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Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function
Xiao-Yan Wen, … , Clara D.M. van Karnebeek, Dirk J. Lefeber
Xiao-Yan Wen, … , Clara D.M. van Karnebeek, Dirk J. Lefeber
Published December 20, 2018
Citation Information: JCI Insight. 2018;3(24):e122373. https://doi.org/10.1172/jci.insight.122373.
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Research Article Genetics Metabolism

Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function

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Abstract

Sialic acids are important components of glycoproteins and glycolipids essential for cellular communication, infection, and metastasis. The importance of sialic acid biosynthesis in human physiology is well illustrated by the severe metabolic disorders in this pathway. However, the biological role of sialic acid catabolism in humans remains unclear. Here, we present evidence that sialic acid catabolism is important for heart and skeletal muscle function and development in humans and zebrafish. In two siblings, presenting with sialuria, exercise intolerance/muscle wasting, and cardiac symptoms in the brother, compound heterozygous mutations [chr1:182775324C>T (c.187C>T; p.Arg63Cys) and chr1:182772897A>G (c.133A>G; p.Asn45Asp)] were found in the N-acetylneuraminate pyruvate lyase gene (NPL). In vitro, NPL activity and sialic acid catabolism were affected, with a cell-type-specific reduction of N-acetyl mannosamine (ManNAc). A knockdown of NPL in zebrafish resulted in severe skeletal myopathy and cardiac edema, mimicking the human phenotype. The phenotype was rescued by expression of wild-type human NPL but not by the p.Arg63Cys or p.Asn45Asp mutants. Importantly, the myopathy phenotype in zebrafish embryos was rescued by treatment with the catabolic products of NPL: N-acetyl glucosamine (GlcNAc) and ManNAc; the latter also rescuing the cardiac phenotype. In conclusion, we provide the first report to our knowledge of a human defect in sialic acid catabolism, which implicates an important role of the sialic acid catabolic pathway in mammalian muscle physiology, and suggests opportunities for monosaccharide replacement therapy in human patients.

Authors

Xiao-Yan Wen, Maja Tarailo-Graovac, Koroboshka Brand-Arzamendi, Anke Willems, Bojana Rakic, Karin Huijben, Afitz Da Silva, Xuefang Pan, Suzan El-Rass, Robin Ng, Katheryn Selby, Anju Mary Philip, Junghwa Yun, X. Cynthia Ye, Colin J. Ross, Anna M. Lehman, Fokje Zijlstra, N. Abu Bakar, Britt Drögemöller, Jacqueline Moreland, Wyeth W. Wasserman, Hilary Vallance, Monique van Scherpenzeel, Farhad Karbassi, Martin Hoskings, Udo Engelke, Arjan de Brouwer, Ron A. Wevers, Alexey V. Pshezhetsky, Clara D.M. van Karnebeek, Dirk J. Lefeber

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Figure 7

Percentage of npl morphants rescued by injection of human WT but not mutant NPL mRNA.

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Percentage of npl morphants rescued by injection of human WT but not mut...
Percentage of embryos with or without skeletal myopathy obtained after injection of Cont MO or npl-atg MO alone, or npl-atg MO in combination with WT human (NPL mRNA WT), or mutant [NPL mRNA MUT (63C + 45D)] human NPL mRNA, or human NPL mRNA with a single mutation for 63C (MUT 63C), or 45D (MUT 45D). Bars represent the mean ± SD of 4 independent injections; 10 groups were preselected for comparison. Statistical significance determined by 2-tailed Student’s t test with Bonferroni’s correction with a factor of 10 using GraphPad Prism software version 7. *P < 0.05, **P < 0.01; ns, not significant. For simplicity, only comparisons to the npl-atg MO abnormal muscle group are represented in the graph. Each bar represents between 50 and 135 embryos. The experiment was repeated 4 times.

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