GLS hyperactivity causes glutamate excess, infantile cataract and profound developmental delay.

Human Molecular Genetics
Lynne RumpingPeter M van Hasselt

Abstract

Loss-of-function mutations in glutaminase (GLS), the enzyme converting glutamine into glutamate, and the counteracting enzyme glutamine synthetase (GS) cause disturbed glutamate homeostasis and severe neonatal encephalopathy. We report a de novo Ser482Cys gain-of-function variant in GLS encoding GLS associated with profound developmental delay and infantile cataract. Functional analysis demonstrated that this variant causes hyperactivity and compensatory downregulation of GLS expression combined with upregulation of the counteracting enzyme GS, supporting pathogenicity. Ser482Cys-GLS likely improves the electrostatic environment of the GLS catalytic site, thereby intrinsically inducing hyperactivity. Alignment of +/-12.000 GLS protein sequences from >1000 genera revealed extreme conservation of Ser482 to the same degree as catalytic residues. Together with the hyperactivity, this indicates that Ser482 is evolutionarily preserved to achieve optimal-but submaximal-GLS activity. In line with GLS hyperactivity, increased glutamate and decreased glutamine concentrations were measured in urine and fibroblasts. In the brain (both grey and white matter), glutamate was also extremely high and glutamine was almost undetectable, demonstra...Continue Reading

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Citations

Oct 12, 2019·Journal of Inherited Metabolic Disease·Lynne RumpingNanda M Verhoeven-Duif
Sep 19, 2019·The New England Journal of Medicine·André B P van KuilenburgClara D M van Karnebeek
Nov 18, 2019·Biochimica Et Biophysica Acta. General Subjects·Lynne RumpingJudith J M Jans

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