NIK deficiency is an autosomal recessive combined immunodeficiency caused by biallelic loss-of-function variants in MAP3K14, which encodes NF-kappaB-inducing kinase (NIK). NIK is the apex kinase of the non-canonical NF-kappaB pathway: on engagement of TNF-receptor-superfamily members such as BAFF receptor, CD40 and the lymphotoxin-beta receptor, NIK accumulates, phosphorylates IKK-alpha and drives processing of the NF-kappaB2 precursor p100 to p52, which with RelB activates a distinct set of target genes. Loss of NIK kinase activity abolishes this pathway and, because NIK also feeds the canonical arm, impairs canonical NF-kappaB signalling as well. The human disease has been reported in only a handful of consanguineous families. Affected children present in infancy or early childhood with recurrent, severe bacterial and viral infections, Cryptosporidium infection, and susceptibility to mycobacteria including disseminated BCG disease after vaccination. Immunologically the picture is a combined defect: B-cell lymphopenia with loss of class-switched memory B cells and hypogammaglobulinemia from impaired B-cell survival, normal total T-cell numbers but perturbed follicular helper and memory T cells, and reduced, poorly cytotoxic NK cells. Immunoglobulin levels characteristically show low IgG and IgA with normal or raised IgM, reflecting a class-switch defect. Two features set NIK deficiency apart from most inborn errors of immunity. First, NIK is required not only in haematopoietic cells but in lymph-node and thymic stromal cells, so patients lack peripheral lymph nodes and have a central-tolerance defect that haematopoietic stem cell transplantation cannot repair. Second, transplanted patients achieve donor chimerism and early T-cell reconstitution yet continue to suffer defective memory responses, persistent hypogammaglobulinemia and late immune dysregulation (seropositive arthritis, autoimmune hepatitis), because the stromal and thymic-epithelial defects are not corrected by replacing the haematopoietic compartment. Immunoglobulin replacement is supportive; most reported patients have died of infection despite treatment.
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name: NIK Deficiency
creation_date: "2026-10-25T05:40:00Z"
category: Mendelian
synonyms:
- MAP3K14 deficiency
- NF-kappaB-inducing kinase deficiency
- functional NIK deficiency
description: >-
NIK deficiency is an autosomal recessive combined immunodeficiency caused by
biallelic loss-of-function variants in MAP3K14, which encodes NF-kappaB-inducing
kinase (NIK). NIK is the apex kinase of the non-canonical NF-kappaB pathway: on
engagement of TNF-receptor-superfamily members such as BAFF receptor, CD40 and
the lymphotoxin-beta receptor, NIK accumulates, phosphorylates IKK-alpha and
drives processing of the NF-kappaB2 precursor p100 to p52, which with RelB
activates a distinct set of target genes. Loss of NIK kinase activity abolishes
this pathway and, because NIK also feeds the canonical arm, impairs canonical
NF-kappaB signalling as well.
The human disease has been reported in only a handful of consanguineous families.
Affected children present in infancy or early childhood with recurrent, severe
bacterial and viral infections, Cryptosporidium infection, and susceptibility to
mycobacteria including disseminated BCG disease after vaccination. Immunologically
the picture is a combined defect: B-cell lymphopenia with loss of class-switched
memory B cells and hypogammaglobulinemia from impaired B-cell survival, normal
total T-cell numbers but perturbed follicular helper and memory T cells, and
reduced, poorly cytotoxic NK cells. Immunoglobulin levels characteristically show
low IgG and IgA with normal or raised IgM, reflecting a class-switch defect.
Two features set NIK deficiency apart from most inborn errors of immunity. First,
NIK is required not only in haematopoietic cells but in lymph-node and thymic
stromal cells, so patients lack peripheral lymph nodes and have a central-tolerance
defect that haematopoietic stem cell transplantation cannot repair. Second,
transplanted patients achieve donor chimerism and early T-cell reconstitution yet
continue to suffer defective memory responses, persistent hypogammaglobulinemia and
late immune dysregulation (seropositive arthritis, autoimmune hepatitis), because
the stromal and thymic-epithelial defects are not corrected by replacing the
haematopoietic compartment. Immunoglobulin replacement is supportive; most reported
patients have died of infection despite treatment.
disease_term:
preferred_term: NIK deficiency
term:
id: MONDO:0018642
label: NIK deficiency
parents:
- Combined immunodeficiency
- Inborn error of immunity
classifications:
harrisons_chapter:
- classification_value: IMMUNE_RHEUMATOLOGIC
- classification_value: GENETICS_ENVIRONMENT_DISEASE
iuis_category:
classification_value: combined immunodeficiency
notes: >-
NIK (MAP3K14) deficiency is a non-canonical NF-kappaB-pathway defect classified
among the combined immunodeficiencies affecting cellular and humoral immunity,
alongside the related non-canonical pathway disorders RELB and NFKB2 deficiency.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
Known only from case reports in a small number of consanguineous families since
the first description in 2014; there is no registry or population estimate. The
index pedigree carried a homozygous p.Pro565Arg allele, and a separate South
African family carried a homozygous p.Val345Met allele.
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We studied a large consanguineous pedigree with two patients (termed P1 and P2) who showed signs of combined immunodeficiency"
explanation: >-
The index report establishes the disease in a single consanguineous family,
which with a few later families is the whole epidemiological record.
inheritance:
- name: Autosomal recessive
description: >-
Biallelic loss-of-function variants in MAP3K14, homozygous in the reported
consanguineous families. Heterozygous parents are healthy.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we study patients suffering from recurrent bacterial, viral and Cryptosporidium infections, and identify a biallelic mutation in the MAP3K14 gene encoding NIK"
explanation: >-
The index family carried a biallelic (homozygous) MAP3K14 mutation segregating
with disease.
genetic:
- name: MAP3K14
gene_term:
preferred_term: MAP3K14
term:
id: hgnc:6853
label: MAP3K14
relationship_type: CAUSATIVE
presence: PRESENT
variant_origin: GERMLINE
notes: >-
Reported alleles are homozygous missense variants that destroy NIK kinase
activity: p.Pro565Arg in the index consanguineous pedigree (PMID:25406581,
a residue near the ATP-coordinating centre of the kinase domain) and p.Val345Met
in a South African family (PMID:29230214). Both abolish or severely reduce
phosphorylation of IKK-alpha and processing of p100 to p52.
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a single homozygous variant on chromosome 17q21 in MAP3K14 (c. C1694G, p. Pro565Arg) present in both patients"
explanation: The homozygous p.Pro565Arg allele in the two index patients.
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "As the NIKPro565Arg mutant is catalytically inactive and therefore deleterious to these functions, the phenotype caused by NIKPro565Arg is hereafter also referred to as functional NIK deficiency."
explanation: >-
Functional assays show the patient allele is catalytically dead, establishing
loss of function rather than segregation alone.
variants:
- name: p.Pro565Arg
description: >-
Homozygous MAP3K14 c.1694C>G, p.Pro565Arg in the index consanguineous pedigree.
Pro565 sits near the ATP-coordinating centre of the kinase domain; the
substitution renders NIK catalytically inactive.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "In the NIKwild-type simulation, Pro565 remains buried within the protein in the vicinity of the ATP-coordinating centre"
explanation: A molecular-dynamics simulation locating Pro565 at the kinase ATP-coordinating centre, explaining why its substitution is catalytically deleterious.
- name: p.Val345Met
description: >-
Homozygous MAP3K14 p.Val345Met in a consanguineous South African family;
predicted deleterious and shown in transfected cells to reduce NIK kinase
activity, lowering phospho-IKK-alpha and p52 and raising p100.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:29230214
reference_title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Functional analysis of NIKVal345Met- versus NIKWT-transfected human embryonic kidney-293T cells showed that this mutation significantly affects the kinase activity of NIK leading to decreased levels of phosphorylated IkappaB kinase-alpha (IKKα), the target of NIK."
explanation: Functional confirmation that p.Val345Met reduces NIK kinase activity toward IKK-alpha.
pathophysiology:
- name: Loss of NIK Kinase Activity
biological_scale: MOLECULAR
description: >-
Biallelic MAP3K14 missense variants abolish the kinase activity of NIK, the MAP3
kinase that is the apex of the non-canonical NF-kappaB pathway. Because NIK
normally phosphorylates IKK-alpha, loss of its activity blocks the downstream
step of p100 processing.
genes:
- preferred_term: MAP3K14
term:
id: hgnc:6853
label: MAP3K14
molecular_functions:
- preferred_term: NIK MAP3-kinase activity
term:
id: GO:0004709
label: MAP kinase kinase kinase activity
modifier: DECREASED
genetic_context:
functional_impact_category: LOSS_OF_FUNCTION
variant_origin: GERMLINE
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Loss of kinase activity of mutant NIK, predicted by in silico analysis and confirmed by functional assays, leads to defective activation of both canonical and non-canonical NF-κB signalling."
explanation: Establishes the proximal lesion, loss of NIK kinase activity impairing NF-kappaB signalling.
downstream:
- target: Impaired p100-to-p52 Processing and Non-canonical NF-kappaB Failure
causal_link_type: DIRECT
evidence:
- reference: PMID:11239468
reference_title: "NF-kappaB-inducing kinase regulates the processing of NF-kappaB2 p100."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "NIK induces p100 processing by stimulating site-specific phosphorylation and ubiquitination of this precursor protein."
explanation: NIK is the kinase that drives p100 processing, so loss of NIK activity blocks this step directly.
- name: Impaired p100-to-p52 Processing and Non-canonical NF-kappaB Failure
biological_scale: MOLECULAR
description: >-
Without NIK activity, IKK-alpha is not phosphorylated, p100 accumulates and is
not processed to p52, and unprocessed p100 sequesters RelB. The RelB-p52
transcription factor therefore fails to form and translocate to the nucleus, so
the gene programme downstream of BAFFR, CD40 and the lymphotoxin-beta receptor is
not activated.
biological_processes:
- preferred_term: non-canonical NF-kappaB signal transduction
term:
id: GO:0038061
label: non-canonical NF-kappaB signal transduction
modifier: DECREASED
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Despite p100 accumulation, p52 protein levels were decreased"
explanation: Patient-derived cells accumulate p100 but fail to generate p52, the hallmark of the non-canonical pathway block.
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In line with this, unprocessed p100 is known to specifically sequester and inhibit RelB5, leading to a severe signalling defect."
explanation: Explains why accumulated p100 compounds the defect by sequestering RelB.
downstream:
- target: Impaired B-cell Survival and Maturation
causal_link_type: DIRECT
evidence:
- reference: PMID:12352969
reference_title: "BAFF-induced NEMO-independent processing of NF-kappa B2 in maturing B cells."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "this requires the BAFF receptor (BAFF-R), the NF-kappa B-inducing kinase (NIK) and protein synthesis, but not NEMO. This NEMO-independent cascade is physiologically relevant for the survival and, hence, progression of maturing splenic B cells."
explanation: BAFFR-driven B-cell survival depends on NIK, so loss of NIK impairs B-cell survival and maturation.
- target: Defective T Follicular Helper and Memory T-cell Responses
causal_link_type: DIRECT
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "we hypothesized that NIKPro565Arg causes reduced ICOSL expression leading to impaired TFH generation."
explanation: Non-canonical NF-kappaB controls ICOSL on B cells, which drives TFH differentiation, so its failure impairs TFH responses.
- target: Defective NK-cell Development and Cytotoxicity
causal_link_type: DIRECT
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses."
explanation: Links the signalling defect to the reduced, poorly cytotoxic NK compartment.
- target: Defective Secondary Lymphoid Organ Development
causal_link_type: DIRECT
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the absence of lymph nodes on repeated clinical examinations suggests that secondary lymphoid organs may be disturbed on loss-of-function of NIK, similar to the observations in mouse models"
explanation: The stromal lymphotoxin-beta receptor arm of the pathway also depends on NIK, giving the lymph-node defect.
- target: Defective Thymic Central Tolerance
causal_link_type: DIRECT
evidence:
- reference: PMID:31481626
reference_title: "Medullary thymic epithelial NF-kB-inducing kinase (NIK)/IKKα pathway shapes autoimmunity and liver and lung homeostasis in mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "NIK or IKKα deficiency abrogated medullary TEC development, and led to breakdown of central tolerance, production of autoreactive T cells, and fatal autoimmune destruction in the liver and lung."
explanation: In mice, loss of NIK in thymic epithelial cells abrogates mTEC development and central tolerance, the thymic arm of the non-canonical pathway's role.
- name: Impaired B-cell Survival and Maturation
biological_scale: CELLULAR
description: >-
BAFFR signals needed to mature beyond the transitional B-cell stage run through
NIK, so NIK-deficient B cells survive poorly, remain in a transitional
CD21low/intermediate state, and are progressively lost. Class-switched memory B
cells are severely reduced.
cell_types:
- preferred_term: B cell
term:
id: CL:0000236
label: B cell
biological_processes:
- preferred_term: B cell homeostasis
term:
id: GO:0001782
label: B cell homeostasis
modifier: DECREASED
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival, and impaired ICOSL expression."
explanation: States the B-cell survival and maturation defect directly.
downstream:
- target: Hypogammaglobulinemia with Impaired Class Switching
causal_link_type: DIRECT
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
quote_role: BACKGROUND
snippet: "In addition, non-canonical NF-κB signalling mediated by Nik controls CSR, in particular to IgA isotype"
explanation: >-
Background in the index report, summarising earlier mouse work (it follows the
aly-mutant sentences and cites ref 21), that NIK-driven non-canonical NF-kappaB
controls class-switch recombination, linking the B-cell defect to the
immunoglobulin consequences.
- target: Decreased total B cell count
causal_link_type: DIRECT
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival"
explanation: Impaired B-cell survival produces the B-cell lymphopenia.
- target: Decreased class-switched memory B cell proportion
causal_link_type: DIRECT
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "impaired generation of CD27+IgD− class-switched memory B cells in the peripheral blood"
explanation: The B-cell maturation defect gives the loss of class-switched memory B cells.
- target: Combined immunodeficiency
causal_link_type: DIRECT
- name: Defective T Follicular Helper and Memory T-cell Responses
biological_scale: CELLULAR
description: >-
Total T-cell numbers are normal, but follicular helper T-cell generation and
memory T-cell differentiation are impaired, and CD127 (IL-7 receptor alpha) on
CD8 memory T cells is reduced, mirroring NIK-deficient mice.
cell_types:
- preferred_term: T follicular helper cell
term:
id: CL:0002038
label: T follicular helper cell
biological_processes:
- preferred_term: T follicular helper cell differentiation
term:
id: GO:0061470
label: T follicular helper cell differentiation
modifier: DECREASED
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In summary, NIKPro565Arg patients exhibit defective differentiation into TFH and impaired function of memory T-cell subsets."
explanation: States the TFH and memory T-cell defect directly.
downstream:
- target: Combined immunodeficiency
causal_link_type: DIRECT
- name: Defective NK-cell Development and Cytotoxicity
biological_scale: CELLULAR
description: >-
NK cells are persistently decreased and fail to become activated: patient NK
cells do not accumulate F-actin at the immunological synapse and produce little
interferon-gamma and TNF-alpha on stimulation.
cell_types:
- preferred_term: natural killer cell
term:
id: CL:0000623
label: natural killer cell
biological_processes:
- preferred_term: natural killer cell activation
term:
id: GO:0030101
label: natural killer cell activation
modifier: DECREASED
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patient-derived NK cells failed to accumulate F-actin at the immunological synapse following incubation with susceptible targets"
explanation: Direct evidence of the NK-cell cytotoxicity defect.
downstream:
- target: Reduced total natural killer cell count
causal_link_type: DIRECT
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "NK-cells were persistently decreased in patients carrying NIKPro565Arg."
explanation: The NK developmental defect produces the reduced NK-cell count.
- target: Decreased natural killer cell-induced killing of target cells
causal_link_type: DIRECT
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses."
explanation: The activation defect produces impaired NK-cell killing.
- target: Combined immunodeficiency
causal_link_type: DIRECT
- name: Defective Secondary Lymphoid Organ Development
biological_scale: TISSUE
description: >-
NIK is required in non-haematopoietic lymph-node stromal cells for lymph-node and
Peyer's patch organogenesis, through the lymphotoxin-beta receptor. Loss of NIK
therefore leaves patients without peripheral lymph nodes, a defect that
haematopoietic stem cell transplantation cannot repair.
biological_processes:
- preferred_term: lymph node development
term:
id: GO:0048535
label: lymph node development
modifier: DECREASED
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Lymphoscintigraphy confirmed absence of lymph nodes."
explanation: Direct clinical confirmation of absent lymph nodes in transplanted patients.
downstream:
- target: Lymph node hypoplasia
causal_link_type: DIRECT
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "No palpable lymph nodes were identified on physical examination or visualized by ultrasonography."
explanation: The lymph-node stromal organogenesis defect produces the absent peripheral lymph nodes.
- name: Defective Thymic Central Tolerance
biological_scale: TISSUE
description: >-
NIK is required in medullary thymic epithelial cells for their maturation and for
the establishment of central tolerance. Its loss impairs negative thymic selection,
so autoreactive T cells escape; because the defect is in non-haematopoietic thymic
stroma, haematopoietic stem cell transplantation does not repair it.
cell_types:
- preferred_term: medullary thymic epithelial cell
term:
id: CL:0002365
label: medullary thymic epithelial cell
biological_processes:
- preferred_term: negative thymic T cell selection
term:
id: GO:0045060
label: negative thymic T cell selection
modifier: DECREASED
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Thymic dysfunction was suspected as an underlying contributor to impaired central tolerance in this pathology."
explanation: The human report attributes the central-tolerance defect to thymic dysfunction that HSCT does not repair.
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Our findings indicate that HSCT alone is insufficient to fully correct the immune disorder in MAP3K14 deficiency, likely due to non-hematopoietic defects in lymph node stromal structures and thymic central tolerance."
explanation: Establishes that the thymic central-tolerance defect is non-haematopoietic and HSCT-resistant.
downstream:
- target: Post-transplant Immune Dysregulation and Autoimmunity
causal_link_type: DIRECT
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Immune dysregulation emerged years after HSCT, with one patient developing seropositive arthritis and the other exhibiting autoimmune hepatitis."
explanation: Links the thymic central-tolerance defect to the late autoimmune manifestations after transplant.
- name: Hypogammaglobulinemia with Impaired Class Switching
biological_scale: ORGANISM
description: >-
The B-cell defect produces hypogammaglobulinemia with low IgG and IgA, while IgM
may be normal or raised, reflecting impaired class-switch recombination.
evidence:
- reference: PMID:29230214
reference_title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Decreased IgG and IgA and elevated IgM levels were identified on a single occasion before any treatment was prescribed."
explanation: The class-switch pattern (low IgG/IgA, raised IgM) in the South African patient.
downstream:
- target: Decreased circulating immunoglobulin concentration
causal_link_type: DIRECT
- target: Decreased circulating IgA concentration
causal_link_type: DIRECT
- target: Increased circulating IgM concentration
causal_link_type: DIRECT
evidence:
- reference: PMID:29230214
reference_title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Decreased IgG and IgA and elevated IgM levels were identified on a single occasion before any treatment was prescribed."
explanation: Impaired class switching raises IgM while IgG and IgA fall.
- name: Post-transplant Immune Dysregulation and Autoimmunity
biological_scale: ORGANISM
description: >-
Years after haematopoietic stem cell transplantation, patients develop
autoimmune manifestations attributed to the uncorrected thymic central-tolerance
defect, including seropositive inflammatory arthritis and autoimmune hepatitis.
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In the fourth post-transplant year, patient P1 developed seropositive oligoarticular arthritis (Figure 1B), accompanied by detectable anti-SSA and anti-SSM autoantibodies, despite persistent hypogammaglobulinemia and a paucity of class-switched memory B cells."
explanation: Documents the seropositive arthritis as a post-transplant autoimmune manifestation.
downstream:
- target: Arthritis
causal_link_type: DIRECT
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At 42 months, she developed seropositive inflammatory arthritis involving multiple joints (Figure 1B), resistant to non-steroidal anti-inflammatory drugs (NSAIDs) and steroids, but partially controlled with methotrexate."
explanation: The post-transplant immune dysregulation manifests as seropositive arthritis.
- target: Autoimmune hepatitis
causal_link_type: DIRECT
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At 24 months, he developed ashy dermatosis and later cholestatic hepatitis with positive anti-LKM1 antibodies."
explanation: The post-transplant immune dysregulation manifests as autoimmune hepatitis.
phenotypes:
- category: Immunologic
name: Combined immunodeficiency
description: Defect of both cellular and humoral immunity with increased susceptibility to recurrent, severe infection.
phenotype_term:
preferred_term: Combined immunodeficiency
term:
id: HP:0005387
label: Combined immunodeficiency
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "two patients (termed P1 and P2) who showed signs of combined immunodeficiency including recurrent, severe bacterial and viral infections and Cryptosporidium infection"
explanation: States the combined immunodeficiency presentation.
sequelae:
- target: Recurrent bacterial infections
- target: Recurrent viral infections
- target: Recurrent Cryptosporidium infection
- target: Persistent CMV viremia
- target: BCGosis
- target: Recurrent pneumonia
- target: Pneumocystis jirovecii pneumonia
- target: Chronic diarrhea
- target: Candida esophagitis
- category: Immunologic
name: Recurrent bacterial infections
phenotype_term:
preferred_term: Recurrent bacterial infections
term:
id: HP:0002718
label: Recurrent bacterial infections
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recurrent, severe bacterial and viral infections and Cryptosporidium infection"
explanation: Recurrent severe bacterial infection in the index patients.
- category: Immunologic
name: Recurrent viral infections
phenotype_term:
preferred_term: Recurrent viral infections
term:
id: HP:0004429
label: Recurrent viral infections
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recurrent, severe bacterial and viral infections and Cryptosporidium infection"
explanation: Recurrent viral infection in the index patients.
- category: Immunologic
name: Recurrent Cryptosporidium infection
phenotype_term:
preferred_term: Recurrent Cryptosporidium infection
term:
id: HP:5210120
label: Recurrent Cryptosporidium infection
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recurrent bacterial, viral and Cryptosporidium infections"
explanation: The index report lists Cryptosporidium among the recurrent infections, supporting recurrence.
- category: Immunologic
name: Persistent CMV viremia
phenotype_term:
preferred_term: Persistent CMV viremia
term:
id: HP:0032247
label: Persistent CMV viremia
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "possibly attributable to the persistent cytomegalovirus (CMV) viremia in P1"
explanation: Persistent CMV viremia in the index patient P1.
- category: Immunologic
name: BCGosis
description: Disseminated Bacillus Calmette-Guerin disease after vaccination, reflecting mycobacterial susceptibility.
phenotype_term:
preferred_term: BCGosis
term:
id: HP:0020087
label: BCGosis
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The disseminated Bacillus Calmette–Guérin infection observed in P1 illustrates mycobacterial susceptibility similar to NEMO57 and IKKβ-deficient patients"
explanation: Disseminated BCG disease in the index patient.
- category: Immunologic
name: Decreased total B cell count
description: >-
B-cell lymphopenia was present in the index patients, but it is not universal:
the MAP3K14 p.Val345Met patient had hypogammaglobulinemia with a normal CD19
count.
phenotype_term:
preferred_term: B-cell lymphopenia
term:
id: HP:0010976
label: Decreased total B cell count
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with mutated NIK exhibit B-cell lymphopenia, decreased frequencies of class-switched memory B cells and hypogammaglobulinemia due to impaired B-cell survival"
explanation: B-cell lymphopenia in NIK-deficient patients.
- category: Immunologic
name: Decreased class-switched memory B cell proportion
phenotype_term:
preferred_term: Decreased class-switched memory B cells
term:
id: HP:0030388
label: Decreased class-switched memory B cell proportion
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Accordingly, patients bearing NIKPro565Arg had severely reduced total B-cell counts and impaired generation of CD27+IgD− class-switched memory B cells in the peripheral blood"
explanation: Reduced class-switched memory B cells.
- category: Immunologic
name: Decreased circulating immunoglobulin concentration
description: Hypogammaglobulinemia, characteristically low IgG and IgA with normal or raised IgM.
phenotype_term:
preferred_term: Hypogammaglobulinemia
term:
id: HP:0004313
label: Decreased circulating immunoglobulin concentration
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypogammaglobulinemia due to impaired B-cell survival"
explanation: Hypogammaglobulinemia from impaired B-cell survival.
- category: Immunologic
name: Increased circulating IgM concentration
phenotype_term:
preferred_term: Elevated IgM
term:
id: HP:0003496
label: Increased circulating IgM level
evidence:
- reference: PMID:29230214
reference_title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Decreased IgG and IgA and elevated IgM levels were identified on a single occasion before any treatment was prescribed."
explanation: Elevated IgM with low IgG/IgA in the South African patient.
- category: Immunologic
name: Decreased circulating IgA concentration
phenotype_term:
preferred_term: Decreased IgA
term:
id: HP:0002720
label: Decreased circulating IgA concentration
evidence:
- reference: PMID:29230214
reference_title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Decreased IgG and IgA and elevated IgM levels were identified on a single occasion before any treatment was prescribed."
explanation: Reduced IgA in the South African patient.
- category: Immunologic
name: Reduced total natural killer cell count
phenotype_term:
preferred_term: Decreased NK cells
term:
id: HP:0040218
label: Reduced total natural killer cell count
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "NK-cells were persistently decreased in patients carrying NIKPro565Arg."
explanation: Persistently reduced NK-cell counts.
- category: Immunologic
name: Decreased natural killer cell-induced killing of target cells
phenotype_term:
preferred_term: Impaired NK-cell cytotoxicity
term:
id: HP:0025808
label: Decreased natural killer cell-induced killing of target cells
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Natural killer (NK) cells are decreased and exhibit defective activation, leading to impaired formation of NK-cell immunological synapses."
explanation: Impaired NK-cell killing via defective immunological synapse.
- category: Immunologic
name: Lymph node hypoplasia
description: Absent peripheral lymph nodes, confirmed by examination and lymphoscintigraphy.
phenotype_term:
preferred_term: Absent peripheral lymph nodes
term:
id: HP:0002732
label: Lymph node hypoplasia
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "No palpable lymph nodes were identified on physical examination or visualized by ultrasonography."
explanation: Absent peripheral lymph nodes on examination and imaging.
- category: Immunologic
name: Recurrent pneumonia
phenotype_term:
preferred_term: Recurrent pneumonia
term:
id: HP:0006532
label: Recurrent pneumonia
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In subsequent years Pneumocystis jirovecii pneumonia, aspergillosis, and CMV pneumonitis (P1)"
explanation: Recurrent pneumonia of multiple etiologies in a NIK-deficient patient.
- category: Immunologic
name: Pneumocystis jirovecii pneumonia
phenotype_term:
preferred_term: Pneumocystis jirovecii pneumonia
term:
id: HP:0020102
label: Pneumocystis jirovecii pneumonia
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In subsequent years Pneumocystis jirovecii pneumonia, aspergillosis, and CMV pneumonitis (P1)"
explanation: Pneumocystis jirovecii pneumonia in a NIK-deficient patient.
- category: Digestive
name: Chronic diarrhea
phenotype_term:
preferred_term: Chronic diarrhea
term:
id: HP:0002028
label: Chronic diarrhea
evidence:
- reference: PMID:29230214
reference_title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She presented with severe chronic diarrhea, recurrent lower respiratory tract infections, as well as oral and esophageal candidiasis."
explanation: Severe chronic diarrhea at presentation in the South African patient.
- category: Immunologic
name: Candida esophagitis
phenotype_term:
preferred_term: Esophageal candidiasis
term:
id: HP:0033351
label: Candida esophagitis
evidence:
- reference: PMID:29230214
reference_title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "She presented with severe chronic diarrhea, recurrent lower respiratory tract infections, as well as oral and esophageal candidiasis."
explanation: Oral and esophageal candidiasis in the South African patient.
- category: Immunologic
name: Arthritis
description: Post-transplant seropositive inflammatory arthritis attributed to immune dysregulation.
phenotype_term:
preferred_term: Seropositive inflammatory arthritis
term:
id: HP:0001369
label: Arthritis
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At 42 months, she developed seropositive inflammatory arthritis involving multiple joints (Figure 1B), resistant to non-steroidal anti-inflammatory drugs (NSAIDs) and steroids, but partially controlled with methotrexate."
explanation: Seropositive inflammatory arthritis as a post-transplant manifestation.
- category: Digestive
name: Autoimmune hepatitis
description: Post-transplant cholestatic hepatitis with anti-LKM1 antibodies.
phenotype_term:
preferred_term: Autoimmune hepatitis
term:
id: HP:5210421
label: Autoimmune hepatitis
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "At 24 months, he developed ashy dermatosis and later cholestatic hepatitis with positive anti-LKM1 antibodies."
explanation: Cholestatic hepatitis with anti-LKM1 antibodies, an autoimmune manifestation.
- category: Immunologic
name: Increased total lymphocyte count
description: >-
Paradoxically elevated peripheral lymphocyte counts were reported in the
MAP3K14 p.Val345Met patient, an atypical feature for a combined immunodeficiency.
The mechanism is unexplained, so no upstream pathophysiology node is asserted.
phenotype_term:
preferred_term: Lymphocytosis
term:
id: HP:0100827
label: Increased total lymphocyte count
evidence:
- reference: PMID:29230214
reference_title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "combined immunodeficiency, disseminated BCG-osis, and paradoxically elevated lymphocytes"
explanation: The South African patient had paradoxically elevated peripheral lymphocyte counts.
treatments:
- name: Hematopoietic Stem Cell Transplantation
description: >-
Allogeneic haematopoietic stem cell transplantation has been used as the only
potentially curative treatment and corrects the haematopoietic lymphocyte
defects. However, it does not repair the non-haematopoietic lymph-node stromal
and thymic-epithelial defects, so memory responses, hypogammaglobulinemia and
central tolerance remain incompletely corrected and late immune dysregulation
can emerge.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: allogeneic hematopoietic stem cell transplantation
term:
id: NCIT:C46089
label: Allogeneic Hematopoietic Stem Cell Transplantation
target_mechanisms:
- target: Impaired B-cell Survival and Maturation
description: Donor-derived cells carry functional NIK, partially reconstituting B-cell differentiation, though class-switched memory B cells remain reduced.
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "B-cell reconstitution was incomplete, characterized by persistent hypogammaglobulinemia and a marked deficiency in class-switched memory B cells, despite donor-derived chimerism."
explanation: HSCT acts on the B-cell maturation defect but corrects it only partially, leaving hypogammaglobulinemia and reduced class-switched memory B cells.
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hematopoietic stem cell transplantation (HSCT) has been considered a curative approach, yet its long-term efficacy remains unclear."
explanation: States HSCT as the considered curative approach with uncertain long-term efficacy.
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "allogeneic haematopoietic stem cell transplantation (aHSCT) improved the overall condition of patient P1, suggesting that functional NIK deficiency is amenable to aHSCT to at least partially correct the disease."
explanation: HSCT at least partially corrected the disease in the index patient P1.
- name: Immunoglobulin Replacement Therapy
description: >-
Lifelong intravenous immunoglobulin supplementation is supportive care for the
hypogammaglobulinemia and remains necessary even after transplantation because of
persistent antibody deficiency.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: intravenous immunoglobulin therapy
term:
id: NCIT:C121331
label: Intravenous Immunoglobulin Therapy
therapeutic_agent:
- preferred_term: human immunoglobulin G
term:
id: NCIT:C80829
label: Human Immunoglobulin G
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Despite complete donor chimerism, IgG levels and switched memory B cells remained low, requiring ongoing IVIG."
explanation: Immunoglobulin replacement remained necessary despite transplantation.
diagnosis:
- name: Molecular genetic testing for biallelic MAP3K14 variants
description: >-
Diagnosis rests on finding biallelic loss-of-function MAP3K14 variants, since the
combined immunodeficiency with normal or raised lymphocyte counts and the atypical
infection spectrum (BCG, Cryptosporidium) overlap with other inborn errors of
immunity. Exome sequencing identified the causal variant in both reported families.
presence: PRESENT
evidence:
- reference: PMID:29230214
reference_title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This study describes the use of exome sequencing to identify a homozygous recessive variant in MAP3K14, NIKVal345Met, in a patient with combined immunodeficiency, disseminated BCG-osis, and paradoxically elevated lymphocytes."
explanation: Exome sequencing established the molecular diagnosis in the South African patient.
- name: Functional non-canonical NF-kappaB pathway testing
description: >-
Supportive functional evidence comes from showing defective p100-to-p52 processing
and reduced RelB nuclear translocation in patient cells on stimulation of BAFFR,
CD40 or the lymphotoxin-beta receptor.
presence: PRESENT
evidence:
- reference: PMID:25406581
reference_title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "resulting in a severely reduced nuclear content of p52 and a lower nuclear content of RelB in patient-derived cells"
explanation: Patient cells show the defective non-canonical NF-kappaB readout used to confirm the functional defect.
discussions:
- discussion_id: gap_nik_anti_ifn_autoantibodies
prompt: >-
Do NIK-deficient patients develop neutralizing anti-type-I-interferon
autoantibodies, as reported after transplantation in the related non-canonical
NF-kappaB disorder RELB deficiency?
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- pathophysiology#Post-transplant Immune Dysregulation and Autoimmunity
rationale: >-
PMID:41280889 could not evaluate anti-type-I-IFN autoantibodies in its NIK
patients but recommends screening for them, because such autoantibodies arise
after HSCT in RELB deficiency and would explain persistent viral susceptibility
despite immune reconstitution. No NIK-deficient patient has yet been tested, so
this is an open question rather than a curated mechanism.
evidence:
- reference: PMID:41280889
reference_title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This should include regular screening for anti-type I IFN autoantibodies to identify patients at risk for delayed infectious complications."
explanation: The human report recommends screening for these autoantibodies, which have not yet been evaluated in NIK deficiency.
animal_models:
- name: aly/aly mouse (spontaneous Nik point mutation)
species: Mouse
genotype: Nik aly/aly (C-terminal point mutation, autosomal recessive)
publication: PMID:10319865
description: >-
The alymphoplasia (aly) mouse carries a spontaneous point mutation in the
C-terminal interaction domain of Nik and is the classic model of the disease. It
lacks all lymph nodes and Peyer's patches, has disorganized splenic and thymic
architecture, and is immunodeficient; transgenic wild-type Nik restores these
structures.
modeled_mechanisms:
- target: Defective Secondary Lymphoid Organ Development
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: Reproduces the systemic absence of lymph nodes and Peyer's patches and disorganized spleen and thymus.
limitations: >-
The aly allele is a hypomorphic C-terminal point mutation in the mouse ortholog
rather than a human kinase-domain missense variant, and the mouse lacks all
lymph nodes whereas the human stromal defect is inferred clinically; species
differences in lymphoid organogenesis limit direct translation.
evidence:
- reference: PMID:10319865
reference_title: "Alymphoplasia is caused by a point mutation in the mouse gene encoding Nf-kappa b-inducing kinase."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "The alymphoplasia (aly) mutation of mouse is autosomal recessive and characterized by the systemic absence of lymph nodes (LN) and Peyer's patches (PP) and disorganized splenic and thymic structures with immunodeficiency."
explanation: Establishes the aly mouse as the Nik-mutant model of absent lymphoid organs and immunodeficiency.
- name: TEC-specific Nik knockout mouse
species: Mouse
genotype: Thymic-epithelial-cell-specific Nik ablation
publication: PMID:31481626
description: >-
Mice with NIK ablated specifically in thymic epithelial cells fail to develop
medullary thymic epithelial cells, break central tolerance, and develop fatal
autoimmune destruction, modelling the thymic central-tolerance arm of the human
disease.
modeled_mechanisms:
- target: Defective Thymic Central Tolerance
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: TISSUE
description: TEC-specific loss of NIK abrogates medullary TEC development and central tolerance, producing autoreactive T cells.
limitations: >-
The model is a conditional tissue-specific knockout rather than the germline
biallelic hypomorphic state of patients, and the fatal early autoimmunity is
more severe and earlier than the human phenotype.
evidence:
- reference: PMID:31481626
reference_title: "Medullary thymic epithelial NF-kB-inducing kinase (NIK)/IKKα pathway shapes autoimmunity and liver and lung homeostasis in mice."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "NIK or IKKα deficiency abrogated medullary TEC development, and led to breakdown of central tolerance, production of autoreactive T cells, and fatal autoimmune destruction in the liver and lung."
explanation: Shows that thymic-epithelial NIK loss breaks central tolerance, the mechanism behind the human autoimmune features.
references:
- reference: PMID:25406581
title: "Biallelic loss-of-function mutation in NIK causes a primary immunodeficiency with multifaceted aberrant lymphoid immunity."
- reference: PMID:29230214
title: "Exome Sequencing Identifies a Novel MAP3K14 Mutation in Recessive Atypical Combined Immunodeficiency."
- reference: PMID:41280889
title: "Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development."
notes: >-
No GeneReviews chapter exists for NIK/MAP3K14 deficiency (checked via the Bookshelf
index and PubMed genereviews[book] on the disease name and synonyms). The entry is
built from the three human reports (PMID:25406581, PMID:29230214, PMID:41280889) and
the mouse mechanistic literature. No ClinGen Gene-Disease Validity assertion is
cached for MAP3K14-NIK deficiency.
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.
Create: NIK Deficiency (MAP3K14) · 2026-10-25T05:47:11Z · View source
Created kb/disorders/NIK_Deficiency.yaml for NIK (MAP3K14) deficiency (MONDO:0018642), an autosomal recessive combined immunodeficiency from biallelic loss-of-function variants abolishing non-canonical NF-kappaB signaling. Curated from the three human reports (PMID:25406581 index p.Pro565Arg family; PMID:29230214 South African p.Val345Met; PMID:41280889 long-term HSCT outcomes) plus mechanistic mouse literature (PMID:10319865 aly mouse, PMID:11239468 p100 processing, PMID:12352969 BAFF/NIK B-cell survival, PMID:31481626 TEC-specific Nik). An 8-node causal pathograph runs from loss of NIK kinase activity through the p100-to-p52 block to B-cell, TFH, NK, and lymphoid-stromal defects and post-transplant autoimmunity; two mouse models linked via modeled_mechanisms. 20 phenotypes, 2 variants, 2 treatments, 2 diagnosis entries. Deep-research requested via falcon with --fallback (no EDISON_API_KEY); it fell back to openscientist, whose report was still running at write time. Validated: just validate (51 snippets, 54 titles, 0 issues), validate-terms, check-entity-refs, check-causal-targets, check-duplicate-keys, check-enum-values, check-coarse-phenotypes, check-qualifier-terms, check-delivery-system, check-genereviews (NO_CHAPTER confirmed).
NIK Deficiency is an ultra-rare, autosomal-recessive combined primary immunodeficiency caused by biallelic loss-of-function mutations in MAP3K14 (HGNC:6853; NCBI Gene 9020; OMIM *604655; Ensembl ENSG00000006062; UniProt Q99558; chr17q21.31), the gene encoding NIK (NF-κB–inducing kinase). NIK is the apical, rate-limiting kinase of the non-canonical (alternative) NF-κB pathway. Disease arises when both alleles carry a kinase-inactivating mutation, abolishing NIK's ability to drive IKKα-mediated processing of the NF-κB2 precursor p100 into active p52, and consequently crippling RelB/p52-dependent transcription. Because NIK also feeds forward into prolonged canonical NF-κB signaling, patients have defects in both arms of the pathway.
The clinical consequence is a multifaceted combined immunodeficiency. The index report (Willmann et al. 2014, PMID: 25406581) described patients with recurrent bacterial, viral, and Cryptosporidium infections, who exhibited B-cell lymphopenia, decreased class-switched memory B cells, hypogammaglobulinemia, impaired ICOSL expression, perturbed follicular-helper (Tfh) and memory T cells, and decreased/defective NK cells with impaired immunological-synapse formation. The disease belongs to a tightly related family of non-canonical NF-κB inborn errors of immunity (alongside NFKB2, RELB, and CHUK/IKKα defects) that share a striking predisposition to neutralizing autoantibodies against type I interferon.
NIK deficiency sits at the loss-of-function pole of a bidirectional, dose-dependent NIK disease axis: too little NIK produces immunodeficiency, while excess NIK activity drives autoimmunity, cancer, sterile inflammation, fibrosis, and metabolic disease (Valiño-Rivas et al. 2019, PMID: 30926358). Diagnosis currently rests on functional validation of kinase activity because no pathogenic MAP3K14 variants are deposited in ClinVar, and the gene is strongly loss-of-function–intolerant in the general population (gnomAD pLI ≈ 1.0) yet the disease is recessive. Allogeneic hematopoietic stem cell transplantation (HSCT) can reconstitute the hematopoietic immune compartment but does not repair the radioresistant stromal/thymic architectural defects, so lifelong immunologic and anti-cytokine autoantibody surveillance is required (Köstel Bal et al. 2025, PMID: 41280889).
This report synthesizes 8 confirmed findings across 34 reviewed papers into a comprehensive disease-knowledge-base entry covering all 15 requested domains. Where primary human data are sparse (reflecting the extreme rarity of the disorder), mechanism is supported by an extensive murine and in vitro literature, and these evidence levels are flagged throughout.
Willmann et al. (2014) identified a biallelic mutation in MAP3K14 (NIK) in patients presenting with recurrent bacterial, viral, and Cryptosporidium infections. The mutation abolishes NIK kinase activity, which was "predicted by in silico analysis and confirmed by functional assays" and "leads to defective activation of both canonical and non-canonical NF-κB signalling" (PMID: 25406581). The immunological phenotype is broad and spans all three major lymphocyte lineages: B-cell lymphopenia, decreased class-switched memory B cells, hypogammaglobulinemia (reflecting impaired B-cell survival), impaired ICOSL expression, perturbed Tfh and memory T-cell compartments, and decreased/defective NK cells with impaired immunological-synapse formation. This single landmark paper establishes the causal gene, the recessive (biallelic) inheritance, and the core molecular lesion — loss of NIK kinase activity — that defines the disease.
Evidence level: Human clinical + in vitro functional assay.
NIK (MAP3K14) is normally held at vanishingly low levels by constitutive degradation through the TRAF2–TRAF3–cIAP1/2 ubiquitin-ligase complex. Engagement of TNF-receptor-superfamily receptors — BAFFR, CD40, LTβR, RANK, and Fn14 — triggers TRAF3 degradation, which stabilizes and allows NIK to accumulate. Accumulated NIK phosphorylates IKKα, which in turn phosphorylates NF-κB2/p100, driving its proteasomal processing to p52 and the nuclear translocation of RelB/p52 heterodimers. Senftleben et al. (2001) established the kinase hierarchy: "IKKalpha is required for B cell maturation, formation of secondary lymphoid organs, increased expression of certain NF-kappaB target genes, and processing of the NF-kappaB2 (p100) precursor. IKKalpha preferentially phosphorylates NF-kappaB2, and this activity requires its phosphorylation by upstream kinases, one of which may be NF-kappaB-inducing kinase (NIK)" (PMID: 11520989). Dash et al. (2020) showed in multiple myeloma that lower TRAF3 expression and higher NIK expression mark pathway activation (PMID: 32350909). In NIK-deficient patients, kinase-dead NIK abolishes p100→p52 processing, collapsing the entire downstream axis.
Evidence level: In vitro / model organism (mechanistic hierarchy); human (disease relevance).
The spontaneous alymphoplasia (aly/aly) mouse carries a loss-of-function point mutation in Nik/Map3k14 and displays absence of lymph nodes and Peyer's patches, disrupted lymphoid architecture, and impaired B-cell formation and immunoglobulin production. Ozcan et al. (2026) summarize: "NIK deficiency causes loss of lymph nodes, disruption of lymphoid organ structure and deficits in B-cell formation and immunoglobulin production" (PMID: 42175627). Conditional deletion of NIK in adult mice reduces B-cell populations and germinal-center B cells and abrogates BAFF responses: "Germline deletion or inactivation of NIK in mice results in the defective development of B cells and secondary lymphoid organs" (Brightbill et al. 2015, PMID: 26116508). NIK additionally supports medullary and cortical thymic-epithelial-cell development (Eshima et al. 2020, PMID: 32145062) and has a cell-intrinsic role in effector/memory T-cell generation (Li et al. 2016, PMID: 26912039). The murine models thus faithfully reproduce the B-cell, secondary-lymphoid-organ, and thymic-architectural defects seen in patients.
Evidence level: Model organism (mouse).
Crystal structures of the apo NIK catalytic domain (both human and murine) reveal an active-like conformation in the absence of phosphorylation. de Leon-Boenig et al. (2012) report: "Structures of the apo NIK kinase domain from both species reveal an active-like conformation in the absence of phosphorylation. ATP consumption and peptide phosphorylation assays confirm that phosphorylation of NIK does not increase enzymatic activity" (PMID: 22921830). The active site is narrow with a flexible gatekeeper residue. This structural biology explains two important facts about the disease: (1) NIK is regulated primarily by protein abundance (stabilization), not by activation-loop phosphorylation, so loss-of-function in disease is achieved by missense mutations that destroy catalytic competence or protein stability rather than by blocking an activating phosphorylation; and (2) the well-defined ATP pocket has enabled structure-based inhibitor design (Li et al. 2013, PMID: 23374866), relevant to the gain-of-function end of the disease axis.
Evidence level: Computational/structural + in vitro biochemistry.
Human inborn errors of the non-canonical NF-κB axis — NFKB2 (p100), RELB, CHUK/IKKα, and MAP3K14/NIK — produce overlapping combined immunodeficiency with hypogammaglobulinemia. A clinically important shared feature is neutralizing autoantibodies against type I interferon. Riller et al. (2025) reported that IKKα (CHUK) kinase-domain–deficient patients have diminished non-canonical (and partially impaired canonical) NF-κB with "neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies" (PMID: 39812688). RelB deficiency likewise "disrupts the non-canonical NF-κB pathway, underlying a T- and B cell immunodeficiency, which, together with neutralizing autoantibodies against type I IFNs" (Moriya 2026, PMID: 42261849). Consistent with membership in this family, the NIK-deficiency HSCT follow-up study emphasized monitoring for anti-cytokine autoantibodies (PMID: 41280889). This predisposition likely reflects failure of central/peripheral tolerance mechanisms that depend on non-canonical NF-κB (AIRE-dependent medullary thymic epithelial cell function).
Evidence level: Human clinical (family of disorders).
NIK sits at the center of a bidirectional, dose-dependent disease axis. Valiño-Rivas et al. (2019) frame NIK as the apical non-canonical NF-κB kinase whose disease spectrum "now ranges from immunodeficiency (when NIK is defective) to autoimmunity, cancer, sterile inflammation, fibrosis, and metabolic disease when NIK is overactive" (PMID: 30926358). NIK deficiency occupies the loss-of-function pole. The physiological processes placed at risk by NIK loss are enumerated by Liu et al. (2019): "The non-canonical NF-κB signalling cascade is essential for lymphoid organogenesis, B cell maturation, osteoclast differentiation, and inflammation in mammals" (PMID: 30894749). NIK also drives prolonged canonical NF-κB via IKKα/β in endothelium (Kucharzewska et al. 2019, PMID: 30837284), explaining the combined-pathway defect. TRAF2, the upstream NIK regulator, stimulates NK-cell cytotoxicity (Albini et al. 2025, PMID: 40229245), consistent with the NK defect observed in patients.
Evidence level: Review synthesis + model organism + human.
Programmatic verification established: MAP3K14 = HGNC:6853, NCBI Gene 9020, OMIM *604655, Ensembl ENSG00000006062, UniProt Q99558, cytoband 17q21.31, GRCh38 chr17:45,263,119–45,317,112 (minus strand), RefSeq NM_003954.5. A ClinVar query (MAP3K14[gene]) returned 30 variant records, all classified VUS or Likely benign (e.g., p.Ser97Ter VUS; p.Val828fs VUS); zero Pathogenic/Likely-pathogenic entries. The disease-causing biallelic kinase-domain variants described in patients are not deposited in ClinVar as pathogenic. This is a critical practical point: a clinical diagnosis cannot currently rely on a ClinVar pathogenicity lookup and must instead be anchored by functional kinase-activity assays, exactly as in the index report where pathogenicity was "predicted by in silico analysis and confirmed by functional assays" (PMID: 25406581).
Evidence level: Database verification (computational) + human.
gnomAD constraint metrics for MAP3K14 (GRCh38) are: pLI = 1.00, observed/expected LoF = 0.16 (LOEUF 90% CI 0.11–0.24), LoF Z = 7.09, missense Z = 5.21 — indicating strong depletion of both predicted-LoF and missense variation in the general population. The apparent paradox — a haploinsufficiency-intolerant gene causing a recessive disease — is resolved by the biology: heterozygous carrier parents are clinically unaffected (Willmann et al. 2014, PMID: 25406581), so the immunodeficiency requires biallelic loss, while the high population constraint likely reflects strong selection against loss in combination with the fact that NIK overactivity (the other pole of the axis) is also deleterious — tight dosage control is evolutionarily favored in both directions.
Evidence level: Population genetics (computational) + human.
Overview. NIK deficiency is a Mendelian, autosomal-recessive combined primary immunodeficiency / inborn error of immunity caused by biallelic loss-of-function mutations in MAP3K14, which encodes NF-κB–inducing kinase (NIK). The disorder produces a multifaceted defect of lymphoid immunity affecting B cells, T cells, and NK cells, together with structural defects of secondary lymphoid organs and thymic epithelium, clinically manifesting as recurrent bacterial, viral, and Cryptosporidium infections.
Key identifiers.
| Resource | Identifier |
|---|---|
| MONDO | MONDO:0018642 |
| Causal gene | MAP3K14 (NIK) |
| HGNC | HGNC:6853 |
| NCBI Gene | 9020 |
| Gene OMIM | *604655 |
| Disease OMIM | Not recorded |
| Ensembl | ENSG00000006062 |
| UniProt | Q99558 |
| Cytoband | 17q21.31 |
| RefSeq transcript | NM_003954.5 |
| ICD-10 / ICD-11 | No specific code; best coded under combined immunodeficiency (ICD-10 D81.-; ICD-11 4A00.-) |
Synonyms / alternative names. MAP3K14 non-severe combined immunodeficiency; non-severe combined immunodeficiency caused by mutation in MAP3K14; primary immunodeficiency with multifaceted aberrant lymphoid immunity; NIK deficiency.
Source of information. The disease-level knowledge is derived from a small number of individual patient reports (index family, Willmann et al. 2014; HSCT long-term follow-up, Köstel Bal et al. 2025) supplemented by aggregated gene/variant resources (OMIM, ClinVar, gnomAD) and an extensive model-organism and in vitro mechanistic literature. There is no large aggregated clinical registry given the disorder's rarity.
Primary cause — genetic. Biallelic loss-of-function mutations in MAP3K14 abolishing NIK kinase activity (F001). The index variant was a kinase-domain mutation confirmed functionally (PMID: 25406581).
Genetic risk factors. The disease is monogenic and fully penetrant with biallelic LoF; there is no evidence for susceptibility loci or modifier genes in humans (too few patients). Carrier status (heterozygous) confers no known clinical risk. Consanguinity is a strong contextual risk factor as for most ultra-rare recessive disorders.
Environmental / infectious contributors. Environmental factors do not cause the disease but act as the trigger for clinical presentation: encapsulated bacteria, herpesviruses (e.g., CMV), and the opportunistic protozoan Cryptosporidium are the organisms that exploit the immune defect. Cryptosporidium infection with potential hepatobiliary involvement is a hallmark that overlaps with other T-cell/combined immunodeficiencies.
Protective factors. None specific are documented. In principle, a functional second MAP3K14 allele (heterozygosity) is fully protective, consistent with recessive inheritance (F008).
Gene–environment interactions. The core interaction is permissive: the genetic lesion removes host defense, and environmental pathogen exposure determines the timing, severity, and organ pattern of disease. No classical GxE modifier data exist.
Phenotypes are drawn primarily from the index clinical report (F001) and HSCT follow-up (F005). Frequencies are qualitative given the tiny cohort.
| Phenotype | Type | HPO suggestion | Onset | Severity | Frequency |
|---|---|---|---|---|---|
| Recurrent bacterial infections | Clinical sign | HP:0002718 | Childhood | Severe | Characteristic |
| Recurrent viral infections (incl. CMV) | Clinical sign | HP:0004429 | Childhood | Severe | Characteristic |
| Chronic Cryptosporidium diarrhea | Clinical sign | HP:0002028 (chronic diarrhea) | Childhood | Severe | Characteristic |
| Sclerosing cholangitis / hepatobiliary involvement | Clinical/laboratory | HP:0100792 | Childhood | Severe | Reported |
| B-cell lymphopenia | Laboratory abnormality | HP:0010976 | Congenital/early | Severe | Consistent |
| Hypogammaglobulinemia | Laboratory abnormality | HP:0002720 | Early | Moderate–severe | Consistent |
| Decreased class-switched memory B cells | Laboratory abnormality | HP:0005404 | Early | Severe | Consistent |
| Decreased/defective NK cells | Laboratory abnormality | HP:0040218 | Early | Moderate–severe | Consistent |
| Perturbed Tfh / memory T cells | Laboratory abnormality | HP:0005415 (abnormal T-cell count) | Early | Moderate | Consistent |
| Impaired NK immunological synapse | Cellular phenotype | — | — | — | In vitro |
| Predisposition to anti–type I IFN autoantibodies | Laboratory abnormality | HP:0002960 (autoimmunity) | Variable | Variable | Shared-family feature |
Quality-of-life impact. Chronic/recurrent infections and chronic diarrhea with hepatobiliary disease substantially impair growth, nutrition, and daily functioning. No formal EQ-5D/SF-36/PROMIS data exist for this ultra-rare disorder.
Causal gene. MAP3K14 / NIK (identifiers in Section 1; F007).
Pathogenic variants. The index disease allele is a kinase-domain mutation causing loss of NIK catalytic activity, validated functionally (F001). No pathogenic or likely-pathogenic MAP3K14 variants are currently in ClinVar (30 records, all VUS/likely-benign; F007). Variant classes expected to cause disease: missense within the kinase domain (as in the index case), and in principle nonsense, frameshift, and splice-site biallelic LoF alleles. All are germline. Functional consequence: loss of function (kinase-dead), impairing both non-canonical and canonical NF-κB (F001, F006).
Allele frequency / constraint. MAP3K14 is strongly LoF-intolerant: pLI = 1.00, o/e LoF = 0.16 (LOEUF 0.11–0.24), LoF Z = 7.09, missense Z = 5.21 (gnomAD; F008). Disease-causing alleles are private/ultra-rare.
Modifier genes / epigenetics / chromosomal abnormalities. No human modifier genes, disease-specific epigenetic marks, or chromosomal abnormalities are documented for NIK deficiency. (Note: in cancers, non-canonical NF-κB activation can occur via MAP3K14 dysregulation — e.g., S100A14/UPF1-mediated stabilization of MAP3K14/NFKB2/RELB transcripts, PMID: 42350366 — but this is the opposite, gain-of-activity pole and not the inherited deficiency.)
Ordered causal chain (initiating lesion → clinical manifestation):
Molecular pathways (Reactome/KEGG): Non-canonical NF-κB signaling (Reactome R-HSA-5676590); canonical NF-κB; TNF-receptor-superfamily signaling.
Cellular processes & GO terms: NIK/NF-κB-inducing kinase activity (GO:0004704 MAP kinase kinase kinase activity); positive regulation of NF-κB transcription factor activity (GO:0051092); B-cell homeostasis (GO:0001782); lymph node development (GO:0048535); I-κB kinase/NF-κB signaling (GO:0007249).
Protein dysfunction: Loss of kinase function in an otherwise constitutively active-like kinase domain regulated by abundance (F004, PMID: 22921830).
Immune system involvement: Combined immunodeficiency (B, T, NK) plus autoimmune/tolerance predisposition (F005).
Molecular profiling: In myeloma, low TRAF3 + high NIK expression mark pathway activation (PMID: 32350909) — a useful readout of the axis, though from the opposite (gain) pole.
Upstream vs downstream: Mutation (upstream) → NIK kinase failure → IKKα → p100/p52 (midstream) → RelB/p52 transcriptional programs in B cells, stroma, TECs, T cells, NK cells (downstream) → clinical infection susceptibility.
Diagnostic approach. Because no pathogenic MAP3K14 variants are catalogued in ClinVar (F007), diagnosis rests on a combination of genetic sequencing + functional validation:
Differential diagnosis: Other combined immunodeficiencies and CVID-spectrum disorders, especially the related non-canonical NF-κB IEIs (NFKB2, RELB, CHUK/IKKα) and other causes of chronic Cryptosporidium infection (e.g., CD40L deficiency, IL-21R deficiency PMID: 33966600, DOCK8 deficiency PMID: 41695074). Distinguishing feature: combined B/T/NK defect with absent secondary lymphoid organs and NIK functional defect.
Screening: Not part of standard newborn screening (which detects T-cell lymphopenia via TRECs; NIK deficiency may be TREC-variable). Cascade/carrier testing in affected families is appropriate once the variant is known.
| Model | Type | Genetic basis | Phenotype recapitulation | Reference |
|---|---|---|---|---|
| aly/aly mouse | Mammalian, spontaneous | Nik/Map3k14 LoF point mutation | Absent LN/Peyer's patches, disrupted lymphoid architecture, impaired B-cell/Ig production | PMID: 42175627 |
| Germline NIK KO | Mammalian, knockout | Full Nik deletion/inactivation | Defective B-cell development and secondary lymphoid organs | PMID: 26116508 |
| Conditional/adult NIK deletion | Mammalian, conditional | Inducible/tissue-specific | Reduced mature B cells and germinal-center B cells; abrogated BAFF responses | PMID: 26116508 |
| T-cell–conditional NIK KO | Mammalian, conditional | T-cell-specific Nik deletion | Reduced effector/memory T cells; impaired infection response; EAE-resistant | PMID: 26912039 |
| aly/aly thymic epithelium | Mammalian | Nik LoF | Abnormal cortical/medullary TEC development | PMID: 32145062 |
Recapitulation & limitations. Mouse models faithfully reproduce the B-cell, secondary-lymphoid-organ, and thymic-architectural features of human disease and were instrumental in defining the pathway. Limitations: murine models may not capture the human anti–type I IFN autoantibody predisposition or the full NK-cell/Cryptosporidium susceptibility, and species differences in immune architecture mean phenotype severity does not map 1:1. Resources: MGI (mouse), with aly/aly as the canonical strain.
Biallelic MAP3K14 LoF mutation
│ (kinase-dead NIK; functionally confirmed)
▼
TNFRSF ligation (BAFFR/CD40/LTβR/RANK/Fn14)
normally stabilizes NIK via TRAF3 degradation
│ ── but kinase-dead NIK cannot act ──
▼
NIK fails to phosphorylate IKKα
▼
IKKα fails to phosphorylate p100 (NFKB2)
▼
p100 NOT processed to p52 ──► no nuclear RelB/p52
│ │
│ └── (also: impaired sustained canonical NF-κB)
▼
┌─────────┬─────────┬─────────┬─────────┬─────────────┐
▼ ▼ ▼ ▼ ▼ ▼
Stroma/ B cells T cells NK cells Tolerance Combined
TEC (inferred) two-pathway
│ │ │ │ │ defect
absent LN/ B-lympho- impaired defective anti-IFN-α
Peyer's, penia, effector/ NK + autoAb
disrupted low memory memory, impaired predisposition
thymus B, hypo- Tfh dys- synapse
gammaglob function
└─────────┴─────────┴─────────┴─────────┴─────────────┘
▼
Recurrent bacterial, viral (CMV), and Cryptosporidium
infections; chronic diarrhea; sclerosing cholangitis
The bidirectional dosage axis (F006) frames NIK deficiency as one pole of a continuum:
| NIK activity | Consequence | Example conditions |
|---|---|---|
| Loss (this disease) | Immunodeficiency | NIK deficiency; aly/aly mouse |
| Normal | Balanced lymphoid development & immunity | — |
| Overactive | Autoimmunity, cancer, fibrosis, bone loss, metabolic disease | Myeloma, RA synovium, osteoporosis, neointimal hyperplasia |
This dosage logic explains the paradox of a recessive disease in a highly LoF-constrained gene (F008): evolution selects against both loss and excess, favoring tight control.
| PMID | Title (abbrev.) | Evidence type | Role |
|---|---|---|---|
| 25406581 | Biallelic LoF mutation in NIK causes PID | Human clinical + in vitro | Defining paper — causal gene, inheritance, core defect (F001) |
| 11520989 | Activation by IKKα of second NF-κB pathway | In vitro / mouse | NIK→IKKα→p100/p52 hierarchy (F002) |
| 26116508 | Conditional NIK deletion disrupts B cells | Mouse | B-cell/lymphoid organ recapitulation (F003) |
| 42175627 | Adipocyte NIK depletion... (states aly/aly phenotype) | Mouse | Lymphoid architecture summary (F003) |
| 32145062 | NIK in cortical thymic epithelial cells | Mouse | Thymic epithelial defect (F003) |
| 26912039 | Cell-intrinsic NIK in T cells | Mouse | T-cell effector/memory defect (F003) |
| 22921830 | Crystal structure of NIK catalytic domain | Structural/in vitro | Active-like, abundance-regulated kinase (F004) |
| 23374866 | NIK inhibitor design, co-crystals | Structural/in vitro | Druggable pocket (F004) |
| 39812688 | IKKα kinase-domain mutations | Human clinical | Anti-IFN-α autoAb in family (F005) |
| 42261849 | Inborn errors in NF-κB pathway (RELB) | Human clinical | Family-shared T/B defect + anti-IFN (F005) |
| 41280889 | Long-term HSCT outcome in NIK deficiency | Human clinical | Treatment; architectural limits; autoAb monitoring |
| 30926358 | NIK as druggable mediator of tissue injury | Review | Bidirectional dosage axis (F006) |
| 30894749 | NIK-SIX axis / non-canonical NF-κB | Review/mechanism | Core physiological functions lost (F006) |
| 30837284 | NIK-IKK in endothelium | In vitro | NIK's canonical-pathway role (F006) |
| 32350909 | Non-canonical NF-κB in myeloma | Human (cancer) | TRAF3-low/NIK-high readout (F002) |
| 40229245 | TRAF2 in inflammation/cancer | Review | TRAF2–NIK regulation; NK cytotoxicity (F006) |
Supporting/context papers (gain-of-function pole, differentials): PMID: 32169603 (NIK inhibitor, bone), PMID: 42350366 (CRC S100A14/MAP3K14), PMID: 33966600 (IL-21R differential), PMID: 41695074 (DOCK8 differential), PMID: 31709944 (Cryptosporidium context).
Report compiled from 8 confirmed findings and 34 reviewed papers over 5 completed investigation iterations. Evidence levels (human clinical / model organism / in vitro / computational) are flagged per finding. NIK deficiency is caused by biallelic loss-of-function mutations in MAP3K14 encoding NF-κB–inducing kinase (NIK).
Checked with linkml-reference-validator 0.4.0.
| Outcome | Count |
|---|---|
| References checked | 21 |
| Resolved | 21 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 0 |
| References weighed for topical relevance | 21 |
| On topic | 16 |
| Off topic | 0 |
All extracted references resolved successfully.
Checked with linkml-term-validator 0.4.5, through the ols: adapter.
| Outcome | Count |
|---|---|
| Terms checked | 33 |
| Resolved | 30 |
| Unresolved (possible confabulation) | 0 |
| Obsolete | 2 |
| Unverifiable | 1 |
| Terms whose name was checked | 15 |
| Terms named correctly | 5 |
| Terms named as a different term | 9 |
| Terms whose name is worth a second look | 1 |
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:0018642 (2 mentions) - the report calls it "MONDO"; MONDO calls it NIK deficiencyHP:0002718 (1 mention) - the report calls it "Clinical sign"; HP calls it Recurrent bacterial infectionsHP:0004429 (1 mention) - the report calls it "Clinical sign"; HP calls it Recurrent viral infectionsHP:0100792 (1 mention) - the report calls it "Clinical/laboratory"; HP calls it AcantholysisHP:0010976 (1 mention) - the report calls it "Laboratory abnormality"; HP calls it Decreased total B cell countHP:0002720 (1 mention) - the report calls it "Laboratory abnormality"; HP calls it Decreased circulating IgA concentrationHP:0005404 (1 mention) - the report calls it "Laboratory abnormality"; HP calls it Increased total B cell countHP:0040218 (1 mention) - the report calls it "Laboratory abnormality"; HP calls it Reduced total natural killer cell countHP:0005415 (1 mention) - the report calls it "abnormal T-cell count"; HP calls it Decreased total CD8+ T cell proportionThese terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:
GO:0004704 (obsolete NF-kappaB-inducing kinase activity) (1 mention)GO:0051092 (obsolete positive regulation of NF-kappaB transcription factor activity) (1 mention)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:
UBERON:0001211 (1 mention) - the report calls it "Peyer's patches / gut-associated lymphoid tissue"; UBERON calls it Peyer's patch, and lists "aggregated lymphoid nodule" among its other names