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Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed...

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Autores principales: De Filippi, Paola, Errichiello, Edoardo, Toscano, Antonio, Mongini, Tiziana, Moggio, Maurizio, Ravaglia, Sabrina, Filosto, Massimiliano, Servidei, Serenella, Musumeci, Olimpia, Giannini, Fabio, Piperno, Alberto, Siciliano, Gabriele, Ricci, Giulia, Di Muzio, Antonio, Rigoldi, Miriam, Tonin, Paola, Croce, Michele Giovanni, Pegoraro, Elena, Politano, Luisa, Maggi, Lorenzo, Telese, Roberta, Lerario, Alberto, Sancricca, Cristina, Vercelli, Liliana, Semplicini, Claudio, Pasanisi, Barbara, Bembi, Bruno, Dardis, Andrea, Palmieri, Ilaria, Cereda, Cristina, Valente, Enza Maria, Danesino, Cesare
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10136686/
https://www.ncbi.nlm.nih.gov/pubmed/37185710
http://dx.doi.org/10.3390/cimb45040186
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author De Filippi, Paola
Errichiello, Edoardo
Toscano, Antonio
Mongini, Tiziana
Moggio, Maurizio
Ravaglia, Sabrina
Filosto, Massimiliano
Servidei, Serenella
Musumeci, Olimpia
Giannini, Fabio
Piperno, Alberto
Siciliano, Gabriele
Ricci, Giulia
Di Muzio, Antonio
Rigoldi, Miriam
Tonin, Paola
Croce, Michele Giovanni
Pegoraro, Elena
Politano, Luisa
Maggi, Lorenzo
Telese, Roberta
Lerario, Alberto
Sancricca, Cristina
Vercelli, Liliana
Semplicini, Claudio
Pasanisi, Barbara
Bembi, Bruno
Dardis, Andrea
Palmieri, Ilaria
Cereda, Cristina
Valente, Enza Maria
Danesino, Cesare
author_facet De Filippi, Paola
Errichiello, Edoardo
Toscano, Antonio
Mongini, Tiziana
Moggio, Maurizio
Ravaglia, Sabrina
Filosto, Massimiliano
Servidei, Serenella
Musumeci, Olimpia
Giannini, Fabio
Piperno, Alberto
Siciliano, Gabriele
Ricci, Giulia
Di Muzio, Antonio
Rigoldi, Miriam
Tonin, Paola
Croce, Michele Giovanni
Pegoraro, Elena
Politano, Luisa
Maggi, Lorenzo
Telese, Roberta
Lerario, Alberto
Sancricca, Cristina
Vercelli, Liliana
Semplicini, Claudio
Pasanisi, Barbara
Bembi, Bruno
Dardis, Andrea
Palmieri, Ilaria
Cereda, Cristina
Valente, Enza Maria
Danesino, Cesare
author_sort De Filippi, Paola
collection PubMed
description Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.
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spelling pubmed-101366862023-04-28 Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD) De Filippi, Paola Errichiello, Edoardo Toscano, Antonio Mongini, Tiziana Moggio, Maurizio Ravaglia, Sabrina Filosto, Massimiliano Servidei, Serenella Musumeci, Olimpia Giannini, Fabio Piperno, Alberto Siciliano, Gabriele Ricci, Giulia Di Muzio, Antonio Rigoldi, Miriam Tonin, Paola Croce, Michele Giovanni Pegoraro, Elena Politano, Luisa Maggi, Lorenzo Telese, Roberta Lerario, Alberto Sancricca, Cristina Vercelli, Liliana Semplicini, Claudio Pasanisi, Barbara Bembi, Bruno Dardis, Andrea Palmieri, Ilaria Cereda, Cristina Valente, Enza Maria Danesino, Cesare Curr Issues Mol Biol Article Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype. MDPI 2023-04-01 /pmc/articles/PMC10136686/ /pubmed/37185710 http://dx.doi.org/10.3390/cimb45040186 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
De Filippi, Paola
Errichiello, Edoardo
Toscano, Antonio
Mongini, Tiziana
Moggio, Maurizio
Ravaglia, Sabrina
Filosto, Massimiliano
Servidei, Serenella
Musumeci, Olimpia
Giannini, Fabio
Piperno, Alberto
Siciliano, Gabriele
Ricci, Giulia
Di Muzio, Antonio
Rigoldi, Miriam
Tonin, Paola
Croce, Michele Giovanni
Pegoraro, Elena
Politano, Luisa
Maggi, Lorenzo
Telese, Roberta
Lerario, Alberto
Sancricca, Cristina
Vercelli, Liliana
Semplicini, Claudio
Pasanisi, Barbara
Bembi, Bruno
Dardis, Andrea
Palmieri, Ilaria
Cereda, Cristina
Valente, Enza Maria
Danesino, Cesare
Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)
title Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)
title_full Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)
title_fullStr Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)
title_full_unstemmed Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)
title_short Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)
title_sort distribution of exonic variants in glycogen synthesis and catabolism genes in late onset pompe disease (lopd)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10136686/
https://www.ncbi.nlm.nih.gov/pubmed/37185710
http://dx.doi.org/10.3390/cimb45040186
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