Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the <i>PYGM</i> Gene
McArdle disease is a rare autosomal recessive condition caused by mutations in the <i>PYGM</i> gene. This gene encodes the skeletal muscle isoform of glycogen phosphorylase or myophosphorylase. Patients with McArdle disease have an inability to obtain energy from their muscle glycogen st...
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| Format: | Article |
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MDPI AG
2023-08-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/11/9/2434 |
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| author | Victoria Cerrada Inés García-Consuegra Joaquín Arenas M. Esther Gallardo |
| author_facet | Victoria Cerrada Inés García-Consuegra Joaquín Arenas M. Esther Gallardo |
| author_sort | Victoria Cerrada |
| collection | DOAJ |
| description | McArdle disease is a rare autosomal recessive condition caused by mutations in the <i>PYGM</i> gene. This gene encodes the skeletal muscle isoform of glycogen phosphorylase or myophosphorylase. Patients with McArdle disease have an inability to obtain energy from their muscle glycogen stores, which manifests as a marked exercise intolerance. Nowadays, there is no cure for this disorder and recommendations are intended to prevent and mitigate symptoms. There is great heterogeneity among the pathogenic variants found in the <i>PYGM</i> gene, and there is no obvious correlation between genotypes and phenotypes. Here, we present the generation of the first human iPSC-based skeletal muscle model harbouring the second most frequent mutation in <i>PYGM</i> in the Spanish population: NM_005609.4: c.2392T>C (p.Trp798Arg). To this end, iPSCs derived from a McArdle patient and a healthy control were both successfully differentiated into skeletal muscle cells using a small molecule-based protocol. The created McArdle skeletal muscle model was validated by confirming distinctive biochemical aspects of the disease such as the absence of myophosphorylase, the most typical biochemical feature of these patients. This model will be very valuable for use in future high-throughput pharmacological screenings. |
| first_indexed | 2024-03-10T23:00:00Z |
| format | Article |
| id | doaj.art-19ec2d62cbd94a1d8acfe2a82625bb80 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-10T23:00:00Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj.art-19ec2d62cbd94a1d8acfe2a82625bb802023-11-19T09:41:15ZengMDPI AGBiomedicines2227-90592023-08-01119243410.3390/biomedicines11092434Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the <i>PYGM</i> GeneVictoria Cerrada0Inés García-Consuegra1Joaquín Arenas2M. Esther Gallardo3Grupo de Investigación Traslacional con Células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neuromusculares, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainLaboratorio de Enfermedades Mitocondriales y Neuromusculares, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainGrupo de Investigación Traslacional con Células iPS, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), 28041 Madrid, SpainMcArdle disease is a rare autosomal recessive condition caused by mutations in the <i>PYGM</i> gene. This gene encodes the skeletal muscle isoform of glycogen phosphorylase or myophosphorylase. Patients with McArdle disease have an inability to obtain energy from their muscle glycogen stores, which manifests as a marked exercise intolerance. Nowadays, there is no cure for this disorder and recommendations are intended to prevent and mitigate symptoms. There is great heterogeneity among the pathogenic variants found in the <i>PYGM</i> gene, and there is no obvious correlation between genotypes and phenotypes. Here, we present the generation of the first human iPSC-based skeletal muscle model harbouring the second most frequent mutation in <i>PYGM</i> in the Spanish population: NM_005609.4: c.2392T>C (p.Trp798Arg). To this end, iPSCs derived from a McArdle patient and a healthy control were both successfully differentiated into skeletal muscle cells using a small molecule-based protocol. The created McArdle skeletal muscle model was validated by confirming distinctive biochemical aspects of the disease such as the absence of myophosphorylase, the most typical biochemical feature of these patients. This model will be very valuable for use in future high-throughput pharmacological screenings.https://www.mdpi.com/2227-9059/11/9/2434induced pluripotent stem celliPSCsMcArdle disease<i>PYGM</i>disease modellingskeletal muscle differentiation |
| spellingShingle | Victoria Cerrada Inés García-Consuegra Joaquín Arenas M. Esther Gallardo Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the <i>PYGM</i> Gene Biomedicines induced pluripotent stem cell iPSCs McArdle disease <i>PYGM</i> disease modelling skeletal muscle differentiation |
| title | Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the <i>PYGM</i> Gene |
| title_full | Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the <i>PYGM</i> Gene |
| title_fullStr | Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the <i>PYGM</i> Gene |
| title_full_unstemmed | Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the <i>PYGM</i> Gene |
| title_short | Creation of an iPSC-Based Skeletal Muscle Model of McArdle Disease Harbouring the Mutation c.2392T>C (p.Trp798Arg) in the <i>PYGM</i> Gene |
| title_sort | creation of an ipsc based skeletal muscle model of mcardle disease harbouring the mutation c 2392t c p trp798arg in the i pygm i gene |
| topic | induced pluripotent stem cell iPSCs McArdle disease <i>PYGM</i> disease modelling skeletal muscle differentiation |
| url | https://www.mdpi.com/2227-9059/11/9/2434 |
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