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GNE Myopathy and Cell Apoptosis: A Comparative Mutation Analysis

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Abstract

In a number of genetic disorders such as GNE myopathy, it is not clear how mutations in target genes result in disease phenotype. GNE myopathy is a progressive neuro-degenerative disorder associated with homozygous or compound heterozygous missense mutations in either epimerase or kinase domain of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE). This bifunctional enzyme catalyses the rate limiting step in sialic acid biosynthesis. Many mechanisms have been suggested as possible cause of muscle degeneration. These include hyposialylation of critical proteins, defects in cytoskeletal network, sarcomere organization and apoptosis. In order to elucidate the role of GNE in cell apoptosis, we have used HEK cell-based model system overexpressing pathologically relevant GNE mutations. These cells display a reduction in the levels of sialic acid-bound glycoconjugates. These mutants GNE overexpressing cells have defect in cell proliferation as compared to vector or wild-type GNE (wtGNE) controls. Moreover, effect of different GNE mutations on cell apoptosis was also observed using staining with annexin V-FITC and TUNEL assay. The downstream apoptosis signalling pathway involving activation of caspases and increased PARP cleavage were observed in all GNE mutant cell lines. In addition, morpho-structural changes in mitochondria in cells overexpressing different GNE mutants were noticed by transmission electron microscopy, and mitochondrial transmembrane potential was found to be altered in absence of functional GNE. Our results clearly indicate role of GNE in mitochondria-dependent cell apoptosis and provide insights into the pathomechanism of GNE myopathy.

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Acknowledgments

We thank Prof. Alok Bhattacharya (School of Life Sciences, Jawaharlal Nehru University, and New Delhi) for thoughtful discussions and progressive comments during the project. This work was supported by grants from the Indian Council of Medical Research, India and Council of Scientific and Industrial Research, Govt. of India. We acknowledge Mr. Ashok and Mr. Prabhat Advanced Instrumentation Research Facility (AIRF), Jawaharlal Nehru University, New Delhi, for technical assistance in confocal microscopy and live cell imaging. We acknowledge Dr. Anwar Alam and Mrs. Sarika (School of Life Sciences, Jawaharlal Nehru University, NewDelhi) for technical assistance in flow cytometry.

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  1. School of Biotechnology, Jawaharlal Nehru University, New Delhi, 110067, India

    Reema Singh & Ranjana Arya

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Figure S1

Determination of DNA damage/nuclear fragmentation by TUNEL assay after supplementation with 5 mM NANA: Representative image of wtGNE and GNE mutants obtained by confocal microscopy, depicting DNA damage/nuclear fragmentation by TUNEL assay. Arrows indicate TUNEL-positive cells (green).The images were viewed using Olympus Fluoview FV1000 laser scan at 60 X magnification. (JPEG 85 kb)

Figure S2

Study of cell apoptosis by Annexin V-FITC/Propidium iodide staining after supplementation with 5 mM NANA: Annexin V-FITC and Propidium iodide staining of wtGNE and different GNE mutant cells were analyzed by flow cytometry after NANA supplementation. B.Graphical representation of fold changein apoptosis of various GNE mutant cells compared to wtGNE cell line. (JPEG 111 kb)

Figure S3

Effect of GNE mutation on mitochondrial dysfunction after 5 mM NANA supplementation: A. Effect of GNE mutation on dissipation of mitochondrial membrane potential (as measured by JC-1) using confocal microscopy, magnification 60 X. B. Histogram shows the ratio of red to green fluorescence intensity observed in various cell lines characterizing Δψ (m). (JPEG 145 kb)

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Singh, R., Arya, R. GNE Myopathy and Cell Apoptosis: A Comparative Mutation Analysis. Mol Neurobiol 53, 3088–3101 (2016). https://doi.org/10.1007/s12035-015-9191-5

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