscle oxidative metabolism.
In a male with McArdle disease (GSD5; 232600), Wu et al. (2011) identified compound heterozygous mutations in the PYGM gene: a 152A-G transition resulting in an asp51-to-gly (D51G) substitution at a highly conserved residue inherited from the asymptomatic mother, and the common R50X (608455.0001) mutation inherited from the father. This was an instance of pseudodominance, as the affected father was compound heterozygous for R50X and another truncating mutation in the PYGM gene.
In a young woman with McArdle disease (GSD5; 232600), Wu et al. (2011) identified a homozygous 3-bp deletion (158_160delACT) in the PYGM gene, resulting in the deletion of the highly conserved tyr53 residue. The patient had onset of exercise intolerance in childhood, and was diagnosed at age 25. She had increased serum creatine kinase and decreased myophosphorylase activity.
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