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

Mol Genet Metab. 2015 Nov;116(3):178-86. doi: 10.1016/j.ymgme.2015.08.007. Epub 2015 Aug 14.

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 Synthetase Deficiency.

Keywords: ATP binding; Asparagine; Epileptic encephalopathy; Exome sequencing; Intellectual disability.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Asparagine / metabolism*
  • Aspartate-Ammonia Ligase / chemistry
  • Aspartate-Ammonia Ligase / deficiency*
  • Aspartate-Ammonia Ligase / genetics*
  • Aspartate-Ammonia Ligase / metabolism
  • Binding Sites
  • Cell Proliferation*
  • Cells, Cultured
  • Computer Simulation
  • Culture Media / chemistry
  • Exome
  • Female
  • Fibroblasts / pathology
  • Humans
  • Intellectual Disability / etiology
  • Intellectual Disability / genetics
  • Male
  • Mutation*
  • Sequence Analysis, DNA

Substances

  • Culture Media
  • Asparagine
  • Adenosine Triphosphate
  • Aspartate-Ammonia Ligase