GNE myopathy is an ultra-rare congenital disorder of glycosylation (CDG) that manifests in early adulthood causing progressive distal muscle atrophy and weakness. GNE-CDG results from mutations in the GNE gene, leading to decreased sialic acid (Sia) production [1]. Although hyposialylation has been presumed to be the main cause of GNE-CDG, its pathomechanism may not be exclusively linked to the impaired Sia pathway [2].

Our purpose is to explore cellular and molecular mechanisms that may contribute to GNE-CDG as means of identifying alternative pharmacological targets.

Although immune-mediated responses are not common in GNE-CDG, inflammatory cell infiltration with increased expression of major histocompatibility complex class I (MHC-I) is occasionally reported in muscle biopsies of early-stage GNE-CDG patients [3]. A GNE knockout (KO) cell model was used to evaluate if GNE mutations affect the expression of MHC-I. The results point to higher expression of MHC-I on the surface of GNE-CDG cells. When the GNE KO cells were supplemented with N-acetylmannosamine (ManNAc) and ManNAc-6-phosphate (ManNAc-6-P), intermediates in the Sia biosynthesis, we observed a Sia increase, and a reduction in MHC-I staining. These findings support the hypothesis that Sia content modulates the presence and stability of the MHC-I complex, as previously reported by us [4], and the involvement of a cytotoxic immune response initiated via MHC-I presentation.

Further work is being conducted to better characterize this immunological link, which may contribute to identifying new biomarkers that facilitate GNE-CDG diagnosis and novel therapeutic approaches.

Acknowledgements: UIDP/04378/2020 and UIDB/04378/2020 (UCIBIO), LA/P/0140/2020 (i4HB), and EJP RD COFUND-EJP N 825575 (EJPRD/0001/2020).

References: [1] doi:10.1186/s13023-018-0802-x. [2] doi:10.1016/j.bbrc.2004.12.157. [3] doi:10.1016/S0960-8966(03)00140-8. [4] doi: 10.3390/pharmaceutics12030249.