Back to Search Start Over

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

Authors :
Paola De Filippi
Edoardo Errichiello
Antonio Toscano
Tiziana Mongini
Maurizio Moggio
Sabrina Ravaglia
Massimiliano Filosto
Serenella Servidei
Olimpia Musumeci
Fabio Giannini
Alberto Piperno
Gabriele Siciliano
Giulia Ricci
Antonio Di Muzio
Miriam Rigoldi
Paola Tonin
Michele Giovanni Croce
Elena Pegoraro
Luisa Politano
Lorenzo Maggi
Roberta Telese
Alberto Lerario
Cristina Sancricca
Liliana Vercelli
Claudio Semplicini
Barbara Pasanisi
Bruno Bembi
Andrea Dardis
Ilaria Palmieri
Cristina Cereda
Enza Maria Valente
Cesare Danesino
Source :
Current Issues in Molecular Biology, Vol 45, Iss 4, Pp 2847-2860 (2023)
Publication Year :
2023
Publisher :
MDPI AG, 2023.

Abstract

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.

Details

Language :
English
ISSN :
14673045 and 14673037
Volume :
45
Issue :
4
Database :
Directory of Open Access Journals
Journal :
Current Issues in Molecular Biology
Publication Type :
Academic Journal
Accession number :
edsdoj.fb85d4b6cff3436c86279d7bcfd0dd27
Document Type :
article
Full Text :
https://doi.org/10.3390/cimb45040186