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Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function. 2018
Xiao-Yan Wen, and
Maja Tarailo-Graovac, and
Koroboshka Brand-Arzamendi, and
Anke Willems, and
Bojana Rakic, and
Karin Huijben, and
Afitz Da Silva, and
Xuefang Pan, and
Suzan El-Rass, and
Robin Ng, and
Katheryn Selby, and
Anju Mary Philip, and
Junghwa Yun, and
X Cynthia Ye, and
Colin J Ross, and
Anna M Lehman, and
Fokje Zijlstra, and
N Abu Bakar, and
Britt Drögemöller, and
Jacqueline Moreland, and
Wyeth W Wasserman, and
Hilary Vallance, and
Monique van Scherpenzeel, and
Farhad Karbassi, and
Martin Hoskings, and
Udo Engelke, and
Arjan de Brouwer, and
Ron A Wevers, and
Alexey V Pshezhetsky, and
Clara Dm van Karnebeek, and
Dirk J Lefeber
Zebrafish Centre for Advanced Drug Discovery and Keenan Research Centre for Biomedical science, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
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.
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