GFPT1 deficiency in muscle leads to myasthenia and myopathy in mice

Abstract

Glutamine-fructose-6-phosphate transaminase 1 (GFPT1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway which yields precursors required for protein and lipid glycosylation. Mutations in GFPT1 and other genes downstream of this pathway cause congenital myasthenic syndrome (CMS) characterized by fatigable muscle weakness owing to impaired neurotransmission. The precise pathomechanisms at the neuromuscular junction (NMJ) owing to a deficiency in GFPT1 is yet to be discovered. One of the challenges we face is the viability of Gfpt1−/− knockout mice. In this study, we use Cre/LoxP technology to generate a muscle-specific GFPT1 knockout mouse model, Gfpt1tm1d/tm1d, characteristic of the human CMS phenotype. Our data suggest a critical role for muscle derived GFPT1 in the development of the NMJ, neurotransmission, skeletal muscle integrity and highlight that a deficiency in skeletal muscle alone is sufficient to cause morphological postsynaptic NMJ changes that are accompanied by presynaptic alterations despite the conservation of neuronal GFPT1 expression. In addition to the conventional morphological NMJ changes and fatigable muscle weakness, Gfpt1tm1d/tm1d mice display a progressive myopathic phenotype with the presence of tubular aggregates in muscle, characteristic of the GFPT1-CMS phenotype. We further identify an upregulation of skeletal muscle proteins glypican-1, farnesyltransferase/geranylgeranyltransferase type-1 subunit α and muscle-specific kinase, which are known to be involved in the differentiation and maintenance of the NMJ. The Gfpt1tm1d/tm1d model allows for further investigation of pathophysiological consequences on genes and pathways downstream of GFPT1 likely to involve misglycosylation or hypoglycosylation of NMJs and muscle targets.

STIM1/ORAI1 Loss-of-Function and Gain-of-Function Mutations Inversely Impact on SOCE and Calcium Homeostasis and Cause Multi-Systemic Mirror Diseases

“…All five genes code for proteins of the glycosylation pathway and procure posttranslational modifications to a wide variety of proteins including STIM1 and ORAI1. Hypoglycosylation of STIM1 and ORAI1 stimulates SOCE and extracellular Ca 2+ influx ( Selcen et al, 2014 ), and the muscle-specific deletion of Gfpt1 in mice causes myasthenia and the occurrence of tubular aggregates in muscle fibers ( Issop et al, 2018 ). These examples show that the dysfunction of proteins directly or indirectly associated with STIM1 and ORAI1 can cause human pathologies overlapping with TAM/STRMK at the clinical and histological level.…”

Clinicopathological‐genetic features of congenital myasthenic syndrome from a Chinese neuromuscular centre

“…Mutations in GFPT1 cause CMS characterized by fatigable muscle weakness owing to impaired neurotransmission. The precise pathomechanisms at the NMJ due to GFPT1 deficiency have yet to be discovered 37 . In our study, the two missense mutations in the GFPT1 mutant patient were previously reported 22–24 .…”

Identification of Candidate Protein Markers in Skeletal Muscle of Laminin-211-Deficient CMD Type 1A-Patients

“…This effect resulted in recovery of muscle force and size leading to increased overall body weight, and extended life span (33). Moreover, glypican-1 has recently been linked to the pathophysiology of a muscular dystrophy complicated by a myasthenic syndrome (34) as well as of laminin α4, which has an important role in NMJ-integrity (29). However, the conclusion of endogenous activation of compensatory mechanisms in muscle of MDC1A-patients is further supported by the increase of C4b-binding protein alpha chain belonging to the complement system that deposits its activation products on innervated motor end-plates in ALS-patients (35).…”