Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine
| Autor: | Marcel E. Dinger, Kerith-Rae Dias, Michael F. Buckley, Mark J. Cowley, Tony Roscioli, Tejaswi Kandula, Ann M. E. Bye, Jaclyn N. Hayner, Jiang Tao, David Miller, Ying Zhu, Michael S. Kilberg, Paula Morris, Rani Sachdev, Michael Cardamone, Edwin P. Kirk, Rebecca Macintosh, Elizabeth E. Palmer |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Asparaginase Endocrinology Diabetes and Metabolism Asparagine synthetase Biology medicine.disease_cause Biochemistry Article chemistry.chemical_compound Endocrinology Adenosine Triphosphate Intellectual Disability Genetics medicine Humans Computer Simulation Exome Asparagine Molecular Biology Cells Cultured Cell Proliferation chemistry.chemical_classification Mutation Binding Sites Wild type Aspartate-Ammonia Ligase Sequence Analysis DNA Fibroblasts Amino acid Culture Media chemistry Female Adenosine triphosphate Aspartate—ammonia ligase |
| Zdroj: | Mol Genet Metab |
| Popis: | Asparagine Synthetase Deficiency is a recently described cause of profound intellectual disability, marked progressive cerebral atrophy and variable seizure disorder. To date there has been limited functional data explaining the underlying pathophysiology. We report a new case with compound heterozygous mutations in the ASNS gene (NM_183356.3:c. [866G>C]; [1010C>T]). Both variants alter evolutionarily conserved amino acids and were predicted to be pathogenic based on in silico protein modelling that suggests disruption of the critical ATP binding site of the ASNS enzyme. In patient fibroblasts, ASNS expression as well as protein and mRNA stability are not affected by these variants. However, there is markedly reduced proliferation of patient fibroblasts when cultured in asparagine-limited growth medium, compared to parental and wild type fibroblasts. Restricting asparagine replicates the physiology within the blood-brain-barrier, with limited transfer of dietary derived asparagine, resulting in reliance of neuronal cells on intracellular asparagine synthesis by the ASNS enzyme. These functional studies offer insight into the underlying pathophysiology of the dramatic progressive cerebral atrophy associated with Asparagine Synthetase Deficiency. |
| Databáze: | OpenAIRE |
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