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Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation
Emmanuel Martin, … , Peter D. Arkwright, Sylvain Latour
Emmanuel Martin, … , Peter D. Arkwright, Sylvain Latour
Published March 12, 2020
Citation Information: JCI Insight. 2020;5(5):e133880. https://doi.org/10.1172/jci.insight.133880.
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Research Article Immunology

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

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Abstract

Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for 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 to be 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 CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT 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 supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.

Authors

Emmanuel Martin, Norbert Minet, Anne-Claire Boschat, Sylvia Sanquer, Steicy Sobrino, Christelle Lenoir, Jean Pierre de Villartay, Maria Leite-de-Moraes, Capucine Picard, Claire Soudais, Tim Bourne, Sophie Hambleton, Stephen M. Hughes, Robert F. Wynn, Tracy A. Briggs, Genomics England Research Consortium, Smita Patel, Monica G. Lawrence, Alain Fischer, Peter D. Arkwright, Sylvain Latour

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Figure 1

Immunophenotyping of CTPS1-deficient patients.

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Immunophenotyping of CTPS1-deficient patients.
(A) Percentages of αβ and...
(A) Percentages of αβ and γδ T cells, NK cells, B cells, monocytes, myeloid dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs) in PBMCs are represented in dot plot graphs. Data were obtained from FACS analysis after cell-specific staining. Reference ranges for age-matched controls (3–18 years) correspond to 21%–98%, 0.9%–17%, 4%–22 %, 6%–24%, 2%–21%, 0.1%–7.8%, 0%–4.5%, 0.1%–3.1%, and 0.8%–0.36% for αβ T cells, γδ T cells, NK cells, B cells, classical CD14++CD16–, intermediate CD14+CD16+, nonclassical CD14+CD16++ monocytes, mDCs, and pDCs, respectively. (B) Frequencies of naive (CD31+CD45RA+CCR7–), central memory (CD45RA–CCR7+CD27–), effector memory (CD45RA–CCR7+CD27–), and exhausted effector memory/TEMRA (CD45RA+CCR7+CD27–) compartments in CD4+ and CD8+ T cells are represented in the dot plot graph. Representative dot plot FACS analysis of naive and memory CD4+ cells (left) and CD8+ cells (right) are also depicted. (C) Frequencies of senescent cells (CD8+CD57+) gated on CD3+ cells are shown in the dot plot graph (left). Representative dot plot FACS analysis of senescent CD8+ cell populations are depicted at right . Data were obtained from FACS analysis of cell-specific staining. (D) Frequencies of naive (CD19+CD27–), memory (CD19+CD27+) (left), circulating marginal zone (MZ) (CD19+CD27+IgM+IgD+) and switched B cells (CD19+CD27+IgM–IgD–) (right) are shown in the dot plot graph. Representative dot plots FACS analysis of naive/memory (left) and marginal zone/switched (right) B cell populations are depicted. Data were obtained from FACS analysis after cell-specific staining. In A–D, black or red dots correspond to a healthy individual donor or a patient, respectively. Each circle represents an independent biological sample. Ten to 19 adult controls and 8 patients were analyzed. The horizontal bars represent the median. Data obtained from 6 independent experiments. Groups of values were compared 2 by 2 using Mann-Whitney U tests. *P < 0.05; **P < 0.01.
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