A Novel Gain-of-Function GLUL Variant Is Associated With Developmental and Epileptic Encephalopathy With Enlarged...

Area of Science:

• Biochemistry
• Genetics
• Neuroscience

Background:

• Glutamate-glutamine metabolism is crucial for brain function.
• Mutations in the GLUL gene, encoding glutamine synthetase, lead to distinct clinical phenotypes.
• Dominant GLUL mutations are associated with developmental and epileptic encephalopathy (DEE), often linked to altered enzyme stability.

Purpose of the Study:

• To characterize a novel de novo GLUL variant (c.522_536dup) in a patient with DEE.
• To investigate the impact of this variant on glutamine synthetase activity and regulation.
• To expand the genotypic and phenotypic spectrum of GLUL-related disorders.

Main Methods:

• Clinical assessment and neuroimaging (brain MRI) of the patient.
• In vitro overexpression assays to compare mutant and wild-type GLUL protein expression and enzyme activity.
• Analysis of enzyme kinetics under varying glutamine concentrations.

Main Results:

• The patient presented with DEE, white matter signal alterations, and enlarged perivascular spaces.
• The c.522_536dup variant did not alter protein expression or basal enzyme activity.
• The mutant GLUL exhibited dysregulated enzyme activity under low and high glutamine conditions, indicating impaired feedback regulation.

Conclusions:

• The c.522_536dup variant represents a novel gain-of-function mutation in the catalytic domain of GLUL.
• This finding supports the role of enzyme stability and regulatory disruption in dominant GLUL-related DEE.
• Enlarged perivascular spaces may serve as a diagnostic clue for GLUL-related disorders.