CTPS1 was first reported in relation to combined immunodeficiency due to CTPS1 deficiency in 2014 (Martin et al., PMID: 24870241). The enzyme (cytidine-5-prime-triphosphate synthetase) is encoded by the CTPS1 gene, and important in the biosynthesis of phospholipids and nucleic acids, and plays a key role in cell growth, development, and tumorigenesis. Only one unique nonsense variant (e.g. splice acceptor) has been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, and experimental data.
Variants in this gene have been reported in at least 10 probands in 3 publications (PMIDs: 35983265, 24870241, 27638562).
This gene-disease relationship is supported by mouse animal models (PMID: 38438357). Deletion of Ctps1 in T cells or treatment with a CTPS1 inhibitor rescued Foxp3-deficient mice from fatal systemic autoimmunity and reduced the severity of experimental autoimmune encephalomyelitis. De novo synthesis of impaired expansion of T and B cell findings support that CTPS1 may represent a target for immune suppression. This gene-disease relationship is also supported by experimental evidence (e.g. expression studies) (PMIDs: 32161190, 24870241). 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. Another functional study showed CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response.
In summary, there is definitive evidence to support the relationship between CTPS1 and autosomal recessive combined immunodeficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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