Ganglioside GM3 Levels Are Altered in a Mouse Model of HIBM: GM3 as a Cellular Marker of the Disease

Abstract

ObjectiveHIBM (Hereditary Inclusion Body Myopathy) is a recessive hereditary disease characterized by adult-onset, slowly progressive muscle weakness sparing the quadriceps. It is caused by a single missense mutation of each allele of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, a bifunctional enzyme catalyzing the first two steps of sialic acid synthesis in mammals. However, the mechanisms and cellular pathways affected by the GNE mutation and causing the muscle weakness could not be identified so far. Based on recent evidence in literature, we investigated a new hypothesis, i.e. the involvement in the disease of the GM3 ganglioside, a specific glycolipid implicated in muscle cell proliferation and differentiation.MethodsqRT-PCR analysis of St3gal5 (GM3 synthase) gene expression and HPLC quantification of GM3 ganglioside were conducted on muscle tissue from a mouse model of HIBM harboring the M712T mutation of GNE (GneM712T/M712T mouse) vs control mice (Gne+/+ mouse).Results St3gal5 mRNA levels were significantly lower in GneM712T/M712T mouse muscles vs Gne+/+ mouse muscles (64.41%±10% of Gne+/+ levels). GM3 ganglioside levels showed also a significant decrease in GneM712T/M712T mouse muscle compared to Gne+/+ mouse muscle (18.09%±5.33% of Gne+/+ levels). Although these GneM712T/M712T mice were described to suffer severe glomerular proteinuria, no GM3 alterations were noted in kidneys, highlighting a tissue specific alteration of gangliosides.ConclusionThe M712T mutation of GNE hampers the muscle ability to synthesize normal levels of GM3. This is the first time that a mutation of GNE can be related to the molecular pathological mechanism of HIBM.

UDP-GlcNAc 2-Epimerase/ManNAc Kinase (GNE): A Master Regulator of Sialic Acid Synthesis

“…Although overall sialylation of HIBM cells and tissues appears normal [109, 111, 116], specific glycoproteins and glycolipids were found to be hyposialylated in HIBM muscle, including alpha-dystroglycan [117], polysialic acid on neural crest adhesion molecule (PSA-NCAM) [118], neprilysin and other O-glycans [119, 120], and the GM3 ganglioside [121]. The contributions of these findings to the pathophysiology of HIBM remain under investigation.…”

A view on sphingolipids and disease

“…Deficiency of this enzyme causes an autosomal recessive infantile-onset symptomatic epilepsy syndrome (Simpson et al, 2004). Impaired formation of ganglioside GM3 in muscle, but not in other organs, was reported from the mouse model of Hereditary Inclusion Body Myopathy, an inherited disease with adult onset that is due to a defect of UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, a bifunctional enzyme that catalyzes the first two steps of sialic acid synthesis in mammals (Paccalet et al, 2010). Fatty acid 2-hydroxylase is a transmembrane monooxygenase of the ER with cytoplasmic oriented active site.…”

Sialylation of Thomsen–Friedenreich Antigen is a Noninvasive Blood-Based Biomarker for GNE Myopathy

“…GNE null mutations have never been identified on both alleles of a patient; this would most likely be lethal since Gne ‘knock-out’ mice do not survive past the embryonic stage [12]. The exact pathology of GNE myopathy remains unknown; symptoms seem to occur due to hyposialylation of a select group of (sialo-) glycans [10,13–17]. More evidence that hyposialylation is a key factor in the pathomechanism came from mouse models, in which hyposialylation and pathology could be prevented by treatment with sialic acid metabolites [18,19].…”