Asparagine Synthetase Deficiency causes reduced proliferation of cells under conditions of limited asparagine

Molecular Genetics and Metabolism
Elizabeth Emma PalmerEdwin P Kirk

Abstract

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 Synth...Continue Reading

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Citations

Jun 3, 2016·Applied Microbiology and Biotechnology·Boyang ZhangDianwen Ju
Oct 17, 2016·Brain & Development·Takahiro YamamotoToshiyuki Fukao
Aug 5, 2017·Metabolic Brain Disease·Neerja GuptaMadhulika Kabra
Nov 1, 2017·The Journal of Biological Chemistry·Carrie L LomelinoMichael S Kilberg
May 16, 2020·Cancer Biotherapy & Radiopharmaceuticals·Chunxin QinZhiyong Zhan
Jul 31, 2018·Frontiers in Genetics·Dorit SchleinitzJohannes Hirrlinger
Aug 4, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Essa AlharbyNaif A M Almontashiri
Sep 2, 2020·International Journal of Molecular Sciences·Rochelin DalanginRobert E Campbell
Jun 28, 2017·Journal of Inherited Metabolic Disease·T J de Koning
Jun 22, 2020·Prenatal Diagnosis·Lauren E ChurchillJulie L Piechan
Jun 9, 2016·Human Molecular Genetics·Elizabeth E PalmerWilliam R Lagor
Dec 4, 2020·Neuropediatrics·Ghada M H Abdel-Salam, Mohamed S Abdel-Hamid
Jun 4, 2021·Journal of Inherited Metabolic Disease·Hideki MatsumotoHidenori Ohnishi

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