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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 1

NPL deficiency and identification of NPL biallelic missense varants in NPL.

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NPL deficiency and identification of NPL biallelic missense varants in N...
(A) Sialic aciduria was determined by quantification of the levels of urinary Neu5Ac excretion and compared with known causes of sialic aciduria. For NPL patient 1, two samples were analyzed at around age 20 years. Salla refers to both ISSD at a very young age and Salla disease. (B) As part of the diagnostics of sialic aciduria, quantification of Neu5Ac levels in fibroblasts was performed, showing normal levels in contrast to known causes (all n = 1). (C) Whole exome sequencing, covering 37.8× for the subject, 30.4× for the mother, and 27.5× for the father, to identify NPL missense varants. (D) Comparison of the amino acid sequences of NPL in human (Q9BXD5.1), zebrafish (CAP19481.1), mouse (NP_083025.1), dog (XP_005622466.1), chicken (NP_001026731.1, Xenopus (NP_001011207.1), and alpaca (XP_015101171.1), as well as 2 mutants. Conserved asparagine (N) and arginine (R) are highlighted. Mutations are shown in red. (E) Biallelic NPL variants c.133A>G (p.Asn45Asp) and c.187C>T (p.Arg63Cys) (reference transcript NM_030769) are mapped on NPL exon 2 and 3, respectively.

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