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

Stephen Hughes, Robert Wynn, Tracy Briggs, Peter Arkwright, et al.

Research output: Contribution to journalArticlepeer-review

Abstract

CTP synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients displayed severe bacterial and viral infections. CTPS1 is responsible of CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T-cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found hypomorphic resulting in 80-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T-cell leukemia fully abolished cell-proliferation. Expression of the CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to the normal, unless by forcing its expression to a level comparable to that of wild-type CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity and thus the loss-of-function of CTPS1T566Dfs26X is completely attributable to protein instability. This study strengthens that CTPS1 represents an attractive herapeutic target to selectively inhibit pathological T-cell proliferation including lymphoma.
Original languageEnglish
JournalJournal of Clinical Investigation Insight
Publication statusAccepted/In press - 2 Feb 2020

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