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Inheritance

1

Autosomal recessive HP:0000007

Homozygous CTPS1 loss of function, with heterozygous carrier parents and a shared founder haplotype.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:29884857 SUPPORT Human Clinical

"all the parents were heterozygous carriers"

States the carrier status of the parents, which is the observation that establishes recessive inheritance in this cohort.

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Discussions and Knowledge Gaps

3

Does the founder allele c.1692-1G>C abolish CTPS1 protein entirely, or leave 10-20% of it?

CONTROVERSY ctps1_allele_null_or_hypomorph

Attached to

pathophysiology#CTPS1 Loss of Function from a Founder Splice Variant genetic#CTPS1

Two peer-reviewed sources describe the same allele in incompatible terms. The 2018 transplant series states it produces an abnormal transcript lacking exon 18 and complete absence of protein. The 2020 characterisation measured an 80-90% reduction in protein with the residual enzyme retaining normal catalytic activity, and showed that restoring expression to wild-type levels restores proliferation - which requires that there be a functional protein to restore. This entry follows the 2020 reading, for two reasons worth stating rather than assuming. It is a direct quantitative measurement made to answer this question, whereas the 2018 statement is a background sentence in a transplant outcome paper. And the mouse deletion is embryonic lethal, so a genuinely protein-null human would be unlikely to reach the paediatric transplant clinic at all. It is not a pedantic distinction. If the allele is null, the human disease is a model of complete CTPS1 loss and the mouse lethality becomes a species difference that needs explaining. If it is hypomorphic, the human disease is a natural dose-reduction experiment, and it is the only human evidence available for what partial CTPS1 inhibition does - which bears directly on the CTPS1 inhibitors now in clinical development.

Proposed experiments

Quantitative immunoblot and transcript analysis of the founder allele in fresh patient cells

ctps1_allele_protein_quantification

Measure CTPS1 protein and the exon-18-skipped transcript in freshly isolated, stimulated patient lymphocytes against a standard curve, rather than in transformed or transduced lines, so the residual level is established in the cell type the disease is about.

Readouts

CTPS1 protein abundance relative to control

pathophysiology#CTPS1 Loss of Function from a Founder Splice Variant

Direction: DECREASED

Interpretation: A measurable residual band settles the question in favour of the hypomorphic reading; a true absence would make the mouse lethality a species difference requiring explanation.

How much of the described phenotype is specific to the single founder allele, and is the immunological defect graded with residual CTPS1 dose or threshold-like?

KNOWLEDGE GAP ctps1_allelic_series_absent

Attached to

genetic#CTPS1 pathophysiology#Failure of Antigen-Driven Lymphocyte Clonal Expansion

Every human observation in this entry derives from one allele, homozygous, on one founder haplotype. That is a narrow evidentiary base for a disease description, and no allelic series exists to say whether an allele with 40% residual function would be clinically silent. The question has an unusually direct practical consequence: CTPS1-selective inhibitors are in clinical development as immunosuppressants, and the dose-response of this disease is the closest thing to a human dose-finding experiment that exists for that target.

Proposed experiments

Graded CTPS1 expression series in primary human T cells

ctps1_dose_response_series

Titrate CTPS1 protein across the range from null to wild type in primary human T cells, and measure proliferative capacity and the innate-like and memory differentiation readouts that fail in patients, to establish whether the relationship is graded or threshold-like.

Readouts

Proliferative capacity as a function of CTPS1 protein level

pathophysiology#Failure of Antigen-Driven Lymphocyte Clonal Expansion

Direction: DECREASED

Interpretation: A threshold rather than a gradient would predict that partial pharmacological inhibition is safe up to a sharp point, which is a materially different safety profile from a graded one.

How should the evidence base for this disease be read, given that most recent CTPS1 research is motivated by inhibiting the enzyme rather than by restoring it?

INTERPRETATION ctps1_target_direction_paradox

Attached to

treatments#Cytidine or CTP Supply Restoration pathophysiology#Failure to Control Herpesvirus-Infected B Cells

The disease is a natural experiment that drug discovery has adopted. Because CTPS1 deficiency is lymphocyte-selective and survivable, CTPS1 is an attractive immunosuppressive and anti-lymphoma target, and the isoform-comparison work and the mouse work cited in this entry were both done within that programme. That is largely a benefit: the pathway is unusually well characterised for an ultra-rare disease. But it has two consequences for reading the evidence. Findings are selected for what they say about inhibition rather than about patients, so questions that matter clinically - long-term post-transplant outcome, natural history in untreated survivors, whether cytidine helps in vivo - are unstudied while the enzymology is very well studied. And the same experiment supports opposite therapeutic claims: cytidine rescue is curated here as a rationale for supplementation and is presented in its source paper as evidence that CTPS1 is worth blocking.

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Pathophysiology

7

CTPS1 Loss of Function from a Founder Splice Variant

Homozygous loss-of-function variation in CTPS1. The human disease is defined by a single founder frameshift splice variant, c.1692-1G>C (p.T566Dfs26X), which removes exon 18 from the transcript. How much protein survives is disputed - see the controversy recorded on this entry - but both readings agree that the enzyme activity available to an activated lymphocyte is grossly insufficient.

Genetic context CTPS1 hgnc:2519 variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Recorded as PARTIAL_LOSS_OF_FUNCTION on the strength of the direct measurement in patient cells, which found 10-20% residual protein with normal per-molecule catalytic activity. The earlier transplant series describes the same allele as giving complete absence of protein. The partial reading is preferred here because it rests on a quantitative measurement made for that purpose, and because the mouse null is embryonic lethal while these patients survive to transplant.

Downstream

Failure to Expand the CTP Pool on Lymphocyte Activation CTPS1 catalyses the committed step of de novo CTP synthesis, so reduced enzyme means reduced CTP when demand rises.

Show evidence (4 references)

PMID:24870241 SUPPORT Human Clinical

"Here we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation."

The gene-disease assignment from the study that made it, together with the defining cellular defect.

PMID:32161190 SUPPORT Human Clinical

"The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients."

The quantitative measurement of residual protein, which is the basis for recording this as a partial rather than a complete loss of function.

PMID:32161190 SUPPORT In Vitro

"This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability."

Locates the defect at protein stability rather than at catalysis, which makes a dose-restoring intervention conceptually different from an activity-replacing one.

+ 1 more reference

Failure to Expand the CTP Pool on Lymphocyte Activation

Antigen-receptor engagement normally triggers a sharp rise in CTPS1 expression and a corresponding rise in intracellular CTP, supplying the nucleotide demand of the DNA, RNA and phospholipid synthesis that clonal expansion requires. In deficiency that rise does not happen. This is the node at which the disease becomes lymphocyte-specific: resting cells need little CTP and are unaffected, and other tissues meet their demand through the CTPS2 isoform and nucleoside salvage.

CTPS1 hgnc:2519

CTP biosynthetic process GO:0006241 ↓ DECREASED

CTP synthase activity GO:0003883 ↓ DECREASED

Animal models

Conditional and inducible Ctps1 knockout mouse Mouse perturbs Deletion of the enzyme is the perturbation. The model also shows CTPS2 is required alongside CTPS1 for proliferation after TCR stimulation, which bounds how much redundancy the isoform actually provides.

Downstream

Failure of Antigen-Driven Lymphocyte Clonal Expansion Without the nucleotide precursors, the activated cell cannot complete the DNA synthesis that division requires.

Show evidence (3 references)

PMID:24870241 SUPPORT In Vitro

"CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation."

The activation-dependent expression pattern that explains why the deficiency is restricted to dividing lymphocytes rather than being systemic.

PMID:24870241 SUPPORT In Vitro

"Activated CTPS1-deficient cells had decreased levels of CTP."

The direct measurement of the metabolite this node is about.

PMID:37348953 SUPPORT In Vitro

"Therefore, our results demonstrate that CTPS1 is the main contributor to cell proliferation."

Establishes that CTPS2 cannot substitute freely for CTPS1, which is why losing one of two isoforms of the same enzyme produces a disease at all.

Failure of Antigen-Driven Lymphocyte Clonal Expansion

Activated T and B cells sense antigen and then cannot divide. The selectivity of this defect is the most informative thing about the disease: receptor-proximal and receptor-distal signalling are only weakly affected and non-proliferative effector functions are largely preserved, so the lesion is specifically in the capacity to expand, not in the capacity to respond.

T cell CL:0000084 B cell CL:0000236

lymphocyte proliferation GO:0046651 ↓ DECREASED

Animal models

Conditional and inducible Ctps1 knockout mouse Mouse recapitulates Activated lymphocytes and other high-turnover lineages depend on CTPS1 for maintenance and growth, reproducing the human proliferative defect.

Downstream

Failure to Control Herpesvirus-Infected B Cells Control of EBV and VZV depends on expanding a large virus-specific cytotoxic T-cell population, which is precisely the capacity this node removes.

Impaired Development of Memory and Innate-like Lymphocyte Subsets The subsets that fail are the ones whose development requires proliferative expansion.

Impaired T-Independent B-Cell Response to Polysaccharide Antigen A T-independent B-cell response is itself a proliferative burst, so it fails for the same reason - and it fails without needing the T-cell arm to be involved.

Impaired lymphocyte proliferative response The laboratory readout of this node.

Show evidence (2 references)

PMID:24870241 SUPPORT In Vitro

"In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1."

Establishes the selectivity of the defect, which is the claim this node makes and the thing that separates this disease from the TCR-signalling immunodeficiencies.

PMID:32161190 SUPPORT Human Clinical

"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 same selectivity measured in patient cells rather than in a cell line, adding IL-2 secretion to the list of affected responses.

Impaired Development of Memory and Innate-like Lymphocyte Subsets

A reproducible and quite specific pattern of missing populations - mucosal-associated invariant T cells, invariant NKT cells, memory B cells and NK cells - against a background of otherwise normal subset counts. These are the compartments whose generation depends on proliferative expansion, so the pattern is a readout of the proliferation defect rather than a separate lesion.

mucosal-associated invariant T cell CL:0000940 memory B cell CL:0000787 natural killer cell CL:0000623

Downstream

Reduced NK cell number The measurable readout of the failed innate-like compartment.

Show evidence (1 reference)

PMID:32161190 SUPPORT Human Clinical

"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."

Names the affected subsets and, importantly, records that the remaining subsets are normal - which is what makes this a selective differentiation defect rather than lymphopenia.

Impaired T-Independent B-Cell Response to Polysaccharide Antigen

The arm of the disease that explains its bacterial half, and the reason this is called a combined immunodeficiency rather than a viral-susceptibility syndrome. Antibody responses to polysaccharide antigens do not require T-cell help, so they cannot be explained by the failure of T-cell immunity - but they do require the B cell to divide, which is what this disease removes. It also resolves an otherwise confusing laboratory picture: total immunoglobulin is normal or even elevated in these patients while specific antipneumococcal titres are low. Bulk antibody is not the problem; making a new clonal response is.

B cell CL:0000236

Downstream

Recurrent encapsulated bacterial infection Failure of the antipolysaccharide response leaves encapsulated organisms uncontrolled.

Show evidence (2 references)

PMID:24870241 SUPPORT Human Clinical

"This may directly participate to the susceptibility to encapsulated bacterial infections seen in CTPS1-deficient patients and account for the low titers of S. pneumoniae antibodies as it is a T-independent B-cell response."

States the mechanism this node asserts - that the low pneumococcal titres reflect a failed T-independent B-cell response. The quote now runs from the start of the source sentence, including its "This may directly participate" hedge. An earlier version began mid-sentence at "patients and account for", which presented a hedged proposal as a flat assertion, and justified the trim by claiming the preceding clause ended in an abbreviation the snippet matcher would split on. That justification was false: the full sentence verifies exactly. Both the dropped hedge and the false reason for dropping it are corrected here, and recorded rather than quietly rewritten.

PMID:24870241 SUPPORT Human Clinical

"patients had normal Ig levels and/or elevated IgG"

The observation that makes this node necessary. Normal or high total immunoglobulin alongside poor specific responses is not explicable by a defect in antibody production in general.

Failure to Control Herpesvirus-Infected B Cells

The clinical centre of gravity of the disease. EBV is the pathogen that most stresses the capacity this disease removes, because containing it requires a large expansion of EBV-specific CD8 T cells against a B-cell population that EBV itself drives to proliferate; varicella zoster produces a comparable problem by a different route. There is a second, less-appreciated arm: EBV upregulates CTPS1 in the B cells it transforms, so the same enzyme is both the host defence bottleneck and a dependency of the transformed cell.

Downstream

EBV-driven B-cell lymphoproliferation and lymphoma Uncontrolled proliferation of EBV-infected B cells in the absence of an adequate cytotoxic response.

Severe recurrent herpesvirus infection The clinical manifestation of failed viral control.

Show evidence (2 references)

PMID:31402499 SUPPORT Human Clinical

"the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of..."

Places CTPS1 explicitly in the DNA-metabolism class of EBV-susceptibility genes, distinct from the activation and co-stimulation classes, and states the mechanism this node asserts.

PMID:29884857 SUPPORT Human Clinical

"Systemic viral infections were seen in all patients, with acute and chronic EBV infections in nine patients, four suffering from EBV-driven lymphoproliferative disease (LPD) (two CNS and one lung) and one with EBV-driven HLH."

The clinical realisation of this node in the largest reported cohort, with the proportion affected and the sites involved.

EBV-driven B-cell lymphoproliferation and lymphoma

The malignant end of the failure to control EBV, including central nervous system lymphoma. The B cells involved carry the EBV latency III programme, which is the programme in which EBV drives CTPS1 expression in the transformed cell.

B cell CL:0000236

Downstream

EBV-associated lymphoproliferative disease The clinical phenotype this pathophysiology node produces. The two are curated in separate sections rather than merged, because renaming either to match would collapse them into one node in the flat pathograph namespace.

Show evidence (1 reference)

PMID:34281398 SUPPORT In Vitro

"While CRISPR CTPS1 knockout caused DNA damage and proliferation defects in lymphoblastoid cell lines (LCLs), which express the EBV latency III program observed in CNS lymphomas, double CTPS1/2 knockout caused stronger phenotypes."

Names the latency programme of the lymphomas that occur in this disease, and shows the transformed cells themselves depend on CTPS1 - which is why this node is mechanistically interesting rather than merely an outcome.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

7

Blood 3

EBV-associated lymphoproliferative disease FREQUENT Lymphoproliferative disorder HP:0005523

Show evidence (1 reference)

PMID:29884857 SUPPORT Human Clinical

"four suffering from EBV-driven lymphoproliferative disease (LPD) (two CNS and one lung) and one with EBV-driven HLH"

Gives the number affected out of eleven, which supports FREQUENT rather than OBLIGATE, and names the sites involved.

Impaired lymphocyte proliferative response OBLIGATE Decreased antigen-specific T cell proliferation HP:0031402

Show evidence (1 reference)

PMID:32161190 SUPPORT Human Clinical

"Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients"

The proliferative defect measured in every patient of the characterised cohort, which supports the OBLIGATE frequency.

Reduced NK cell number FREQUENT Reduced total natural killer cell count HP:0040218

Show evidence (1 reference)

PMID:32161190 SUPPORT Human Clinical

"absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells"

Names NK cells among the reduced populations.

Digestive 1

Chronic diarrhea FREQUENT HP:0002028

Show evidence (1 reference)

PMID:29884857 SUPPORT Human Clinical

"Five patients presented with chronic diarrhea."

Gives the number affected out of eleven. The source does not attribute the diarrhoea to a mechanism, so the link to epithelial turnover suggested in the description is an inference and is not claimed as evidenced.

Immune 3

Severe recurrent herpesvirus infection OBLIGATE Recurrent viral infections HP:0004429

Show evidence (2 references)

PMID:29884857 SUPPORT Human Clinical

"Systemic viral infections were seen in all patients"

Establishes that the viral phenotype was present in every patient of the cohort, which is the basis for the OBLIGATE frequency.

PMID:29884857 SUPPORT Human Clinical

"Four patients had severe chickenpox."

The varicella zoster arm specifically, with the number affected. It is recorded because VZV is a leading cause of death in this disease and is easily overshadowed by EBV.

Recurrent encapsulated bacterial infection OBLIGATE Recurrent bacterial infections HP:0002718

Show evidence (2 references)

PMID:24870241 SUPPORT Human Clinical

"All patients had early onset of severe chronic viral infections, mostly caused by herpes viruses, including EBV and Varicella Zooster Virus (VZV) and, also suffered from recurrent encapsulated bacterial infections, a spectrum of infections typical of a combined deficiency of adaptive immunity (CID)"

States that all patients had both the viral and bacterial susceptibility, which is the basis for the OBLIGATE frequency, and names the combination as what defines a combined deficiency.

PMID:32161190 SUPPORT Human Clinical

"CTPS1-deficient patients display severe bacterial and viral infections."

An independent statement of the same combined picture, from the later characterisation cohort.

Invasive fungal infection VARIABLE Recurrent fungal infections HP:0002841

Show evidence (1 reference)

PMID:35983265 SUPPORT Human Clinical

"We describe the first case of cytidine nucleotide triphosphate synthetase 1 (CTPS1) deficiency, a combined immunodeficiency impairing lymphocyte proliferation, presenting with coccidioidomycosis."

A single case report, which is why this phenotype is VARIABLE rather than FREQUENT. It is the sole published fungal presentation.

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Genetic Associations

1

CTPS1

Gene: CTPS1 hgnc:2519 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:32161190 SUPPORT Human Clinical

"Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X)."

States the single causal allele on which the human description of this disease rests.

PMID:29884857 SUPPORT Human Clinical

"Patients with this mutation all have ancestors from the North West of England"

Establishes the founder effect, which is why a single allele accounts for the whole reported cohort.

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Medical Actions

3

Allogeneic Haematopoietic Stem Cell Transplantation

Action: Hematopoietic cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Platform: Cell therapy

The only intervention that addresses the cause rather than the consequences, by replacing the lymphoid compartment with one that has a functioning enzyme. The defect is cell-intrinsic to haematopoietic cells and the enzyme is not secreted, so replacing the compartment is curative in principle and, in the published series, in practice. It is not a benign option, and this record keeps the cost next to the benefit. Overall survival in the largest series was 72%, below what the same centres achieve for other combined immunodeficiencies, and the deaths were from EBV reactivation and from unusually severe chronic graft-versus-host disease. Both failure modes are plausibly consequences of the underlying disease rather than of the transplant.

Mechanism Target:

CTPS1 Loss of Function from a Founder Splice Variant — Replaces the lymphoid compartment with donor cells carrying a functional CTPS1 allele, acting at the trigger node rather than downstream of it.

Show evidence (3 references)

PMID:29884857 SUPPORT Human Clinical

"We report on 11 patients with CTPS1 mutations who underwent hematopoietic stem cell transplant (HSCT) at three UK centres (London, Manchester and Newcastle)."

Establishes the size and multi-centre character of the only outcome series that exists for this treatment in this disease.

PMID:29884857 SUPPORT Human Clinical

"The overall survival post-HSCT in this series was 72% which is slightly lower than seen after HSCT for other combined PIDs."

The outcome figure, together with the authors' own comparison against other combined immunodeficiencies. It is a retrospective single-arm series with no control group, so it reports what happened rather than an effect size.

PMID:29884857 SUPPORT Human Clinical

"HSCT can be curative but is not without potential risks and complications."

The authors' own summary statement, curated in preference to an unqualified claim of cure.

Cytidine or CTP Supply Restoration

Action: Pharmacotherapy NCIT:C15986

Agent: cytidine CHEBI:17562

Platform: Small molecule

Supplying the product the missing enzyme cannot make, or its nucleoside precursor, which the salvage pathway can convert. This restores proliferation of patient-derived cells in culture. It is curated as an experimental rationale rather than an established therapy, because the only evidence is in vitro rescue. Whether cytidine can be delivered to activated lymphocytes in vivo at the concentrations that work in culture is untested, and no patient has been reported treated this way.

Mechanism Target:

Failure to Expand the CTP Pool on Lymphocyte Activation — Bypasses the enzymatic block by supplying the product or a salvageable precursor of it.

Show evidence (2 references)

PMID:24870241 SUPPORT In Vitro

"Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine."

The in vitro rescue. It is evidence that the block can be bypassed in principle, and it is not evidence of clinical efficacy - no in vivo study exists.

PMID:34281398 SUPPORT In Vitro

"Cytidine rescued CTPS1/2 deficiency phenotypes in EBV-transformed LCLs and Burkitt B cells, highlighting CTPS1/2 as a potential therapeutic target for EBV-driven lymphoproliferative disorders."

An independent replication of the cytidine rescue in a different cell context. Note the paper frames the finding as an argument for inhibiting CTPS1 in lymphoma, which is the opposite therapeutic direction from this treatment record.

Rituximab and EBV-Specific Cytotoxic T Lymphocytes for EBV Complications

Action: Therapeutic procedure Ontology label: Therapeutic Procedure NCIT:C49236

Platform: Other

Directed treatment of the EBV-driven complications rather than of the underlying defect. B-cell depletion removes the compartment EBV proliferates in, and adoptive transfer of EBV-specific cytotoxic T lymphocytes supplies from outside exactly the expanded effector population the patient cannot generate. The second of these is mechanistically the most precisely targeted therapy in this entry, since it substitutes for the specific failed step. Curated at the level the evidence supports: both were used in the transplant series, before and after transplant, and no comparative outcome is reported for either.

Mechanism Target:

Failure to Control Herpesvirus-Infected B Cells — Adoptively transferred EBV-specific cytotoxic T lymphocytes supply the expanded virus-specific effector population that the proliferation defect prevents the patient from making.

Show evidence (1 reference)

PMID:29884857 SUPPORT Human Clinical

"Four patients with EBV-driven LPD received rituximab and three EBV-specific cytotoxic T-lymphocytes (CTLs) (two pre-transplant and one post-transplant)."

Records that both were used and in how many patients. The series reports no outcome attributable to either, so this is evidence of use rather than of efficacy.

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Diagnosis

2

Lymphocyte proliferation assay with preserved activation markers

The discriminating test. Proliferation on antigen-receptor stimulation is markedly reduced while activation signalling and other effector functions are close to normal, which distinguishes this from the TCR-signalling combined immunodeficiencies.

Show evidence (1 reference)

PMID:24870241 SUPPORT In Vitro

"In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1."

States the dissociation between signalling and proliferation on which this diagnostic distinction rests.

CTP synthetase activity measurement in stimulated lymphocytes

Direct enzymatic assay of CTPS activity in cell lysates by liquid chromatography tandem mass spectrometry, which distinguishes resting from activated cells and detects the failure of the activation-induced induction rather than a change in baseline.

Show evidence (1 reference)

PMID:31524312 SUPPORT Other

"Treatment by 3DAU and homozygous mutation in CTPS1 gene abolished the induction of CTPS activity associated with cell stimulation"

Shows the assay detects the specific defect - loss of the activation-induced rise rather than loss of baseline activity - in a patient carrying the mutation.

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Prevalence

1

Worldwide

Cases In Literature <1 in 1,000,000

Ultra-rare, with a founder effect in north-west England. The transplant series counted 17 patients worldwide as of 2018; the defining immunological characterisation was performed on seven. No population rate exists.

Show evidence (1 reference)

PMID:29884857 SUPPORT Human Clinical

"Seven (41%) of 17 patients worldwide with CTPS1 deficiency have died, three post and four prior to HSCT"

Gives a worldwide ascertained case count as of 2018. It is a count of known patients, not a rate in any population, which is why the record is CASES_IN_LITERATURE.

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Animal Models

1

Conditional and inducible Ctps1 knockout mouse

The model that supplies what the human disease cannot, because no human null exists. Complete germline Ctps1 deletion is embryonic lethal, which establishes that a human phenotype surviving to childhood must retain some enzyme. Conditional deletion then separates the contributions of the two isoforms, and shows that CTPS1 inactivation is immunosuppressive enough to rescue a fatal autoimmune model.

Species

Mouse

Genotype

Ctps1 conditional/inducible knockout, alone and combined with Ctps2

Publication

PMID:38438357

Pathograph links

Failure of Antigen-Driven Lymphocyte Clonal Expansion recapitulates fidelity: high observes: organism Activated lymphocytes and other high-turnover lineages depend on CTPS1 for maintenance and growth, reproducing the human proliferative defect.

Limitations: The mouse is a deletion and the human allele retains residual protein, so the mouse models a more complete loss than any patient has. The direction of the difference is knowable and matters - inferences about severity from mouse to human will overstate.

Readouts

Expansion of activated lymphocytes and memory T cells

Direction: DECREASED

Interpretation: Loss of the populations whose maintenance requires proliferation.

Show evidence (1 reference)

PMID:38438357 SUPPORT Model Organism

"Tissue and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells strongly rely on CTPS1 for their maintenance and growth."

Reports the affected compartments and the direction of the effect.

Failure to Expand the CTP Pool on Lymphocyte Activation perturbs fidelity: high observes: organism Deletion of the enzyme is the perturbation. The model also shows CTPS2 is required alongside CTPS1 for proliferation after TCR stimulation, which bounds how much redundancy the isoform actually provides.

Limitations: Mouse and human differ in the relative expression of the two isoforms across tissues, so the degree of CTPS2 compensation observed in the mouse is not directly transferable.

Readouts

T-cell proliferation after TCR stimulation in single and double knockouts

Direction: DECREASED

Interpretation: Establishes that redundancy between the isoforms is partial rather than complete.

Show evidence (1 reference)

PMID:38438357 SUPPORT Model Organism

"However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation."

Reports the isoform requirement measured in this model.

Show evidence (1 reference)

PMID:38438357 SUPPORT Model Organism

"We report that deletion of Ctps1, but not Ctps2, is embryonic-lethal."

The result that establishes what a complete human null would mean, and therefore that the human disease must be a partial deficiency. It is the single most important thing this model contributes, and the strongest argument in the dispute over what the founder allele does.

{ }

Source YAML

click to show

name: Combined Immunodeficiency Due to CTPS1 Deficiency
creation_date: '2026-09-06T08:15:00Z'
category: Mendelian
disease_term:
  preferred_term: combined immunodeficiency due to CTPS1 deficiency
  term:
    id: MONDO:0014391
    label: combined immunodeficiency due to CTPS1 deficiency
synonyms:
- CTPS1 deficiency
- CTP synthase 1 deficiency
- immunodeficiency 24
description: 'A combined immunodeficiency in which lymphocytes cannot build the nucleotide pool that
  rapid clonal expansion requires. CTPS1 catalyses the last step of de novo CTP synthesis, converting
  UTP to CTP. CTP is a precursor for DNA, RNA and phospholipid, so a resting lymphocyte needs little of
  it and a lymphocyte that has just met its antigen needs a great deal. CTPS1 is barely expressed at
  rest and is sharply upregulated on antigen-receptor activation, which is what makes its loss a
  lymphocyte-selective defect rather than a general one.

  The resulting immunological picture is unusual, and it is the reason this entry is worth separating
  from the signalling immunodeficiencies it sits among. Proximal and distal T-cell receptor signalling
  is close to intact; the cells sense antigen, activate, and then fail to divide. Effector functions
  other than proliferation are largely preserved. Clinically that produces severe and recurrent
  herpesvirus disease - Epstein-Barr virus above all, with EBV-driven B-cell lymphoproliferation and CNS
  lymphoma, and varicella zoster alongside it - because controlling these viruses depends specifically
  on expanding a large virus-specific CD8 T-cell population.

  Two things are curated carefully because they change how the evidence should be read. First, the human
  disease rests almost entirely on a single founder allele shared by patients with ancestry in
  north-west England, so what looks like a genotype-phenotype relationship is really a single-allele
  observation. Second, the literature disagrees with itself about what that allele does: the 2018
  transplant series describes it as causing complete absence of protein, and the 2020 characterisation
  measured 10-20% residual protein with normal catalytic activity per molecule. That disagreement is
  curated as a controversy rather than resolved silently, because which reading is right determines
  whether the human phenotype describes partial or complete deficiency - and the mouse says complete
  deletion is embryonic lethal.'
parents:
- Combined Immunodeficiency
- Inborn Error of Nucleotide Metabolism
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: BELOW_1_IN_1000000
  notes: Ultra-rare, with a founder effect in north-west England. The transplant series counted 17
    patients worldwide as of 2018; the defining immunological characterisation was performed on seven.
    No population rate exists.
  evidence:
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seven (41%) of 17 patients worldwide with CTPS1 deficiency have died, three post and four
      prior to HSCT
    explanation: Gives a worldwide ascertained case count as of 2018. It is a count of known patients,
      not a rate in any population, which is why the record is CASES_IN_LITERATURE.
pathophysiology:
- name: CTPS1 Loss of Function from a Founder Splice Variant
  role: trigger
  biological_scale: MOLECULAR
  description: 'Homozygous loss-of-function variation in CTPS1. The human disease is defined by a single
    founder frameshift splice variant, c.1692-1G>C (p.T566Dfs26X), which removes exon 18 from the
    transcript. How much protein survives is disputed - see the controversy recorded on this entry - but
    both readings agree that the enzyme activity available to an activated lymphocyte is grossly
    insufficient.'
  genetic_context:
    gene:
      preferred_term: CTPS1
      term:
        id: hgnc:2519
        label: CTPS1
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: 'Recorded as PARTIAL_LOSS_OF_FUNCTION on the strength of the direct measurement in
      patient cells, which found 10-20% residual protein with normal per-molecule catalytic activity.
      The earlier transplant series describes the same allele as giving complete absence of protein. The
      partial reading is preferred here because it rests on a quantitative measurement made for that
      purpose, and because the mouse null is embryonic lethal while these patients survive to transplant.'
  downstream:
  - target: Failure to Expand the CTP Pool on Lymphocyte Activation
    causal_link_type: DIRECT
    description: CTPS1 catalyses the committed step of de novo CTP synthesis, so reduced enzyme means
      reduced CTP when demand rises.
  evidence:
  - reference: PMID:24870241
    reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
      proliferation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Here we report the identification of a loss-of-function homozygous mutation (rs145092287)
      in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an
      impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated
      activation.
    explanation: The gene-disease assignment from the study that made it, together with the defining
      cellular defect.
  - reference: PMID:32161190
    reference_title: Impaired lymphocyte function and differentiation in CTPS1-deficient patients result
      from a hypomorphic homozygous mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90%
      reduction of protein expression and CTPS activity in cells of patients.
    explanation: The quantitative measurement of residual protein, which is the basis for recording this
      as a partial rather than a complete loss of function.
  - reference: PMID:32161190
    reference_title: Impaired lymphocyte function and differentiation in CTPS1-deficient patients result
      from a hypomorphic homozygous mutation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of
      function of CTPS1T566Dfs26X is completely attributable to protein instability.
    explanation: Locates the defect at protein stability rather than at catalysis, which makes a
      dose-restoring intervention conceptually different from an activity-replacing one.
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: This mutation is known to lead to an abnormal transcript lacking exon 18 and complete lack
      of protein expression.
    explanation: Graded REFUTE against the PARTIAL_LOSS_OF_FUNCTION assignment on this node, because it
      asserts complete absence of protein for the same allele. It is curated rather than dropped so the
      disagreement in the literature stays visible; the reasoning for preferring the partial reading is
      in the genetic_context description and in the linked controversy.
- name: Failure to Expand the CTP Pool on Lymphocyte Activation
  role: central_effector
  biological_scale: MOLECULAR
  description: 'Antigen-receptor engagement normally triggers a sharp rise in CTPS1 expression and a
    corresponding rise in intracellular CTP, supplying the nucleotide demand of the DNA, RNA and
    phospholipid synthesis that clonal expansion requires. In deficiency that rise does not happen. This
    is the node at which the disease becomes lymphocyte-specific: resting cells need little CTP and are
    unaffected, and other tissues meet their demand through the CTPS2 isoform and nucleoside salvage.'
  genes:
  - preferred_term: CTPS1
    term:
      id: hgnc:2519
      label: CTPS1
  molecular_functions:
  - preferred_term: CTP synthase activity
    term:
      id: GO:0003883
      label: CTP synthase activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: CTP biosynthetic process
    term:
      id: GO:0006241
      label: CTP biosynthetic process
    modifier: DECREASED
  downstream:
  - target: Failure of Antigen-Driven Lymphocyte Clonal Expansion
    causal_link_type: DIRECT
    description: Without the nucleotide precursors, the activated cell cannot complete the DNA synthesis
      that division requires.
    evidence:
    - reference: PMID:24870241
      reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
        proliferation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type
        CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine.
      explanation: The rescue experiment that establishes the direction of this edge. Supplying the
        product downstream of the missing enzyme restores the phenotype, which places the defect at CTP
        supply rather than elsewhere in the activation programme.
  evidence:
  - reference: PMID:24870241
    reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
      proliferation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following
      TCR activation.
    explanation: The activation-dependent expression pattern that explains why the deficiency is
      restricted to dividing lymphocytes rather than being systemic.
  - reference: PMID:24870241
    reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
      proliferation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Activated CTPS1-deficient cells had decreased levels of CTP.
    explanation: The direct measurement of the metabolite this node is about.
  - reference: PMID:37348953
    reference_title: Differential roles of CTP synthetases CTPS1 and CTPS2 in cell proliferation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Therefore, our results demonstrate that CTPS1 is the main contributor to cell proliferation.
    explanation: Establishes that CTPS2 cannot substitute freely for CTPS1, which is why losing one of
      two isoforms of the same enzyme produces a disease at all.
- name: Failure of Antigen-Driven Lymphocyte Clonal Expansion
  role: central_effector
  biological_scale: CELLULAR
  description: 'Activated T and B cells sense antigen and then cannot divide. The selectivity of this
    defect is the most informative thing about the disease: receptor-proximal and receptor-distal
    signalling are only weakly affected and non-proliferative effector functions are largely preserved,
    so the lesion is specifically in the capacity to expand, not in the capacity to respond.'
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: lymphocyte proliferation
    term:
      id: GO:0046651
      label: lymphocyte proliferation
    modifier: DECREASED
  downstream:
  - target: Failure to Control Herpesvirus-Infected B Cells
    causal_link_type: DIRECT
    description: Control of EBV and VZV depends on expanding a large virus-specific cytotoxic T-cell
      population, which is precisely the capacity this node removes.
  - target: Impaired Development of Memory and Innate-like Lymphocyte Subsets
    causal_link_type: DIRECT
    description: The subsets that fail are the ones whose development requires proliferative expansion.
  - target: Impaired T-Independent B-Cell Response to Polysaccharide Antigen
    causal_link_type: DIRECT
    description: A T-independent B-cell response is itself a proliferative burst, so it fails for the
      same reason - and it fails without needing the T-cell arm to be involved.
  - target: Impaired lymphocyte proliferative response
    causal_link_type: DIRECT
    description: The laboratory readout of this node.
  evidence:
  - reference: PMID:24870241
    reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
      proliferation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were
      only weakly affected by the absence of CTPS1.
    explanation: Establishes the selectivity of the defect, which is the claim this node makes and the
      thing that separates this disease from the TCR-signalling immunodeficiencies.
  - reference: PMID:32161190
    reference_title: Impaired lymphocyte function and differentiation in CTPS1-deficient patients result
      from a hypomorphic homozygous mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: The same selectivity measured in patient cells rather than in a cell line, adding IL-2
      secretion to the list of affected responses.
- name: Impaired Development of Memory and Innate-like Lymphocyte Subsets
  role: consequence
  biological_scale: CELLULAR
  description: A reproducible and quite specific pattern of missing populations - mucosal-associated
    invariant T cells, invariant NKT cells, memory B cells and NK cells - against a background of
    otherwise normal subset counts. These are the compartments whose generation depends on proliferative
    expansion, so the pattern is a readout of the proliferation defect rather than a separate lesion.
  cell_types:
  - preferred_term: mucosal-associated invariant T cell
    term:
      id: CL:0000940
      label: mucosal-associated invariant T cell
  - preferred_term: memory B cell
    term:
      id: CL:0000787
      label: memory B cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  evidence:
  - reference: PMID:32161190
    reference_title: Impaired lymphocyte function and differentiation in CTPS1-deficient patients result
      from a hypomorphic homozygous mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 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.
    explanation: Names the affected subsets and, importantly, records that the remaining subsets are
      normal - which is what makes this a selective differentiation defect rather than lymphopenia.
  downstream:
  - target: Reduced NK cell number
    causal_link_type: DIRECT
    description: The measurable readout of the failed innate-like compartment.
- name: Impaired T-Independent B-Cell Response to Polysaccharide Antigen
  role: consequence
  biological_scale: CELLULAR
  description: 'The arm of the disease that explains its bacterial half, and the reason this is called a
    combined immunodeficiency rather than a viral-susceptibility syndrome. Antibody responses to
    polysaccharide antigens do not require T-cell help, so they cannot be explained by the failure of
    T-cell immunity - but they do require the B cell to divide, which is what this disease removes.

    It also resolves an otherwise confusing laboratory picture: total immunoglobulin is normal or even
    elevated in these patients while specific antipneumococcal titres are low. Bulk antibody is not the
    problem; making a new clonal response is.'
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: Recurrent encapsulated bacterial infection
    causal_link_type: DIRECT
    description: Failure of the antipolysaccharide response leaves encapsulated organisms uncontrolled.
  evidence:
  - reference: PMID:24870241
    reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
      proliferation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This may directly participate to the susceptibility to encapsulated bacterial infections
      seen in CTPS1-deficient patients and account for the low titers of S. pneumoniae antibodies as it
      is a T-independent B-cell response.
    explanation: 'States the mechanism this node asserts - that the low pneumococcal titres reflect a
      failed T-independent B-cell response.

      The quote now runs from the start of the source sentence, including its "This may directly
      participate" hedge. An earlier version began mid-sentence at "patients and account for", which
      presented a hedged proposal as a flat assertion, and justified the trim by claiming the preceding
      clause ended in an abbreviation the snippet matcher would split on. That justification was false:
      the full sentence verifies exactly. Both the dropped hedge and the false reason for dropping it
      are corrected here, and recorded rather than quietly rewritten.'
  - reference: PMID:24870241
    reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
      proliferation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: patients had normal Ig levels and/or elevated IgG
    explanation: The observation that makes this node necessary. Normal or high total immunoglobulin
      alongside poor specific responses is not explicable by a defect in antibody production in general.
- name: Failure to Control Herpesvirus-Infected B Cells
  role: consequence
  biological_scale: ORGANISM
  description: 'The clinical centre of gravity of the disease. EBV is the pathogen that most stresses the
    capacity this disease removes, because containing it requires a large expansion of EBV-specific CD8
    T cells against a B-cell population that EBV itself drives to proliferate; varicella zoster produces
    a comparable problem by a different route. There is a second, less-appreciated arm: EBV upregulates
    CTPS1 in the B cells it transforms, so the same enzyme is both the host defence bottleneck and a
    dependency of the transformed cell.'
  downstream:
  - target: EBV-driven B-cell lymphoproliferation and lymphoma
    causal_link_type: DIRECT
    description: Uncontrolled proliferation of EBV-infected B cells in the absence of an adequate
      cytotoxic response.
  - target: Severe recurrent herpesvirus infection
    causal_link_type: DIRECT
    description: The clinical manifestation of failed viral control.
  evidence:
  - reference: PMID:31402499
    reference_title: 'Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr
      virus: Lessons from genetic diseases.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved
      in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory
      pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of
      proliferating EBV-infected B cells and the occurrence of lymphoma
    explanation: Places CTPS1 explicitly in the DNA-metabolism class of EBV-susceptibility genes, distinct
      from the activation and co-stimulation classes, and states the mechanism this node asserts.
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Systemic viral infections were seen in all patients, with acute and chronic EBV infections
      in nine patients, four suffering from EBV-driven lymphoproliferative disease (LPD) (two CNS and one
      lung) and one with EBV-driven HLH.
    explanation: The clinical realisation of this node in the largest reported cohort, with the
      proportion affected and the sites involved.
- name: EBV-driven B-cell lymphoproliferation and lymphoma
  role: outcome
  biological_scale: ORGANISM
  description: The malignant end of the failure to control EBV, including central nervous system
    lymphoma. The B cells involved carry the EBV latency III programme, which is the programme in which
    EBV drives CTPS1 expression in the transformed cell.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  downstream:
  - target: EBV-associated lymphoproliferative disease
    causal_link_type: DIRECT
    description: The clinical phenotype this pathophysiology node produces. The two are curated in
      separate sections rather than merged, because renaming either to match would collapse them into
      one node in the flat pathograph namespace.
  evidence:
  - reference: PMID:34281398
    reference_title: Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth
      and Survival.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: While CRISPR CTPS1 knockout caused DNA damage and proliferation defects in lymphoblastoid
      cell lines (LCLs), which express the EBV latency III program observed in CNS lymphomas, double
      CTPS1/2 knockout caused stronger phenotypes.
    explanation: Names the latency programme of the lymphomas that occur in this disease, and shows the
      transformed cells themselves depend on CTPS1 - which is why this node is mechanistically
      interesting rather than merely an outcome.
phenotypes:
- category: Infectious
  name: Severe recurrent herpesvirus infection
  frequency: OBLIGATE
  description: Severe, acute and chronic infection with Epstein-Barr virus and varicella zoster virus,
    presenting in the first decade of life. The bacterial half of the combined picture is curated as its
    own phenotype below, with its own mechanism.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
  evidence:
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Systemic viral infections were seen in all patients
    explanation: Establishes that the viral phenotype was present in every patient of the cohort, which
      is the basis for the OBLIGATE frequency.
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four patients had severe chickenpox.
    explanation: The varicella zoster arm specifically, with the number affected. It is recorded because
      VZV is a leading cause of death in this disease and is easily overshadowed by EBV.
- category: Infectious
  name: Recurrent encapsulated bacterial infection
  frequency: OBLIGATE
  description: Recurrent infection with encapsulated organisms, with low antipneumococcal titres against
    normal or elevated total immunoglobulin. It is the bacterial half of the combined deficiency, and it
    has its own mechanism - the failed T-independent B-cell response - rather than being a consequence
    of the T-cell defect.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:24870241
    reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
      proliferation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients had early onset of severe chronic viral infections, mostly caused by herpes
      viruses, including EBV and Varicella Zooster Virus (VZV) and, also suffered from recurrent
      encapsulated bacterial infections, a spectrum of infections typical of a combined deficiency of
      adaptive immunity (CID)
    explanation: States that all patients had both the viral and bacterial susceptibility, which is the
      basis for the OBLIGATE frequency, and names the combination as what defines a combined deficiency.
  - reference: PMID:32161190
    reference_title: Impaired lymphocyte function and differentiation in CTPS1-deficient patients result
      from a hypomorphic homozygous mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CTPS1-deficient patients display severe bacterial and viral infections.
    explanation: An independent statement of the same combined picture, from the later characterisation
      cohort.
- category: Hematologic
  name: EBV-associated lymphoproliferative disease
  frequency: FREQUENT
  description: Non-malignant and malignant EBV-driven B-cell lymphoproliferation, including central
    nervous system and pulmonary disease, and EBV-driven haemophagocytic lymphohistiocytosis.
  phenotype_term:
    preferred_term: Lymphoproliferative disorder
    term:
      id: HP:0005523
      label: Lymphoproliferative disorder
  evidence:
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: four suffering from EBV-driven lymphoproliferative disease (LPD) (two CNS and one lung) and
      one with EBV-driven HLH
    explanation: Gives the number affected out of eleven, which supports FREQUENT rather than OBLIGATE,
      and names the sites involved.
- category: Immunologic
  name: Impaired lymphocyte proliferative response
  frequency: OBLIGATE
  description: The laboratory hallmark - markedly reduced proliferation of T cells on antigen-receptor
    stimulation, with preserved responses in other assays.
  phenotype_term:
    preferred_term: Decreased antigen-specific T cell proliferation
    term:
      id: HP:0031402
      label: Decreased antigen-specific T cell proliferation
  evidence:
  - reference: PMID:32161190
    reference_title: Impaired lymphocyte function and differentiation in CTPS1-deficient patients result
      from a hypomorphic homozygous mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly
      decreased in all patients
    explanation: The proliferative defect measured in every patient of the characterised cohort, which
      supports the OBLIGATE frequency.
- category: Immunologic
  name: Reduced NK cell number
  frequency: FREQUENT
  description: Low natural killer cell counts, part of the selective pattern of missing innate-like and
    memory compartments.
  phenotype_term:
    preferred_term: Reduced total natural killer cell count
    term:
      id: HP:0040218
      label: Reduced total natural killer cell count
  evidence:
  - reference: PMID:32161190
    reference_title: Impaired lymphocyte function and differentiation in CTPS1-deficient patients result
      from a hypomorphic homozygous mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells,
      and NK cells
    explanation: Names NK cells among the reduced populations.
- category: Gastrointestinal
  name: Chronic diarrhea
  frequency: FREQUENT
  description: Chronic diarrhoea as a presenting feature in nearly half of the transplant cohort. The
    mouse shows intestinal epithelium among the high-turnover tissues that depend on CTPS1, which is a
    plausible but unproven explanation.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Five patients presented with chronic diarrhea.
    explanation: Gives the number affected out of eleven. The source does not attribute the diarrhoea to
      a mechanism, so the link to epithelial turnover suggested in the description is an inference and is
      not claimed as evidenced.
- category: Infectious
  name: Invasive fungal infection
  frequency: VARIABLE
  description: Reported as a presenting feature in one patient, as seronegative mediastinal
    coccidioidomycosis. Recorded because a defect in lymphocyte expansion predicts susceptibility to
    organisms requiring sustained cell-mediated control, and because the seronegativity is itself a
    consequence of the B-cell defect.
  phenotype_term:
    preferred_term: Recurrent fungal infections
    term:
      id: HP:0002841
      label: Recurrent fungal infections
  evidence:
  - reference: PMID:35983265
    reference_title: Seronegative Mediastinal Coccidioidomycosis as a Novel Presentation of CTPS1
      Combined Immunodeficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We describe the first case of cytidine nucleotide triphosphate synthetase 1 (CTPS1)
      deficiency, a combined immunodeficiency impairing lymphocyte proliferation, presenting with
      coccidioidomycosis.
    explanation: A single case report, which is why this phenotype is VARIABLE rather than FREQUENT. It
      is the sole published fungal presentation.
genetic:
- name: CTPS1
  gene_term:
    preferred_term: CTPS1
    term:
      id: hgnc:2519
      label: CTPS1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: All originally reported patients are homozygous for one founder splice variant, c.1692-1G>C
    (p.T566Dfs26X), and share ancestry in north-west England. This is worth keeping in view when reading
    the human evidence, because the reported genotype-phenotype relationship is essentially a
    single-allele observation - allelic series information is absent rather than negative.
  evidence:
  - reference: PMID:32161190
    reference_title: Impaired lymphocyte function and differentiation in CTPS1-deficient patients result
      from a hypomorphic homozygous mutation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous
      frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X).
    explanation: States the single causal allele on which the human description of this disease rests.
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with this mutation all have ancestors from the North West of England
    explanation: Establishes the founder effect, which is why a single allele accounts for the whole
      reported cohort.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: Homozygous CTPS1 loss of function, with heterozygous carrier parents and a shared founder
    haplotype.
  evidence:
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: all the parents were heterozygous carriers
    explanation: States the carrier status of the parents, which is the observation that establishes
      recessive inheritance in this cohort.
animal_models:
- name: Conditional and inducible Ctps1 knockout mouse
  species: Mouse
  genotype: Ctps1 conditional/inducible knockout, alone and combined with Ctps2
  publication: PMID:38438357
  description: 'The model that supplies what the human disease cannot, because no human null exists.
    Complete germline Ctps1 deletion is embryonic lethal, which establishes that a human phenotype
    surviving to childhood must retain some enzyme. Conditional deletion then separates the contributions
    of the two isoforms, and shows that CTPS1 inactivation is immunosuppressive enough to rescue a fatal
    autoimmune model.'
  modeled_mechanisms:
  - target: Failure of Antigen-Driven Lymphocyte Clonal Expansion
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: ORGANISM
    description: Activated lymphocytes and other high-turnover lineages depend on CTPS1 for maintenance
      and growth, reproducing the human proliferative defect.
    limitations: The mouse is a deletion and the human allele retains residual protein, so the mouse
      models a more complete loss than any patient has. The direction of the difference is knowable and
      matters - inferences about severity from mouse to human will overstate.
    readouts:
    - name: Expansion of activated lymphocytes and memory T cells
      target: Failure of Antigen-Driven Lymphocyte Clonal Expansion
      direction: DECREASED
      interpretation: Loss of the populations whose maintenance requires proliferation.
      evidence:
      - reference: PMID:38438357
        reference_title: Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity
          in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: Tissue and cells with high proliferation and renewal rates, such as intestinal
          epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells
          strongly rely on CTPS1 for their maintenance and growth.
        explanation: Reports the affected compartments and the direction of the effect.
  - target: Failure to Expand the CTP Pool on Lymphocyte Activation
    relationship: PERTURBS
    fidelity: HIGH
    model_scale: ORGANISM
    description: Deletion of the enzyme is the perturbation. The model also shows CTPS2 is required
      alongside CTPS1 for proliferation after TCR stimulation, which bounds how much redundancy the
      isoform actually provides.
    limitations: Mouse and human differ in the relative expression of the two isoforms across tissues, so
      the degree of CTPS2 compensation observed in the mouse is not directly transferable.
    readouts:
    - name: T-cell proliferation after TCR stimulation in single and double knockouts
      target: Failure to Expand the CTP Pool on Lymphocyte Activation
      direction: DECREASED
      interpretation: Establishes that redundancy between the isoforms is partial rather than complete.
      evidence:
      - reference: PMID:38438357
        reference_title: Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity
          in mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR
          stimulation.
        explanation: Reports the isoform requirement measured in this model.
  evidence:
  - reference: PMID:38438357
    reference_title: Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in
      mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We report that deletion of Ctps1, but not Ctps2, is embryonic-lethal.
    explanation: The result that establishes what a complete human null would mean, and therefore that
      the human disease must be a partial deficiency. It is the single most important thing this model
      contributes, and the strongest argument in the dispute over what the founder allele does.
treatments:
- name: Allogeneic Haematopoietic Stem Cell Transplantation
  therapeutic_modality: CELL_THERAPY
  description: 'The only intervention that addresses the cause rather than the consequences, by replacing
    the lymphoid compartment with one that has a functioning enzyme. The defect is cell-intrinsic to
    haematopoietic cells and the enzyme is not secreted, so replacing the compartment is curative in
    principle and, in the published series, in practice.

    It is not a benign option, and this record keeps the cost next to the benefit. Overall survival in
    the largest series was 72%, below what the same centres achieve for other combined immunodeficiencies,
    and the deaths were from EBV reactivation and from unusually severe chronic graft-versus-host
    disease. Both failure modes are plausibly consequences of the underlying disease rather than of the
    transplant.'
  treatment_term:
    preferred_term: Hematopoietic cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_mechanisms:
  - target: CTPS1 Loss of Function from a Founder Splice Variant
    description: Replaces the lymphoid compartment with donor cells carrying a functional CTPS1 allele,
      acting at the trigger node rather than downstream of it.
  evidence:
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report on 11 patients with CTPS1 mutations who underwent hematopoietic stem cell
      transplant (HSCT) at three UK centres (London, Manchester and Newcastle).
    explanation: Establishes the size and multi-centre character of the only outcome series that exists
      for this treatment in this disease.
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The overall survival post-HSCT in this series was 72% which is slightly lower than seen
      after HSCT for other combined PIDs.
    explanation: The outcome figure, together with the authors' own comparison against other combined
      immunodeficiencies. It is a retrospective single-arm series with no control group, so it reports
      what happened rather than an effect size.
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: HSCT can be curative but is not without potential risks and complications.
    explanation: The authors' own summary statement, curated in preference to an unqualified claim of
      cure.
- name: Cytidine or CTP Supply Restoration
  therapeutic_modality: SMALL_MOLECULE
  description: 'Supplying the product the missing enzyme cannot make, or its nucleoside precursor, which
    the salvage pathway can convert. This restores proliferation of patient-derived cells in culture.

    It is curated as an experimental rationale rather than an established therapy, because the only
    evidence is in vitro rescue. Whether cytidine can be delivered to activated lymphocytes in vivo at
    the concentrations that work in culture is untested, and no patient has been reported treated this
    way.'
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cytidine
      term:
        id: CHEBI:17562
        label: cytidine
  target_mechanisms:
  - target: Failure to Expand the CTP Pool on Lymphocyte Activation
    description: Bypasses the enzymatic block by supplying the product or a salvageable precursor of it.
  evidence:
  - reference: PMID:24870241
    reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
      proliferation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type
      CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine.
    explanation: The in vitro rescue. It is evidence that the block can be bypassed in principle, and it
      is not evidence of clinical efficacy - no in vivo study exists.
  - reference: PMID:34281398
    reference_title: Epstein-Barr Virus Induced Cytidine Metabolism Roles in Transformed B-Cell Growth
      and Survival.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Cytidine rescued CTPS1/2 deficiency phenotypes in EBV-transformed LCLs and Burkitt B cells,
      highlighting CTPS1/2 as a potential therapeutic target for EBV-driven lymphoproliferative
      disorders.
    explanation: An independent replication of the cytidine rescue in a different cell context. Note the
      paper frames the finding as an argument for inhibiting CTPS1 in lymphoma, which is the opposite
      therapeutic direction from this treatment record.
- name: Rituximab and EBV-Specific Cytotoxic T Lymphocytes for EBV Complications
  therapeutic_modality: OTHER
  description: 'Directed treatment of the EBV-driven complications rather than of the underlying defect.
    B-cell depletion removes the compartment EBV proliferates in, and adoptive transfer of EBV-specific
    cytotoxic T lymphocytes supplies from outside exactly the expanded effector population the patient
    cannot generate. The second of these is mechanistically the most precisely targeted therapy in this
    entry, since it substitutes for the specific failed step.

    Curated at the level the evidence supports: both were used in the transplant series, before and after
    transplant, and no comparative outcome is reported for either.'
  treatment_term:
    preferred_term: Therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_mechanisms:
  - target: Failure to Control Herpesvirus-Infected B Cells
    description: Adoptively transferred EBV-specific cytotoxic T lymphocytes supply the expanded
      virus-specific effector population that the proliferation defect prevents the patient from making.
  evidence:
  - reference: PMID:29884857
    reference_title: Hematopoietic stem cell transplantation for cytidine triphosphate synthase 1 (CTPS1)
      deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Four patients with EBV-driven LPD received rituximab and three EBV-specific cytotoxic
      T-lymphocytes (CTLs) (two pre-transplant and one post-transplant).
    explanation: Records that both were used and in how many patients. The series reports no outcome
      attributable to either, so this is evidence of use rather than of efficacy.
diagnosis:
- name: Lymphocyte proliferation assay with preserved activation markers
  description: The discriminating test. Proliferation on antigen-receptor stimulation is markedly
    reduced while activation signalling and other effector functions are close to normal, which
    distinguishes this from the TCR-signalling combined immunodeficiencies.
  evidence:
  - reference: PMID:24870241
    reference_title: CTP synthase 1 deficiency in humans reveals its central role in lymphocyte
      proliferation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were
      only weakly affected by the absence of CTPS1.
    explanation: States the dissociation between signalling and proliferation on which this diagnostic
      distinction rests.
- name: CTP synthetase activity measurement in stimulated lymphocytes
  description: Direct enzymatic assay of CTPS activity in cell lysates by liquid chromatography tandem
    mass spectrometry, which distinguishes resting from activated cells and detects the failure of the
    activation-induced induction rather than a change in baseline.
  evidence:
  - reference: PMID:31524312
    reference_title: CTP synthetase activity assay by liquid chromatography tandem mass spectrometry in
      the multiple reaction monitoring mode.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Treatment by 3DAU and homozygous mutation in CTPS1 gene abolished the induction of CTPS
      activity associated with cell stimulation
    explanation: Shows the assay detects the specific defect - loss of the activation-induced rise rather
      than loss of baseline activity - in a patient carrying the mutation.
discussions:
- discussion_id: ctps1_allele_null_or_hypomorph
  kind: CONTROVERSY
  prompt: Does the founder allele c.1692-1G>C abolish CTPS1 protein entirely, or leave 10-20% of it?
  attaches_to:
  - pathophysiology#CTPS1 Loss of Function from a Founder Splice Variant
  - genetic#CTPS1
  rationale: 'Two peer-reviewed sources describe the same allele in incompatible terms. The 2018
    transplant series states it produces an abnormal transcript lacking exon 18 and complete absence of
    protein. The 2020 characterisation measured an 80-90% reduction in protein with the residual enzyme
    retaining normal catalytic activity, and showed that restoring expression to wild-type levels
    restores proliferation - which requires that there be a functional protein to restore.

    This entry follows the 2020 reading, for two reasons worth stating rather than assuming. It is a
    direct quantitative measurement made to answer this question, whereas the 2018 statement is a
    background sentence in a transplant outcome paper. And the mouse deletion is embryonic lethal, so a
    genuinely protein-null human would be unlikely to reach the paediatric transplant clinic at all.

    It is not a pedantic distinction. If the allele is null, the human disease is a model of complete
    CTPS1 loss and the mouse lethality becomes a species difference that needs explaining. If it is
    hypomorphic, the human disease is a natural dose-reduction experiment, and it is the only human
    evidence available for what partial CTPS1 inhibition does - which bears directly on the CTPS1
    inhibitors now in clinical development.'
  proposed_experiments:
  - experiment_id: ctps1_allele_protein_quantification
    name: Quantitative immunoblot and transcript analysis of the founder allele in fresh patient cells
    description: Measure CTPS1 protein and the exon-18-skipped transcript in freshly isolated, stimulated
      patient lymphocytes against a standard curve, rather than in transformed or transduced lines, so
      the residual level is established in the cell type the disease is about.
    readouts:
    - name: CTPS1 protein abundance relative to control
      target: pathophysiology#CTPS1 Loss of Function from a Founder Splice Variant
      direction: DECREASED
      interpretation: A measurable residual band settles the question in favour of the hypomorphic
        reading; a true absence would make the mouse lethality a species difference requiring explanation.
- discussion_id: ctps1_allelic_series_absent
  kind: KNOWLEDGE_GAP
  prompt: How much of the described phenotype is specific to the single founder allele, and is the
    immunological defect graded with residual CTPS1 dose or threshold-like?
  attaches_to:
  - genetic#CTPS1
  - pathophysiology#Failure of Antigen-Driven Lymphocyte Clonal Expansion
  rationale: 'Every human observation in this entry derives from one allele, homozygous, on one founder
    haplotype. That is a narrow evidentiary base for a disease description, and no allelic series exists
    to say whether an allele with 40% residual function would be clinically silent. The question has an
    unusually direct practical consequence: CTPS1-selective inhibitors are in clinical development as
    immunosuppressants, and the dose-response of this disease is the closest thing to a human
    dose-finding experiment that exists for that target.'
  proposed_experiments:
  - experiment_id: ctps1_dose_response_series
    name: Graded CTPS1 expression series in primary human T cells
    description: Titrate CTPS1 protein across the range from null to wild type in primary human T cells,
      and measure proliferative capacity and the innate-like and memory differentiation readouts that
      fail in patients, to establish whether the relationship is graded or threshold-like.
    readouts:
    - name: Proliferative capacity as a function of CTPS1 protein level
      target: pathophysiology#Failure of Antigen-Driven Lymphocyte Clonal Expansion
      direction: DECREASED
      interpretation: A threshold rather than a gradient would predict that partial pharmacological
        inhibition is safe up to a sharp point, which is a materially different safety profile from a
        graded one.
- discussion_id: ctps1_target_direction_paradox
  kind: INTERPRETATION
  prompt: How should the evidence base for this disease be read, given that most recent CTPS1 research
    is motivated by inhibiting the enzyme rather than by restoring it?
  attaches_to:
  - treatments#Cytidine or CTP Supply Restoration
  - pathophysiology#Failure to Control Herpesvirus-Infected B Cells
  rationale: 'The disease is a natural experiment that drug discovery has adopted. Because CTPS1
    deficiency is lymphocyte-selective and survivable, CTPS1 is an attractive immunosuppressive and
    anti-lymphoma target, and the isoform-comparison work and the mouse work cited in this entry were
    both done within that programme. That is largely a benefit: the pathway is unusually well
    characterised for an ultra-rare disease. But it has two consequences for reading the evidence.
    Findings are selected for what they say about inhibition rather than about patients, so questions
    that matter clinically - long-term post-transplant outcome, natural history in untreated survivors,
    whether cytidine helps in vivo - are unstudied while the enzymology is very well studied. And the
    same experiment supports opposite therapeutic claims: cytidine rescue is curated here as a rationale
    for supplementation and is presented in its source paper as evidence that CTPS1 is worth blocking.'
notes: 'Boundary with the EBV-susceptibility immunodeficiencies. Several entries in this knowledge base
  describe defects presenting with severe EBV disease, among them the SH2D1A and XIAP forms of X-linked
  lymphoproliferative disease and CD27-related lymphoproliferative disorder. CTPS1 deficiency is grouped
  with them clinically and is mechanistically distinct: those are defects of T-B cell interaction or of
  cytotoxicity, and this is a defect of nucleotide supply that limits expansion. The review cited on the
  herpesvirus control node makes exactly this distinction, placing CTPS1 in a DNA-metabolism category
  separate from the activation and co-stimulation categories.

  On the naming. MONDO carries this as combined immunodeficiency due to CTPS1 deficiency and OMIM lists
  it as immunodeficiency 24. This knowledge base has a series of Immunodeficiency_NN entries, and this
  one deliberately uses the MONDO mechanism-naming form, because the mechanism is the informative part
  of the name here and the number is not.

  A note on one cached reference, because it affects how its snippets should be read. PMID:29884857 is a
  Bone Marrow Transplantation letter with no abstract in PubMed. just fetch-reference recovered its text
  through an institutional repository, so the cached body is an author accepted manuscript embedded in a
  RIS bibliographic export, with the article text duplicated across the N2 and AB fields. That text
  carries manuscript line numbers inline - phrases such as "an affected 39 sibling" and "2 x 106 55
  EBV-CTLs" contain stray line numbers, not data. Every snippet quoted from this reference was chosen to
  avoid those spans. The content is genuine and on topic; the transcription is not clean, and a snippet
  spanning a damaged span would pass exact-match validation while misquoting the published article.

  On the immunoglobulin picture. Patients have normal or elevated total IgG alongside low specific
  antipneumococcal titres. That combination is diagnostically distinctive and is curated on the
  T-independent B-cell node, because it is the observation that rules out a general antibody-production
  defect and points at the failure to mount a new clonal response.

  One apparent tension worth flagging for a reader rather than resolving. PMID:24870241 states that none
  of its patients had extra-haematopoietic manifestations, while the transplant series reports chronic
  diarrhoea in five of eleven. The two are most likely scoping the phrase differently - a gut symptom
  during systemic viral illness is not obviously an extra-haematopoietic manifestation of the genetic
  defect - but neither paper reconciles them and this entry does not either.

  No clinical_trials records are asserted. CTPS1-selective inhibitors are in clinical development, but
  those trials are in lymphoma and autoimmunity rather than in this disease, so they belong to the target
  and not to this entry.'

📚

References & Deep Research

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Combined Immunodeficiency Due to CTPS1 Deficiency · 2026-09-06T08:52:30Z · View source

De novo curation of CTPS1 deficiency, a combined immunodeficiency of nucleotide supply rather than of signalling. One openscientist deep-research run was performed (research/Combined_Immunodeficiency_Due_To_CTPS1_Deficiency-deep-research-openscientist.md; 18/18 references verified, confabulation_rate 0.0, 14 of 18 on topic, 39 of 42 terms verified). The report converged independently on the same key papers found by direct PubMed search, and supplied one lead the search had missed, PMID:29884857 (the HSCT series), which was verified before use. Two curation decisions are worth flagging for review. First, the entry records a CONTROVERSY: PMID:29884857 states the founder allele gives complete absence of protein and PMID:32161190 measured 10-20 percent residual protein with normal per-molecule catalytic activity. Both are curated, the second as SUPPORT and the first as REFUTE against the PARTIAL_LOSS_OF_FUNCTION assignment, so the disagreement stays visible rather than being silently resolved; the mouse embryonic lethality is the tiebreaker argument. Second, PMID:29884857 is an abstract-less Bone Marrow Transplantation letter whose cached body is an author accepted manuscript embedded in a RIS export, with manuscript line numbers bled inline into the text. Snippets were chosen to avoid the damaged spans and notes records this, because a snippet spanning one would pass exact-match validation while misquoting the published article. Three ontology bindings were caught wrong by the term validator before commit: HP:0011840 is Abnormal T cell physiology not Abnormal lymphocyte physiology, HP:0410385 is a memory CD8 term not an NK count term, and CL:0000940 needed its canonical label. Validated: schema, terms, 36/36 snippets, entity refs, causal targets, history.

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Combined Immunodeficiency Due to CTPS1 Deficiency — Comprehensive Disease Report

openscientist-autonomous 15 citations 2026-09-06T08:25:55.964191

Combined Immunodeficiency Due to CTPS1 Deficiency — Comprehensive Disease Report

Disease: Combined Immunodeficiency Due to CTPS1 Deficiency MONDO: MONDO:0014391 · OMIM: #615897 (Immunodeficiency 24) · Orphanet: ORPHA:319391 · Category: Mendelian (autosomal recessive) Causal gene: CTPS1 (HGNC:2519; NCBI Gene 1503; UniProt P17812), chromosome 1p34.2

Summary

Combined immunodeficiency due to CTPS1 deficiency is an ultra-rare autosomal-recessive inborn error of immunity (IEI) first defined in humans in 2014. It is caused by biallelic loss-of-function variants in CTPS1, the gene encoding cytidine-5′-triphosphate synthase 1 — the enzyme that catalyzes the final, rate-limiting step of de novo pyrimidine biosynthesis (the ATP-dependent amination of UTP to CTP). Nearly all reported patients are homozygous for a single recurrent founder splice/frameshift allele (rs145092287; c.1692-1G>C, p.Thr566AspfsTer26), which behaves as a hypomorph that reduces CTPS1 protein and enzymatic activity by 80–90% owing to protein instability rather than loss of intrinsic catalytic function (PMID: 24870241; PMID: 32161190).

The disease is a "metabolic" combined immunodeficiency: the core lesion is an inability of activated T and B lymphocytes to sustain the massive nucleotide demand of clonal proliferation. Resting T cells express little CTPS1, but the enzyme is rapidly upregulated after antigen-receptor engagement; when it is deficient, antigen-driven proliferation collapses while proximal and distal T-cell receptor (TCR) signaling remain largely intact. The immunologic footprint is distinctive — near-absent proliferation and IL-2 secretion after TCR stimulation, combined with selective depletion of proliferation-dependent lineages (mucosal-associated invariant T [MAIT] cells, invariant NKT [iNKT] cells, memory B cells, and NK cells). Clinically, patients present in early childhood with severe, chronic, recurrent herpesvirus infections — especially Epstein–Barr virus (EBV) — recurrent encapsulated-bacterial infections, occasional invasive fungal disease, and a strong predisposition to EBV-driven B-cell lymphoproliferation and lymphoma (PMID: 31402499; PMID: 35983265).

The proliferation defect is metabolically reversible: adding exogenous CTP or its salvageable nucleoside precursor cytidine, or re-expressing wild-type CTPS1, restores normal T-cell proliferation in vitro. Definitive cure is achieved by allogeneic hematopoietic stem cell transplantation (HSCT). The same biology that makes CTPS1 loss immunodeficient makes the enzyme an attractive, isoform-selective drug target: pharmacologic CTPS1 inhibitors (e.g., STP938) are in clinical trials for relapsed/refractory lymphomas, and genetic or chemical CTPS1 inactivation rescues fatal autoimmunity in mouse models — the therapeutic mirror image of the human disease (PMID: 38438357; PMID: 37226519; PMID: 34583994).

Key Findings

Finding 1 — CTPS1 deficiency is an autosomal-recessive combined immunodeficiency caused by loss-of-function CTPS1 variants that cripple lymphocyte proliferation

The founding study used exome sequencing to identify a homozygous loss-of-function variant in CTPS1 as the cause of a novel, life-threatening immunodeficiency. The defining functional abnormality is that antigen-activated T and B cells fail to proliferate, even though proximal and distal TCR signaling are only weakly affected — establishing the disorder as a proliferation-specific (rather than signaling) defect. The causal gene is CTPS1 (HGNC:2519) on chromosome 1p34.2, and the disease is catalogued as OMIM #615897. As stated in the landmark paper, "we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation" (PMID: 24870241).

Finding 2 — Mechanism: CTPS1 is rate-limiting for de novo CTP synthesis and is rapidly upregulated on TCR activation to fuel clonal expansion

CTPS1 catalyzes the ATP-dependent amination of UTP to CTP, the final and rate-limiting step of de novo CTP/pyrimidine synthesis. Activated CTPS1-deficient cells have decreased CTP levels, and the proliferation defect is metabolic and reversible: normal proliferation is restored by re-expressing wild-type CTPS1 or by supplying exogenous CTP or its nucleoside precursor cytidine (via the salvage pathway). Critically, CTPS1 is expressed at low levels in resting T cells but rapidly induced after TCR activation — explaining why the defect is unmasked specifically during the proliferative burst of an adaptive response. The paper reports: "Activated CTPS1-deficient cells had decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation" (PMID: 24870241).

Finding 3 — Immunophenotype: selective loss of MAIT, iNKT, memory B, and NK cells with impaired T-cell proliferation and IL-2 secretion; the founder allele is a hypomorph

Immunophenotyping of a cohort of 7 patients (all homozygous for c.1692-1G>C, p.T566Dfs26X) showed absence or low numbers of MAIT cells, iNKT cells, memory B cells, and NK cells, while other lymphocyte subsets were normal. Proliferation and IL-2 secretion in response to TCR activation were markedly decreased in all patients, whereas other T-cell effector functions were preserved — a pattern that distinguishes this disease from classical SCID (where thymic output itself fails). The molecular basis is a hypomorphic allele: the mutant protein is unstable, giving an 80–90% reduction in protein expression and activity, but the residual protein is catalytically normal when expressed at wild-type levels. Two verbatim statements anchor this: "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"; and "The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients" (PMID: 32161190).

Finding 4 — Clinical presentation: early-onset severe/chronic herpesvirus (especially EBV) infection, encapsulated-bacterial infection, and EBV-driven B-cell lymphoproliferation/lymphoma

CTPS1 deficiency presents in early childhood with severe, recurrent, chronic viral infections — particularly EBV and other herpesviruses (VZV, HSV, CMV) — plus recurrent encapsulated-bacterial infections and a marked predisposition to EBV-associated non-malignant and malignant B-cell lymphoproliferative disorders. CTPS1 is repeatedly listed among the IEIs in which defective antigen-driven T-cell expansion impairs elimination of proliferating EBV-infected B cells. A review of EBV-susceptibility genetics places it precisely: "the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9)" (PMID: 31402499). The infectious spectrum also extends to invasive fungal disease: the first reported case presenting "with coccidioidomycosis" documents "the first case of cytidine nucleotide triphosphate synthetase 1 (CTPS1) deficiency, a combined immunodeficiency impairing lymphocyte proliferation, presenting with coccidioidomycosis" (PMID: 35983265).

Finding 5 — Genetics/epidemiology: ultra-rare recessive disorder driven by a recurrent founder splice variant

The disorder is inherited autosomal-recessively, and reported patients are largely homozygous for a single recurrent founder variant, rs145092287 (c.1692-1G>C, p.T566Dfs26X), whose sharing across unrelated families indicates a founder effect. The disease is ultra-rare (ORPHA:319391; OMIM #615897; MONDO:0014391), with only a few dozen genetically confirmed patients described worldwide since 2014, frequently from consanguineous unions. Consanguinity and parental carrier status are the principal genetic risk context; no environmental risk or protective factors beyond pathogen exposure are established. The founder allele is documented in the discovery paper — "we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans" (PMID: 24870241) — and its precise nomenclature is confirmed in the cohort study as "a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X)" (PMID: 32161190).

Finding 6 — Mouse models: Ctps1 is embryonic-lethal when deleted and is required by high-turnover tissues, activated lymphocytes, and memory T cells

Conditional/inducible mouse studies show that deletion of Ctps1 (but not its paralog Ctps2) is embryonic-lethal, and that high-proliferation/renewal tissues — intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells — strongly depend on CTPS1. Both CTPS1 and CTPS2 are required for TCR-driven T-cell proliferation. These models faithfully recapitulate the human proliferation-dependence of adaptive immunity. As reported: "deletion of Ctps1, but not Ctps2, is embryonic-lethal. Tissue and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells strongly rely on CTPS1 for their maintenance and growth. However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation" (PMID: 38438357).

Finding 7 — Treatment: allogeneic HSCT is curative; CTPS1 inhibition is the therapeutic mirror image

Allogeneic HSCT has been used successfully as definitive, curative treatment by replacing the CTPS1-deficient hematopoietic compartment (PMID: 29884857). Conversely, pharmacologic CTPS1 inhibition is an emerging immunosuppressive/anticancer strategy that harnesses the disease mechanism deliberately. In mice, "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. These findings support that CTPS1 may represent a target for immune suppression" (PMID: 38438357). A clinical-stage selective inhibitor is documented: "de novo CTP synthesis pathway enzyme CTPS1 whose inhibitor (STP938) is already in clinical trials for relapsed/refractory lymphomas (NCT05463263)" (PMID: 37226519).

Finding 8 — CTPS1 is a structurally validated, isoform-selective drug target with a functional confirmatory assay

Cryo-EM structural studies establish the structural basis for isoform-specific (CTPS1 vs CTPS2) small-molecule inhibition (PMID: 34583994), and CTPS activity in patient lymphocytes can be quantified by LC-MS/MS measurement of CTP, providing a functional confirmatory diagnostic assay (PMID: 31524312). Together with the clinical-stage inhibitor STP938 (PMID: 37226519) and mouse rescue-of-autoimmunity data (PMID: 38438357), these establish CTPS1 as a validated, druggable, isoform-selective target — the reverse-translation counterpart of the deficiency.

Detailed Report by Template Section

1. Disease Information

CTPS1 deficiency is a combined (T- and B-cell) immunodeficiency in which activated lymphocytes cannot proliferate adequately because they cannot generate sufficient CTP for the DNA/RNA and phospholipid synthesis of clonal expansion.

Resource	Identifier
MONDO	MONDO:0014391
OMIM	#615897 (Immunodeficiency 24; IMD24)
Orphanet	ORPHA:319391
ICD-10 / ICD-11	D81.8 (other combined immunodeficiencies) / 4A00.1Y
MeSH	closest: "Immunologic Deficiency Syndromes"/"Severe Combined Immunodeficiency" (no dedicated term)
Gene	CTPS1, HGNC:2519; NCBI Gene 1503; Ensembl ENSG00000171793; UniProt P17812; 1p34.2

Synonyms: CTP synthase 1 deficiency; CTP synthetase 1 deficiency; cytidine triphosphate synthase 1 deficiency; Immunodeficiency 24 (IMD24); combined immunodeficiency due to impaired CTP synthesis.

Nature of evidence: aggregated disease-level evidence from published patient case series and mechanistic studies (not routine EHR data). Pivotal cohorts are small individual-patient series (~8 patients in PMID: 24870241; 7 immunophenotyped patients in PMID: 32161190).

2. Etiology

Primary cause (genetic): biallelic loss-of-function CTPS1 variants; almost all patients homozygous for the founder allele c.1692-1G>C (p.T566Dfs26X).
Genetic risk factors: the causal variant itself; consanguinity/carrier parents create the recessive risk context. No GWAS/susceptibility loci (monogenic).
Modifier gene (candidate): CTPS2 (paralog); residual CTPS2 activity plausibly contributes to survival and to the hypomorphic phenotype (inferred from mouse redundancy; PMID: 38438357).
Environmental risk factors: none causal. Pathogen exposure (especially EBV) is the essential trigger that unmasks disease. Sex is not a risk factor (autosomal).
Protective factors: intact salvage pathway (cytidine→CTP) and CTPS2 are compensatory (inferred; salvage rescues the cellular defect in vitro, PMID: 24870241).
Gene–environment interaction: the CTPS1 lesion is clinically silent until a proliferation-demanding challenge occurs; EBV is paradigmatic because it drives B-cell proliferation and requires vigorous CD8⁺ T-cell expansion to control (PMID: 31402499).

3. Phenotypes

Onset is typically early childhood/infancy; severity severe; course chronic/recurrent with acute decompensations. Frequencies are qualitative given small cohorts.

Phenotype	Type	Suggested HPO	Onset	Frequency
Recurrent/chronic viral infection (esp. EBV; also VZV, HSV, CMV)	Infectious sign	HP:0004429; HP:0006515	Infancy–early childhood	Very frequent
Recurrent encapsulated-bacterial infection	Infectious sign	HP:0002718; HP:0002783	Early childhood	Frequent
EBV-driven B-cell lymphoproliferation / lymphoma	Neoplasm	HP:0005523; HP:0002665	Childhood	Frequent predisposition
Impaired T-cell proliferation & ↓IL-2 on TCR stimulation	Laboratory	HP:0002850	Congenital (functional)	Obligate
Low/absent MAIT, iNKT, memory B, NK cells	Laboratory	HP:0011840; HP:0040218	Congenital	Characteristic
Hemophagocytic lymphohistiocytosis (HLH)	Clinical	HP:0003261	Childhood	Occasional
Invasive fungal infection (e.g., coccidioidomycosis)	Infectious sign	HP:0002841	Childhood	Rare/atypical
Failure to thrive / recurrent fever	Symptom/sign	HP:0001508; HP:0011947	Infancy	Frequent

Distinctively, naïve T-cell output/thymic function and proximal TCR signaling are largely preserved, separating this disease from classical SCID (PMID: 24870241; PMID: 32161190). Quality of life: no formal EQ-5D/SF-36/PROMIS data exist; qualitatively the untreated burden is high (recurrent hospitalization, malignancy risk, shortened survival), while successful HSCT can restore substantially normal function.

4. Genetic / Molecular Information

Causal gene: CTPS1 (EC 6.3.4.2), ~591-aa cytosolic enzyme with a glutaminase (GATase) domain and a synthetase/ligase (amidoligase) domain.
Principal variant: NM_001905.4:c.1692-1G>C, p.(Thr566AspfsTer26), rs145092287. Type: splice-acceptor → frameshift → premature stop. Classification: Pathogenic. Consequence: loss of function via protein instability (80–90% ↓ protein/activity), residual protein catalytically normal (PMID: 32161190).
Allele frequency: very rare in gnomAD/dbSNP; no healthy homozygotes.
Origin: germline, autosomal recessive (not somatic).
Functional class: loss of function (hypomorphic); no GOF or dominant-negative.
Modifier genes: CTPS2 (partial redundancy). Epigenetics: none disease-specific (CTPS1 is transcriptionally induced by TCR activation — a regulatory feature, not an epigenetic-disease mechanism). Chromosomal abnormalities: none.

5. Environmental Information

No causal toxic/lifestyle factors. Infectious agents central to clinical expression: EBV/HHV-4 (dominant), other herpesviruses (VZV, HSV, CMV, HHV-6), encapsulated bacteria, and fungi (Coccidioides; PMID: 35983265). These are triggers/opportunists, not the disease cause.

6. Mechanism / Pathophysiology

Ordered causal chain:

Biallelic CTPS1 LOF variant (c.1692-1G>C, p.T566Dfs26X) leads to a frameshifted, unstable protein.
Protein instability results in 80–90% reduced CTPS1 protein/activity (residual protein catalytically normal) (PMID: 32161190).
Reduced activity impairs the rate-limiting de novo step UTP→CTP, causing decreased CTP when demand is high (PMID: 24870241).
Antigen-receptor activation normally triggers rapid CTPS1 upregulation; in deficiency this surge fails, so CTP becomes limiting for DNA/RNA/phospholipid synthesis during clonal expansion (PMID: 24870241).
CTP limitation blocks proliferation of activated T and B cells and reduces IL-2, while proximal/distal signaling and non-proliferative effector functions are preserved (branch: signaling intact, proliferation lost) (PMID: 32161190).
The proliferation block preferentially depletes proliferation-dependent lineages — MAIT, iNKT, memory B, NK cells (PMID: 32161190) (inferred link).
Impaired clonal expansion results in failure to expand EBV-specific CD8⁺ T cells, leading to uncontrolled herpesvirus infection and failure to eliminate EBV-infected proliferating B cells → EBV-driven B-cell lymphoproliferation/lymphoma (PMID: 31402499).
Reversal branch: exogenous CTP/cytidine (salvage) or wild-type CTPS1 rescues proliferation in vitro, and HSCT cures in vivo; pharmacologic CTPS1 inhibition reproduces the block therapeutically (PMID: 24870241; PMID: 29884857; PMID: 38438357).

Detail by category: Pathway — de novo pyrimidine/CTP biosynthesis (KEGG map00240; Reactome nucleotide metabolism), downstream of TCR→PI3K/AKT/mTOR and MYC-driven metabolic reprogramming (MYC positively regulates CTPS1; PMID: 37226519). Cellular process — S-phase/DNA replication and lymphocyte clonal expansion (GO:0006241 CTP biosynthetic process; GO:0044210 de novo CTP biosynthesis; GO:0042098 T-cell proliferation; GO:0042100 B-cell proliferation; GO:0007049 cell cycle). Protein dysfunction — LOF via instability; CTPS tetramerizes/polymerizes into filaments ("cytoophidia"), and an isoform-specific inhibitor pocket has been resolved by cryo-EM (PMID: 34583994). Metabolic change — ↓ intracellular CTP (CHEBI:17677); substrate UTP (CHEBI:15713); precursor cytidine (CHEBI:17562); glutamine (CHEBI:28300). Biochemical assay — reduced CTPS activity by LC-MS/MS CTP quantification (PMID: 31524312). Cell types (CL): CD8⁺ T (CL:0000625), CD4⁺ T (CL:0000624), B/memory B (CL:0000236/CL:0000787), NK (CL:0000623), MAIT (CL:0000940), iNKT (CL:0000921).

7. Anatomical Structures Affected

Organ/system: immune (hematolymphoid) system — bone marrow (UBERON:0002371), thymus (UBERON:0002370), spleen (UBERON:0002106), lymph nodes (UBERON:0000029). Secondary: lung (UBERON:0002048; recurrent pneumonia, mediastinal fungal disease), liver/spleen (EBV disease, HLH), gastrointestinal tract (UBERON:0000160), and any lymphoma site.
Tissue/cell: lymphoid tissue and circulating activated/proliferating lymphocytes; mouse data implicate high-renewal intestinal epithelium and erythroid/thymic lineages (PMID: 38438357).
Subcellular: cytosol (GO:0005829), with downstream demand in the nucleus (DNA replication) and at membranes (phospholipids); CTPS filaments (GO:0097268).
Lateralization: systemic/generalized (not lateralized).

8. Temporal Development

Congenital defect with clinical onset usually in infancy/early childhood, subacute-to-chronic, unmasked by the first significant viral (often EBV) challenge. Course is chronic and relapsing, punctuated by acute potentially fatal episodes (severe herpesvirus infection, HLH, lymphoma); progressive toward life-threatening complications without cure; lifelong unless corrected by HSCT. No formal staging; no spontaneous remission of the underlying defect, but treatment-induced immune reconstitution follows successful HSCT. Critical window: early diagnosis and HSCT before refractory infection/malignancy; uncontrolled pre-transplant infection worsens outcome (PMID: 33462728).

9. Inheritance and Population

Autosomal recessive (OMIM #615897). Ultra-rare (Orphanet prevalence <1/1,000,000; only a few dozen confirmed cases worldwide since 2014). Penetrance for the immunologic defect is high/complete in biallelic LOF individuals, with variable clinical expressivity (onset, infection spectrum, lymphoma/HLH). Founder effect for c.1692-1G>C (rs145092287) across unrelated families (PMID: 24870241; PMID: 32161190); consanguinity frequently contributory. Carrier frequency not precisely established (rare in gnomAD); targeted single-variant carrier testing feasible in founder families. Sex ratio ~1:1; age distribution predominantly pediatric at presentation. No genetic anticipation (not repeat-expansion); germline mosaicism not reported.

10. Diagnostics

Immunology/labs: immunophenotyping shows low/absent MAIT, iNKT, memory B, NK cells with otherwise near-normal subsets; lymphocyte proliferation assays show markedly reduced proliferation and IL-2 on TCR/anti-CD3 stimulation with preserved proximal signaling (PMID: 32161190); CTPS activity assay (LC-MS/MS CTP quantification) is a functional confirmatory biomarker (PMID: 31524312); EBV viral load typically high/persistent.
Genetic testing (definitive): WES or targeted IEI/PIRD NGS panels including CTPS1 are first-line; single-gene/targeted testing for c.1692-1G>C for founder-associated families and cascade testing; WGS for atypical/splice cases. CMA, karyotype, FISH, mtDNA, and repeat-expansion testing are not applicable. CTPS1 is included on international IEI/PIRD panels (PMID: 38644452).
Imaging/pathology: non-specific imaging for infection/lymphoproliferation; biopsy with EBER in situ hybridization/IHC for EBV⁺ B-cell disease; marrow for HLH.
Differential diagnosis: other EBV-susceptibility/CID IEIs — CD27, CD70, RASGRP1, MAGT1 (XMEN), ITK, SH2D1A (XLP1), XIAP, PIK3CD/PIK3R1, CORO1A, STK4, and SCID (PMID: 26424649; PMID: 31402499; PMID: 36209991).
Screening: standard TREC-based newborn SCID screening does not reliably detect CTPS1 deficiency (naïve T-cell output preserved); cascade carrier screening and prenatal/preimplantation testing apply when the variant is known.

11. Outcome / Prognosis

Without curative treatment, prognosis is poor with high risk of death from overwhelming viral infection, HLH, or lymphoma in childhood/adolescence; uncontrolled pre-transplant infection is associated with mortality (5 of 9 IEI children in a pre-HSCT VST series, including CTPS1 patients, died before transplant; PMID: 33462728). Allogeneic HSCT is curative and can restore normal immune function (PMID: 29884857). Prognostic factors: timing of diagnosis/HSCT, infection control at transplant, donor match; EBV load and lymphoproliferation portend worse outcome. No disease-specific validated QoL instruments reported; formal survival statistics not established given rarity.

12. Treatment

Modality	Detail	NCIT
Allogeneic HSCT (curative)	Replaces the CTPS1-deficient hematopoietic compartment; best before refractory infection/malignancy (PMID: 29884857)	C15431 (HSCT); C107137 (allogeneic HSCT)
Supportive pharmacotherapy	Antiviral/antibacterial/antifungal prophylaxis & treatment; immunoglobulin replacement	C578 (IVIG)
EBV-LPD/lymphoma management	Rituximab for EBV⁺ B-cell lymphoproliferation; chemotherapy for lymphoma	C1702 (rituximab)
Adoptive cellular therapy	EBV/virus-specific T cells (VST) as pre-HSCT bridge — limited efficacy once infection prolonged (PMID: 33462728)	—
Metabolic-rationale (experimental)	Cytidine/CTP supplementation rescues proliferation in vitro (proof of concept, not standard) (PMID: 24870241)	—
Reverse-translation	Selective CTPS1 inhibitors (STP938; NCT05463263) treat lymphoma/autoimmunity — not a treatment for the deficiency (PMID: 37226519; PMID: 38438357)	—

Algorithm: diagnose → control infections (antimicrobials ± VST) and manage lymphoproliferation → proceed to allogeneic HSCT as definitive cure. Pharmacogenomics: not applicable.

13. Prevention

Primary: not preventable individually (monogenic); population-level via genetic counseling and carrier/cascade screening in at-risk (often consanguineous) families, with prenatal/PGT options when the familial variant is known.
Secondary: early molecular diagnosis (IEI panels/WES) in children with severe EBV disease/CID; TREC screening does not reliably detect it, so clinical vigilance is essential.
Tertiary: antimicrobial/antiviral prophylaxis, EBV monitoring, avoidance of live vaccines, prompt infection treatment, pre-emptive lymphoproliferation management, timely HSCT.
Immunization: live vaccines contraindicated; inactivated vaccines with caveat of variable responses.
Counseling: autosomal-recessive recurrence risk (25% for carrier couples); cascade relative testing.

14. Other Species / Natural Disease

CTPS1 is evolutionarily conserved. Mouse ortholog Ctps1 (Mus musculus, NCBI:txid10090); paralog CTPS2 conserved across species; CTP synthetase activity is ancient (yeast URA7/URA8, bacterial pyrG). No naturally occurring CTPS1-deficiency disease is described in companion animals or wildlife (no established OMIA phenotype); knowledge derives from humans and engineered models. Complete loss is expected to be lethal across species (consistent with mouse embryonic lethality), so a viable natural analog would require a hypomorphic allele. Not zoonotic (non-infectious genetic disorder).

15. Model Organisms

Mouse (principal model; PMID: 38438357): conditional/inducible Ctps1 (and Ctps2) knockouts and lineage-specific (e.g., T-cell) deletions plus pharmacologic-inhibition models. Ctps1 (not Ctps2) deletion is embryonic-lethal; activated B/T lymphocytes and memory T cells strongly depend on CTPS1, recapitulating the human proliferation defect; T-cell Ctps1 deletion or CTPS1 inhibition rescues Foxp3-deficient mice from fatal autoimmunity and reduces EAE. Limitations: complete null is embryonic-lethal (cannot model constitutive postnatal whole-body loss); human disease is caused by a hypomorphic allele, so conditional/partial models are required; mice are not EBV hosts, so the EBV-specific human disease is not reproduced.
Cellular/in vitro: patient primary lymphocytes; CRISPR CTPS1 knockout in T-cell leukemia/lymphoma lines abolishes proliferation and causes DNA damage (PMID: 32161190; PMID: 37226519); reconstitution and cytidine/CTP-rescue assays; recombinant enzyme for cryo-EM/inhibitor design (PMID: 34583994); engineered Ctps1/Ctps2-knockout CHO auxotroph lines as bioproduction tools (PMID: 35249214).
Resources: MGI (Ctps1), IMPC/IMSR for engineered alleles.

Mechanistic Model / Interpretation

 CTPS1 LoF variant (c.1692-1G>C, p.T566Dfs26X)
    │  (protein instability)
    ▼
 80–90% ↓ CTPS1 protein & activity  ─────────►  residual protein catalytically NORMAL
    │                                     (defect = amount, not intrinsic function)
    ▼
 ↓ de novo CTP synthesis (UTP ─X─► CTP), rate-limiting
    │
   [TCR/BCR activation demands rapid CTPS1 upregulation — cannot occur]
    ▼
 CTP becomes LIMITING during clonal expansion
    │
     ┌──────┴───────────────────────────────┐
     ▼                                        ▼
 Proliferation & IL-2 BLOCKED        Proximal/distal signaling &
 in activated T & B cells            non-proliferative effectors PRESERVED
     │
     ├──► Selective depletion: MAIT, iNKT, memory B, NK cells
     │
     └──► Failure to expand EBV-specific CD8+ T cells
 │
 ▼
      Uncontrolled EBV/herpesviruses ──► EBV-driven B-cell
      + recurrent bacterial/fungal        lymphoproliferation / lymphoma
      infection
 │
 [Metabolic bypass: exogenous cytidine/CTP or WT CTPS1
  RESCUES proliferation in vitro → HSCT cures in vivo;
  CTPS1 inhibitors reproduce the block therapeutically]

The unifying concept is that CTPS1 is a proliferation gatekeeper for adaptive immunity: dispensable for resting-cell metabolism and lymphocyte signaling, but indispensable for the nucleotide-biosynthesis burst that clonal expansion requires. This explains the paradoxical phenotype — near-normal lymphocyte numbers and signaling, but functional collapse of antigen-driven immunity, with the sharpest clinical consequence against EBV, the pathogen whose control most depends on massive CD8⁺ T-cell expansion.

Evidence Base

PMID	Title (abbrev.)	Evidence type	Role
24870241	CTP synthase 1 deficiency reveals central role in lymphocyte proliferation	Human + in vitro	Foundational: causal gene/variant, proliferation defect, CTP↓, cytidine/CTP rescue, TCR-induced upregulation
32161190	Impaired lymphocyte function… hypomorphic homozygous mutation	Human cohort (n=7) + in vitro	Immunophenotype (MAIT/iNKT/memory B/NK loss); hypomorph 80–90% ↓; founder allele nomenclature
38438357	Inactivation of CTPS1 prevents fatal autoimmunity in mice	Mouse	Embryonic lethality; high-turnover tissue dependence; CTPS1/CTPS2 roles; inhibitor rescues autoimmunity
31402499	Signaling pathways in T-cell immunity against EBV	Review	Places CTPS1 among EBV-susceptibility IEIs via defective T-cell expansion
35983265	Seronegative mediastinal coccidioidomycosis in CTPS1 CID	Case report	Expands infectious spectrum to invasive fungal disease
37226519	MYC-induced cytidine metabolism… cGAS-STING in MCL	In vitro/translational	Clinical-stage selective inhibitor STP938 (NCT05463263); MYC→CTPS1
34583994	Structural basis for isoform-specific inhibition of CTPS1	Structural (cryo-EM)	Validates CTPS1 as druggable, isoform-selective target
31524312	CTPS activity assay by LC-MS/MS	Methods	Functional confirmatory assay measuring CTP
29884857	HSCT for CTPS1 deficiency	Clinical	Definitive curative therapy
33462728	Failure of VST pre-HSCT in IEIs	Clinical series	Bridging VST has limited efficacy once infection prolonged
29176466	NGS in a boy with EBV lymphoma — CTPS2 VUS	Case report	Raises CTPS2 as candidate phenocopy
39380841	CTPS1 + ATR inhibition in p53-deficient myeloma	In vitro	Reinforces CTPS1 metabolic-vulnerability biology
25956014	Advances in immunology 2014	Review	Contextualizes CTPS1 among new IEI genes
38644452	PIRD mutation spectrum in Turkey	Cohort/panel	CTPS1 on international IEI/PIRD panels
26424649, 29942301, 36209991	PIDs associated with EBV disease (reviews)	Review	CTPS1 among EBV-LPD-predisposing IEIs

All papers are mutually consistent; none challenges the core model. The clearest independent replications are the founder-allele identity and hypomorphic mechanism across PMID: 24870241 and PMID: 32161190, and the mouse-model corroboration of proliferation-dependence in PMID: 38438357.

Supported vs Refuted Hypotheses

Supported: (i) CTPS1 LOF causes a combined immunodeficiency via impaired de novo CTP synthesis and consequent failure of activated-lymphocyte proliferation (strong: human + in vitro + mouse). (ii) The defect is metabolically bypassable by cytidine/CTP salvage and curable by HSCT (strong). (iii) A single founder splice allele underlies most cases (strong). (iv) Mouse models recapitulate the proliferation-dependent phenotype and reveal CTPS1 as a druggable immunosuppressive target (strong).

Refuted / not supported: the defect is not a proximal TCR-signaling defect (signaling is largely intact) and not a classical thymic-output SCID (naïve T-cell production preserved). No evidence for gain-of-function or dominant-negative action, environmental causation, or chromosomal/epigenetic mechanisms.

Limitations and Knowledge Gaps

Small cohorts / limited allelic diversity. Nearly all human data derive from patients homozygous for a single founder allele; genotype–phenotype consequences of other, non-founder LOF variants are essentially untested.
Epidemiology. No reliable prevalence, incidence, carrier-frequency, or survival statistics; disease known only from case reports and small cohorts.
Quality-of-life / long-term outcome data are absent; no validated instruments applied.
CTPS2 as modifier/phenocopy remains unresolved (the reported CTPS2 VUS is unproven; PMID: 29176466).
Metabolic (cytidine) therapy is supported only by in vitro rescue; no clinical trial in patients.
Model-organism gap: murine null is embryonic-lethal and mice are not EBV hosts, so no model fully reproduces the human EBV-driven disease.
Epigenetics, environmental modifiers, pharmacogenomics are effectively not applicable/not studied for this Mendelian disorder.
No large-scale patient omics (transcriptomic/proteomic/metabolomic) datasets are published.

Proposed Follow-up Experiments / Actions

International genotype–phenotype registry for CTPS1 deficiency to capture non-founder alleles, natural history, HSCT outcomes, and lymphoma incidence.
Functionally characterize additional CTPS1 variants (stability, catalytic activity, CTP rescue) using the LC-MS/MS CTP assay (PMID: 31524312) and cryo-EM-informed structure–function analysis (PMID: 34583994).
Test cytidine/uridine-nucleoside supplementation as adjunctive/bridging therapy in patient cells and, if promising, compassionate-use, building on in vitro rescue (PMID: 24870241).
Optimize HSCT timing/conditioning and define pre-transplant EBV/lymphoma control (including improved VST protocols delivered before prolonged infection) (PMID: 29884857; PMID: 33462728).
Develop humanized/EBV-permissive models (EBV-challenged humanized mice with CTPS1-null lymphocytes) to model the EBV-specific disease and test gene-correction/gene-therapy approaches.
Resolve CTPS2 candidacy through segregation, functional assays, and cohort screening (PMID: 29176466).
Leverage the reverse-translation link: use CTPS1-inhibitor programs (STP938; PMID: 37226519) to refine understanding of on-target immunosuppression, informing drug-safety (drug-induced phenocopy of the deficiency) and precision-immunosuppression opportunities.

Ontology Term Quick-Reference

Disease: MONDO:0014391; OMIM:615897; ORPHA:319391
Gene/protein: HGNC:2519 (CTPS1); UniProt P17812; NCBI Gene 1503
Chemicals (CHEBI): CTP CHEBI:17677; UTP CHEBI:15713; cytidine CHEBI:17562; L-glutamine CHEBI:28300; ATP CHEBI:30616
Biological process (GO): GO:0006241 (CTP biosynthetic process); GO:0044210 (de novo CTP biosynthesis); GO:0042098 (T-cell proliferation); GO:0042100 (B-cell proliferation); GO:0007049 (cell cycle)
Cellular component (GO): GO:0005829 (cytosol); GO:0097268 (cytoophidium/filament)
Cell types (CL): CL:0000625 (CD8⁺ T); CL:0000624 (CD4⁺ T); CL:0000236 (B cell); CL:0000787 (memory B); CL:0000623 (NK); CL:0000940 (MAIT); CL:0000921 (iNKT)
Anatomy (UBERON): UBERON:0002371 (bone marrow); UBERON:0002370 (thymus); UBERON:0002106 (spleen); UBERON:0000029 (lymph node); UBERON:0002048 (lung); UBERON:0000160 (intestine)
Treatment (NCIT): C15431 (HSCT); C107137 (allogeneic HSCT); C1702 (rituximab); C578 (IVIG)

Report compiled from 8 confirmed findings and 22 reviewed papers over 5 investigation iterations. Evidence types span human clinical/cohort, model organism (mouse), in vitro/cellular, structural, and review literature. Key PMIDs cited inline.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	18
Resolved	18
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	18
On topic	14
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	42
Resolved	39
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	3
Terms whose name was checked	24
Terms named correctly	11
Terms named as a different term	7
Terms whose name is worth a second look	6

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0014391 (4 mentions) - the report calls it "MONDO"; MONDO calls it combined immunodeficiency due to CTPS1 deficiency
HP:0002850 (1 mention) - the report calls it "Laboratory"; HP calls it Decreased circulating IgM concentration
HP:0003261 (1 mention) - the report calls it "Clinical"; HP calls it Increased circulating IgA concentration
HP:0002841 (1 mention) - the report calls it "Infectious sign"; HP calls it Recurrent fungal infections
CL:0000625 (2 mentions) - the report calls it "CD8⁺ T"; CL calls it CD8-positive, alpha-beta T cell
CL:0000624 (2 mentions) - the report calls it "CD4⁺ T"; CL calls it CD4-positive, alpha-beta T cell
CL:0000921 (2 mentions) - the report calls it "iNKT"; CL calls it type I NK T cell

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

GO:0044210 (2 mentions) - the report calls it "de novo CTP biosynthesis"; GO calls it 'de novo' CTP biosynthetic process
CL:0000787 (2 mentions) - the report calls it "memory B"; CL calls it memory B cell
CL:0000623 (2 mentions) - the report calls it "NK"; CL calls it natural killer cell, and lists "NK cell" among its other names
CL:0000940 (2 mentions) - the report calls it "MAIT"; CL calls it mucosal-associated invariant T cell, and lists "MAIT" among its other names
GO:0005829 (2 mentions) - the report calls it "Subcellular: cytosol", "cytosol"; GO calls it cytosol**
GO:0097268 (2 mentions) - the report calls it "cytoophidium/filament"; GO calls it cytoophidium

Terms named inconsistently

The report gives these identifiers more than one name of its own:

GO:0005829 - called "Subcellular:** cytosol", "cytosol"

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, OMIM.

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Discussions and Knowledge Gaps

Pathophysiology

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Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Animal Models

Source YAML

References & Deep Research

Deep Research

Combined Immunodeficiency Due to CTPS1 Deficiency — Comprehensive Disease Report

Summary

Key Findings

Finding 1 — CTPS1 deficiency is an autosomal-recessive combined immunodeficiency caused by loss-of-function CTPS1 variants that cripple lymphocyte proliferation

Finding 2 — Mechanism: CTPS1 is rate-limiting for de novo CTP synthesis and is rapidly upregulated on TCR activation to fuel clonal expansion

Finding 3 — Immunophenotype: selective loss of MAIT, iNKT, memory B, and NK cells with impaired T-cell proliferation and IL-2 secretion; the founder allele is a hypomorph

Finding 4 — Clinical presentation: early-onset severe/chronic herpesvirus (especially EBV) infection, encapsulated-bacterial infection, and EBV-driven B-cell lymphoproliferation/lymphoma

Finding 5 — Genetics/epidemiology: ultra-rare recessive disorder driven by a recurrent founder splice variant

Finding 6 — Mouse models: Ctps1 is embryonic-lethal when deleted and is required by high-turnover tissues, activated lymphocytes, and memory T cells

Finding 7 — Treatment: allogeneic HSCT is curative; CTPS1 inhibition is the therapeutic mirror image

Finding 8 — CTPS1 is a structurally validated, isoform-selective drug target with a functional confirmatory assay

Detailed Report by Template Section

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Supported vs Refuted Hypotheses

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Ontology Term Quick-Reference

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver