GLUL

The GLUL gene encodes glutamine synthetase, a critical enzyme that converts glutamate and ammonia into glutamine—supporting neurotransmitter balance, ammonia detoxification, and cellular metabolism. 

Mutations in GLUL are linked to two rare but distinct disorders: autosomal recessive congenital glutamine deficiency and dominant developmental and epileptic encephalopathy 116 (DEE116), each with unique biochemical and clinical profiles.

What is GLUL (Glutamate-Ammonia Ligase/Glutamine Synthetase)?

The GLUL gene provides the instructions for producing glutamine synthetase (GS), an essential enzyme responsible for synthesizing glutamine from glutamate and ammonia in an ATP-dependent reaction. 

This process is vital for ammonia detoxification, acid-base balance, and maintaining sufficient levels of glutamine, a key amino acid involved in neurotransmitter regulation, immune function, and nucleotide biosynthesis. 

GLUL is highly expressed in the brain, liver, and muscle. Astrocytes in the brain play a major role in managing glutamate toxicity and supporting neuron function.

GLUL Mutations and Disease

Mutations in the GLUL gene, which encodes the enzyme glutamine synthetase (GS), have been linked to two distinct clinical conditions: congenital glutamine deficiency and Developmental and Epileptic Encephalopathy 116 (DEE116). 

These disorders differ in inheritance pattern, clinical presentation, and biochemical findings.

Congenital Glutamine Deficiency

Congenital glutamine deficiency is a rare autosomal recessive disorder caused by biallelic (homozygous or compound heterozygous) mutations in GLUL. 

These mutations result in severely reduced or absent GS activity, leading to near-complete deficiency of glutamine in serum and cerebrospinal fluid (CSF).

Clinical Presentation:

• Neonatal-onset severe encephalopathy
• Multiorgan failure, including cardiac and respiratory compromise
• Profound hypotonia, seizures, and abnormal EEG
• Severe brain malformations, such as:
  
  • Lissencephaly-like features (agyria)
  • Enlarged ventricles
  • White matter hyperintensities
  • Paraventricular cysts and pericerebral space enlargement
• Failure to thrive, despite feeding support
• Epidermal necrolysis-like rash and voluminous yellow stools

Biochemical Findings:

• Undetectable glutamine in serum, urine, and CSF
• Normal glutamate and ammonia levels
• Other metabolic labs typically unremarkable

Prognosis:

Congenital glutamine deficiency is rapidly progressive and typically fatal in the neonatal period.

Developmental and Epileptic Encephalopathy 116 (DEE116)

DEE116 is a dominant neurological disorder caused by de novo heterozygous mutations in GLUL, often affecting the gene’s start codon. 

These mutations lead to the production of a truncated GS protein that is enzymatically active but degradation-resistant, resulting in pathological glutamine accumulation in brain tissue despite normal serum and CSF levels.

Clinical Presentation:

Normal early development, followed by:

• Early-onset, treatment-resistant epilepsy
• Severe developmental regression
• Hypotonia
• White matter abnormalities on brain imaging (e.g., hypomyelination, enlarged perivascular spaces)
• Plasma and CSF glutamine levels are typically normal

Pathogenic Mechanism:

These mutations disrupt the protein's normal regulation by removing its N-terminal degron, rendering GS insensitive to feedback degradation and promoting chronic glutamine overproduction.

Diagnostic Consideration:

GLUL testing should be considered in infants and children with unexplained early-onset epilepsy, especially when standard metabolic evaluations are normal.

When Is GLUL-Related Testing Relevant?

While GLUL-related testing is not a routine clinical practice, it may be relevant in several specialized or research-focused scenarios. 

Neurological Disorders

Altered GS activity in the brain has been associated with:

• Epilepsy (including early-onset, drug-resistant forms)
• Alzheimer’s disease
• Hepatic encephalopathy (neurological dysfunction due to liver failure)

In these conditions, disrupting glutamate-glutamine cycling or ammonia detoxification may contribute to disease pathophysiology. 

GLUL gene testing should also be considered in infants or children with developmental and epileptic encephalopathy when routine metabolic testing is inconclusive.

Congenital Glutamine Deficiency

Biallelic mutations in GLUL cause a rare autosomal recessive disorder marked by:

• Severe neonatal encephalopathy
• Multiorgan failure
• Undetectable serum and CSF glutamine

Genetic testing of GLUL is appropriate in neonates with these features to confirm a diagnosis of congenital glutamine deficiency.

Cancer Research and Tumor Profiling

GS plays context-dependent roles in cancer:

Overexpression of GS may support tumor growth in certain cancers by enabling glutamine synthesis under nutrient-deprived conditions.

In gastric cancer, reduced GLUL expression is linked to tumor progression and poor survival, highlighting a potential tumor-suppressive function.

GLUL expression may be a prognostic biomarker or therapeutic target in research and experimental oncology settings.

Vascular and Developmental Disorders

GLUL is essential for endothelial cell migration and angiogenesis, partly by regulating the RHOJ signaling pathway. Abnormalities in GS may contribute to vascular development disorders.

Test Procedure and Interpretation

Testing for GLUL is performed as a genetic test to look for mutations in the gene that would alter functional protein availability. The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for GLUL genetic testing are considered to be without mutations that can alter the activity of the GLUL proteins.

What Do Changes in Glutamine Synthetase Mean?

In research and select clinical scenarios, GS expression or function changes can signal significant physiological disturbances. 

In the brain, reduced GS can impair ammonia clearance and glutamate recycling, leading to neurotoxicity. In contrast, excess GS activity, such as from gain-of-function GLUL variants, may cause chronic overproduction of glutamine, disrupting normal neuron-glia interactions and contributing to epileptic encephalopathy.

In cancer, the role of GS is context-dependent. Some tumors rely on GS for glutamine biosynthesis under nutrient-deprived conditions, making it a metabolic vulnerability. In gastric cancer, however, GLUL appears to act independently of its enzymatic function, binding to and stabilizing N-cadherin, thereby suppressing metastasis and antagonizing β-catenin signaling.

What Does the Absence of Pathogenic GLUL Mutations Mean?

The absence of GLUL mutations does not rule out inherited neuropathies, as CMT is genetically heterogeneous. Many other genes are known to cause similar clinical presentations. 

A negative GLUL result should prompt consideration of further genetic testing, particularly if there is a strong clinical suspicion of hereditary neuropathy.

Clinical Implications

GLUL-related disease mechanisms range from loss-of-function (congenital deficiency) to gain-of-function/stabilization (DEE116). Understanding the context is critical for interpreting GLUL variants. 

While routine clinical testing is limited, GLUL evaluation may be warranted in select pediatric neurology or oncology cases. 

Research also supports the potential for GS-targeted therapies, such as methionine sulfoximine, especially for glutamine-addicted tumors or GS-stabilization disorders.

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