GCLC – Gamma-glutamylcysteine Synthetase Deficiency

Gamma-glutamylcysteine ligase catalytic subunit (GCLC) catalyzes the first and rate-limiting step of glutathione biosynthesis. Biallelic loss-of-function mutations in GCLC cause gamma-glutamylcysteine synthetase deficiency, a rare autosomal recessive disorder characterized by chronic hemolytic anemia, reticulocytosis, and leukocytosis.

Gamma-glutamylcysteine synthetase deficiency has been described in nine patients from seven unrelated families worldwide (PMID:40277844). We report a novel case in a 4.11-year-old Arab-Muslim Israeli boy presenting at day 2 with severe anemia (Hb 7.2 g/dL), reticulocytosis, and leukocytosis, requiring multiple transfusions (PMID:40277844). Family studies confirmed autosomal recessive inheritance.

Molecular analysis identified a homozygous c.379C>T (p.Arg127Cys) variant in GCLC, previously shown to abolish enzymatic activity in patient fibroblasts and required rescue by the regulatory subunit GCLM (PMID:21657237). This missense change segregates with disease and has not been observed in the homozygous state in control populations.

Functional studies in GCLC-null mouse fibroblasts expressing p.Arg127Cys demonstrated markedly reduced glutathione production, which was partially restored by co-expression of GCLM, supporting haploinsufficiency as the primary mechanism of pathogenesis (PMID:21657237). Concordant in vitro assays across bacterial and mammalian systems confirm the deleterious impact of this variant on enzyme kinetics.

No conflicting evidence has been reported to date. The body of genetic and experimental data supports a strong gene–disease relationship between GCLC and gamma-glutamylcysteine synthetase deficiency.

Key take-home: Identification of homozygous c.379C>T (p.Arg127Cys) in GCLC confirms diagnosis of gamma-glutamylcysteine synthetase deficiency, enabling targeted management of chronic hemolytic anemia.

References

• Hematology reports • 2025 • Hemolytic Anemia Due to Gamma-Glutamylcysteine Synthetase Deficiency: A Rare Novel Case in an Arab-Muslim Israeli Child. PMID:40277844
• Biochemistry • 2011 • Enzymatic defects underlying hereditary glutamate cysteine ligase deficiency are mitigated by association of the catalytic and regulatory subunits. PMID:21657237

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