Stephen Henry Holland, Ricardo Carmona-Martinez, Daniel O'Neil, Kelly Ho, Kaela O'Connor, Yoshiteru Azuma, Andreas Roos, Sally Spendiff, Hanns Lochmüller
{"title":"半乳糖治疗可恢复谷氨酰胺-果糖-6-磷酸转氨酶1 (Gfpt1)缺陷小鼠的神经肌肉接点传递。","authors":"Stephen Henry Holland, Ricardo Carmona-Martinez, Daniel O'Neil, Kelly Ho, Kaela O'Connor, Yoshiteru Azuma, Andreas Roos, Sally Spendiff, Hanns Lochmüller","doi":"10.1093/hmg/ddaf140","DOIUrl":null,"url":null,"abstract":"<p><p>Congenital myasthenic syndromes (CMS) arise from mutations to proteins involved in neuromuscular junction (NMJ) development, maintenance, and neurotransmission. To date, mutations in more than 35 genes have been linked to CMS development. Glutamine fructose-6-phosphate transaminase 1 (GFPT1/Gfpt1) serves as the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), producing the byproduct (UDP-GlcNAc) necessary for protein glycosylation. Gfpt1-deficient models have impaired protein glycosylation, impacting key proteins at the NMJ. The Leloir pathway is a galactose metabolizing pathway which produces UDP-GalNAc as its final product. The enzyme UDP-GalNAc Epimerase (GALE) can also convert excess UDP-GalNAc into UDP-GlcNAc, the byproduct of the HBP. We hypothesized that treatment with galactose both in vitro and in vivo in Gfpt1-deficient models would rescue impaired protein O-GlcNAcylation and reverse the glycosylation status of key NMJ-associated proteins. We show that galactose treatment in vitro activated the Leloir pathway and rescued protein O-GlcNAcylation in Gfpt1-deficient C2C12 myoblasts. In addition, we demonstrated that galactose therapy rescued neuromuscular deficits, improved muscle fatigue and restored NMJ morphology in a skeletal muscle-specific Gfpt1 knockout mouse model. Lastly, we showed that galactose treatment rescued protein O-GlcNAcylation in skeletal muscle, preserving the glycosylation status of the delta (δ) subunit of the acetylcholine receptor (AChRδ). Taken together, we suggest that galactose supplementation can be further explored as a therapy for GFPT1-CMS patients.</p>","PeriodicalId":13070,"journal":{"name":"Human molecular genetics","volume":" ","pages":"1765-1779"},"PeriodicalIF":3.2000,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12529661/pdf/","citationCount":"0","resultStr":"{\"title\":\"Galactose treatment rescues neuromuscular junction transmission in glutamine-fructose-6-phosphate transaminase 1 (Gfpt1) deficient mice.\",\"authors\":\"Stephen Henry Holland, Ricardo Carmona-Martinez, Daniel O'Neil, Kelly Ho, Kaela O'Connor, Yoshiteru Azuma, Andreas Roos, Sally Spendiff, Hanns Lochmüller\",\"doi\":\"10.1093/hmg/ddaf140\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Congenital myasthenic syndromes (CMS) arise from mutations to proteins involved in neuromuscular junction (NMJ) development, maintenance, and neurotransmission. To date, mutations in more than 35 genes have been linked to CMS development. Glutamine fructose-6-phosphate transaminase 1 (GFPT1/Gfpt1) serves as the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), producing the byproduct (UDP-GlcNAc) necessary for protein glycosylation. Gfpt1-deficient models have impaired protein glycosylation, impacting key proteins at the NMJ. The Leloir pathway is a galactose metabolizing pathway which produces UDP-GalNAc as its final product. The enzyme UDP-GalNAc Epimerase (GALE) can also convert excess UDP-GalNAc into UDP-GlcNAc, the byproduct of the HBP. We hypothesized that treatment with galactose both in vitro and in vivo in Gfpt1-deficient models would rescue impaired protein O-GlcNAcylation and reverse the glycosylation status of key NMJ-associated proteins. We show that galactose treatment in vitro activated the Leloir pathway and rescued protein O-GlcNAcylation in Gfpt1-deficient C2C12 myoblasts. In addition, we demonstrated that galactose therapy rescued neuromuscular deficits, improved muscle fatigue and restored NMJ morphology in a skeletal muscle-specific Gfpt1 knockout mouse model. Lastly, we showed that galactose treatment rescued protein O-GlcNAcylation in skeletal muscle, preserving the glycosylation status of the delta (δ) subunit of the acetylcholine receptor (AChRδ). Taken together, we suggest that galactose supplementation can be further explored as a therapy for GFPT1-CMS patients.</p>\",\"PeriodicalId\":13070,\"journal\":{\"name\":\"Human molecular genetics\",\"volume\":\" \",\"pages\":\"1765-1779\"},\"PeriodicalIF\":3.2000,\"publicationDate\":\"2025-10-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12529661/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Human molecular genetics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1093/hmg/ddaf140\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Human molecular genetics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1093/hmg/ddaf140","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Congenital myasthenic syndromes (CMS) arise from mutations to proteins involved in neuromuscular junction (NMJ) development, maintenance, and neurotransmission. To date, mutations in more than 35 genes have been linked to CMS development. Glutamine fructose-6-phosphate transaminase 1 (GFPT1/Gfpt1) serves as the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), producing the byproduct (UDP-GlcNAc) necessary for protein glycosylation. Gfpt1-deficient models have impaired protein glycosylation, impacting key proteins at the NMJ. The Leloir pathway is a galactose metabolizing pathway which produces UDP-GalNAc as its final product. The enzyme UDP-GalNAc Epimerase (GALE) can also convert excess UDP-GalNAc into UDP-GlcNAc, the byproduct of the HBP. We hypothesized that treatment with galactose both in vitro and in vivo in Gfpt1-deficient models would rescue impaired protein O-GlcNAcylation and reverse the glycosylation status of key NMJ-associated proteins. We show that galactose treatment in vitro activated the Leloir pathway and rescued protein O-GlcNAcylation in Gfpt1-deficient C2C12 myoblasts. In addition, we demonstrated that galactose therapy rescued neuromuscular deficits, improved muscle fatigue and restored NMJ morphology in a skeletal muscle-specific Gfpt1 knockout mouse model. Lastly, we showed that galactose treatment rescued protein O-GlcNAcylation in skeletal muscle, preserving the glycosylation status of the delta (δ) subunit of the acetylcholine receptor (AChRδ). Taken together, we suggest that galactose supplementation can be further explored as a therapy for GFPT1-CMS patients.
期刊介绍:
Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include:
the molecular basis of human genetic disease
developmental genetics
cancer genetics
neurogenetics
chromosome and genome structure and function
therapy of genetic disease
stem cells in human genetic disease and therapy, including the application of iPS cells
genome-wide association studies
mouse and other models of human diseases
functional genomics
computational genomics
In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.