Gfpt1, or Glutamine-fructose-6-phosphate transaminase 1, is the first rate-limiting enzyme of the hexosamine biosynthesis pathway (HBP) [1,2,5]. The HBP produces uridine diphosphate-N-acetyl glucosamine (UDP-GlcNAc), which is crucial for N-or O-linked glycosylation, post-translational modifications that modulate protein activity and expression [1].

In a muscle-specific knock-in (KI) mouse model simulating a congenital myasthenic syndrome (CMS) patient with a Gfpt1 frameshift variant, aged Gfpt1-KI mice showed poor exercise performance and abnormal neuromuscular junction structures. Also, markers of the unfolded protein response (UPR) were elevated in skeletal muscles, but autophagy was not induced and protein aggregates increased. This indicates that lack of Gfpt1 in skeletal muscles can trigger ER stress and maladaptive UPR [3]. In knockout (KO) of the muscle-specific long isoform of Gfpt1 (Gfpt1-L) in skeletal muscle, aged KO mice had impaired insulin-mediated glucose uptake, muscle weakness, and fatigue due to abnormal neuromuscular junction formation and maintenance. Additionally, the amounts of Gfpt1 and UDP-HexNAc increased, suppressing the glycolytic pathway [4].

In conclusion, Gfpt1 is essential for the hexosamine biosynthesis pathway, which is involved in protein glycosylation. Mouse models, including Gfpt1-KI and Gfpt1-L KO models, have revealed its role in muscle-related functions such as exercise performance, neuromuscular junction integrity, glucose uptake, and glycolysis, especially in relation to CMS. These models contribute to understanding the biological functions of Gfpt1 and its implications in related disease areas [3,4].