UGP2 and Pompe Disease

The current evidence linking UGP2 (HGNC:12527) to glycogen storage disease II (Pompe disease, MONDO_0009290) is limited. In a multi‐patient exome sequencing study involving 30 late‑onset Pompe disease patients (PMID:37185710), variants in several genes involved in glycogen synthesis and catabolism were examined, with UGP2 being one candidate. However, no single UGP2 variant showed a robust genotype‑phenotype correlation, and segregation data supporting its involvement are minimal. Furthermore, although the study explored the possibility that UGP2 might act as a phenotypic modifier, the overall clinical impact of UGP2 variants on Pompe disease severity remains unsubstantiated. The inheritance pattern for Pompe disease is autosomal recessive, but specific biallelic mutations in UGP2 have not been definitively linked to the disease phenotype in these studies. Consequently, from a diagnostic decision‑making perspective, current evidence does not support UGP2 as a major disease gene for Pompe disease.

In contrast, functional assessments of UGP2 in a separate study have demonstrated that loss of UGP2, particularly via a recurrent start‐loss variant (c.34A>G (p.Met12Val)), can lead to severe epileptic encephalopathy (PMID:31820119). Despite this, the experimental findings in neural tissues do not provide direct mechanistic evidence for a role in Pompe disease pathology. The available functional data in Pompe disease‐relevant tissues are insufficient to support a clear pathogenic mechanism linking UGP2 variation to glycogen accumulation in lysosomes. Overall, while UGP2 remains an interesting candidate due to its role in glycogen metabolism, further genetic and functional studies are required to validate its contribution to Pompe disease. Key take‑home: At present, UGP2’s utility in clinical diagnostics for Pompe disease is limited and should be interpreted with caution in commercial and future publication settings.

References

• Current issues in molecular biology • 2023 • Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD) PMID:37185710
• Acta neuropathologica • 2020 • Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases PMID:31820119

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