GCLC – Cystic Fibrosis Severity Modifier

Glutamate-cysteine ligase catalytic subunit (GCLC) is the rate-limiting enzyme in glutathione biosynthesis, essential for cellular redox homeostasis and defense against oxidative stress. Variants in GCLC have been proposed as genetic modifiers that influence the clinical course of cystic fibrosis (CF). Understanding this modifier role has implications for prognosis and tailored antioxidant therapies.

CF is an autosomal recessive disease caused by CFTR mutations and characterized by chronic pulmonary infection, pancreatic insufficiency, and progressive lung damage. Modifier genes affecting glutathione metabolism may alter susceptibility to microbial colonization and inflammatory injury in CF patients.

A cross-sectional study of 180 unrelated CF patients assessed GCLC polymorphisms (–129C>T and –3506A>G) alongside CFTR genotypes and 28 clinical variables. The –129C>T CC genotype correlated with increased mucoid Pseudomonas aeruginosa colonization (p = 0.044) and –3506A>G AA genotype with non-mucoid P. aeruginosa (p = 0.012) (PMID:24593045). No segregation analysis was performed, reflecting the modifier role rather than primary causation.

In vitro functional assays of the ethnically restricted p.Pro462Ser (c.1384C>T) variant demonstrate significantly reduced enzyme activity in bacterial and mammalian expression systems, lower intracellular glutathione levels, and increased caspase activation upon apoptotic stimulation compared to wild-type p.Pro462 (462P > 462S) (PMID:20655259). These data support a loss-of-function mechanism that may exacerbate oxidative stress in CF airways.

No conflicting evidence has been reported. Together, genetic association and functional studies provide convergent support that GCLC variants can modulate CF severity by diminishing glutathione synthesis and increasing vulnerability to infection and inflammation. This modifier insight may guide antioxidant supplementation trials and risk stratification.

Key Take-home: GCLC polymorphisms, particularly c.1384C>T (p.Pro462Ser), are supported by clinical association and functional assays as modifiers of cystic fibrosis severity, offering avenues for personalized antioxidant therapy.

References

• BMC medical genetics • 2014 • Polymorphisms in the glutathione pathway modulate cystic fibrosis severity: a cross-sectional study. PMID:24593045
• Molecular genetics and metabolism • 2010 • An ethnic-specific polymorphism in the catalytic subunit of glutamate-cysteine ligase impairs the production of glutathione intermediates in vitro. PMID:20655259

Evidence Based Scoring (AI generated)