Sialic acid catabolism by N-acetylneuraminate pyruvate lyase is essential for muscle function
| Autor: | Alexey V. Pshezhetsky, Hilary Vallance, Katheryn Selby, Jacqueline Moreland, Udo F. H. Engelke, Martin Hoskings, Anju M. Philip, Farhad Karbassi, Colin J. D. Ross, Maja Tarailo-Graovac, Arjan P.M. de Brouwer, Xiao-Yan Wen, Dirk Lefeber, Bojana Rakic, Koroboshka Brand-Arzamendi, Monique van Scherpenzeel, Fokje Zijlstra, Anke P. Willems, Robin Ng, Clara D.M. van Karnebeek, Wyeth W. Wasserman, Ron A. Wevers, N. Abu Bakar, X. Cynthia Ye, Anna Lehman, Britt I. Drögemöller, Suzan El-Rass, Junghwa Yun, Karin Huijben, Xuefang Pan, Afitz Da Silva |
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| Přispěvatelé: | Paediatric Metabolic Diseases, AGEM - Inborn errors of metabolism, ANS - Cellular & Molecular Mechanisms |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Sialuria Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine All institutes and research themes of the Radboud University Medical Center Muscular Diseases medicine Animals Humans Muscle Skeletal Myopathy Zebrafish Edema Cardiac biology Catabolism Genetic Diseases Inborn Sialic Acid Storage Disease Gene Expression Regulation Developmental Oxo-Acid-Lyases Skeletal muscle Hexosamines Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] General Medicine Metabolism medicine.disease biology.organism_classification Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] Phenotype N-Acetylneuraminic Acid Sialic acid Disease Models Animal HEK293 Cells 030104 developmental biology medicine.anatomical_structure chemistry Biochemistry Gene Knockdown Techniques Mutation medicine.symptom 030217 neurology & neurosurgery Research Article |
| Zdroj: | Jci Insight, 3, 24 Jci Insight, 3 JCI insight, 3(24). The American Society for Clinical Investigation |
| ISSN: | 2379-3708 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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