Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous...

Area of Science:

• Immunology
• Biochemistry
• Genetics

Background:

• Cytidine triphosphate (CTP) synthetase 1 (CTPS1) is crucial for CTP nucleotide production, essential for DNA and RNA synthesis.
• CTPS1 deficiency, caused by a specific frameshift mutation (c.1692-1G>C, p.T566Dfs26X), leads to severe bacterial and viral infections.
• The study investigates lymphocyte defects in patients with CTPS1 deficiency.

Purpose of the Study:

• To characterize lymphocyte defects in CTPS1 deficiency.
• To understand the functional impact of the CTPS1T566Dfs26X mutation.
• To evaluate CTPS1 as a therapeutic target for pathological T cell proliferation.

Main Methods:

• Immune phenotyping of lymphocytes from 7 CTPS1-deficient patients.
• Analysis of T cell proliferation and IL-2 secretion upon TCR activation.
• Functional assessment of the CTPS1T566Dfs26X mutant protein in T cell leukemia models.

Main Results:

• Patients showed reduced numbers of specific lymphocyte subsets, including invariant NKT and memory B cells.
• T cell proliferation and IL-2 secretion were significantly decreased in CTPS1-deficient patients.
• The CTPS1T566Dfs26X mutant protein exhibited reduced expression and activity due to instability, not altered enzymatic function.

Conclusions:

• CTPS1 deficiency results in profound lymphocyte defects and impaired T cell function.
• The loss of CTPS1 function is primarily due to protein instability of the CTPS1T566Dfs26X mutant.
• CTPS1 is a potential therapeutic target for inhibiting aberrant T cell proliferation, such as in lymphoma.