Global Landscape of SLC37A4 Variants and Their Potential Amenability to Pharmacological Chaperone Therapy in Glycogen Storage Disease Type Ib

Glycogen storage disease Ib (GSD Ib) is an ultra-rare metabolic disease caused by variants in the SLC37A4 gene affecting activity of the glucose-6-phosphate transporter (G6PT). G6PT mediates transport of glucose-6 phosphate from the cytoplasm into the lumen of the endoplasmic reticulum, thereby playing a key role in glucose homeostasis. To date, no approved therapies directly restore G6PT function, highlighting a major unmet need. Pharmacological chaperone (PC) therapies, including those targeting membrane transporters, are a known and clinically employed therapeutic strategy. The efficacy of PC therapy is highly dependent on the underlying pathogenic variant. While certain missense variants may respond favorably, particularly those associated with protein misfolding and residual function, null variants are generally considered unsuitable targets due to the absence of a protein that could be rescued. To the best of our knowledge, no previous review has systematically examined the global landscape of SLC37A4 variants. The aim of this review was to collect the spectrum and frequency of SLC37A4 variants reported worldwide and connect them with all available structural and functional data. In 425 GSD Ib patients, we found that approximately 10% of all variants are strong PC candidates and 14–30% are reasonable but lower-confidence candidates (other missense non-deactivating variants), while the rest are poor PC candidates (substrate-pocket variants) and null variants (nonsense, frameshift and splicing). Although functional studies are required to definitely validate PC-responsive missense variants in the SLC37A4 gene, our review suggests, for the first time, the existence of a minimal threshold at which a PC approach may become clinically relevant for GSD Ib patients.