An inborn error of immunity attributed to haploinsufficiency of IVNS1ABP, which encodes the influenza virus NS1A-binding protein (NS1-BP), a BTB-Kelch protein that co-regulates mRNA splicing and nuclear export. The reported patients share severe warts and a distinctive naive T cell surface phenotype. The most important thing to say about this entry is how thin its evidence base is, and the entry is written around that rather than around a mechanism it cannot support. The gene-disease relationship rests on a single publication: a whole-genome sequencing study of 1,318 participants with primary immunodeficiency, in which a Bayesian association method flagged IVNS1ABP as a candidate. The signal is three independent heterozygous protein-truncating variants with none in controls, and the authors then did the work that turns a statistical hit into a claim - they confirmed roughly 50% protein, noted the gene's loss-of-function intolerance, and found a shared clinical and immunophenotypic picture across the three patients. That is a good-quality candidate-gene result. It is not a replicated disease description. There is no second cohort, no ClinGen gene-disease validity assertion, and no Orphanet record. The posterior probability of association the method itself reported was 0.33, which the entry records verbatim rather than paraphrasing as "supported", because a reader judging this evidence needs the number rather than an adjective. What the entry therefore does: it curates the human observations that were made, grades the mechanism as unestablished, and separates the rich non-disease literature on what NS1-BP does molecularly from the question of what its loss does to the immune system. No causal edge is drawn from the molecular function to the immune phenotype, because nobody has drawn one.
Ask a research question about Immunodeficiency 70. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
Conditions with similar clinical presentations that must be differentiated from Immunodeficiency 70:
name: Immunodeficiency 70
creation_date: "2026-09-11T21:00:00Z"
category: Mendelian
disease_term:
preferred_term: immunodeficiency 70
term:
id: MONDO:0033542
label: immunodeficiency 70
synonyms:
- IMD70
- IVNS1ABP haploinsufficiency
- NS1-BP haploinsufficiency
description: >-
An inborn error of immunity attributed to haploinsufficiency of IVNS1ABP, which encodes
the influenza virus NS1A-binding protein (NS1-BP), a BTB-Kelch protein that co-regulates
mRNA splicing and nuclear export. The reported patients share severe warts and a
distinctive naive T cell surface phenotype.
The most important thing to say about this entry is how thin its evidence base is, and
the entry is written around that rather than around a mechanism it cannot support.
The gene-disease relationship rests on a single publication: a whole-genome sequencing
study of 1,318 participants with primary immunodeficiency, in which a Bayesian
association method flagged IVNS1ABP as a candidate. The signal is three independent
heterozygous protein-truncating variants with none in controls, and the authors then
did the work that turns a statistical hit into a claim - they confirmed roughly 50%
protein, noted the gene's loss-of-function intolerance, and found a shared clinical and
immunophenotypic picture across the three patients.
That is a good-quality candidate-gene result. It is not a replicated disease
description. There is no second cohort, no ClinGen gene-disease validity assertion, and
no Orphanet record. The posterior probability of association the method itself reported
was 0.33, which the entry records verbatim rather than paraphrasing as "supported",
because a reader judging this evidence needs the number rather than an adjective.
What the entry therefore does: it curates the human observations that were made, grades
the mechanism as unestablished, and separates the rich non-disease literature on what
NS1-BP does molecularly from the question of what its loss does to the immune system.
No causal edge is drawn from the molecular function to the immune phenotype, because
nobody has drawn one.
parents:
- Inborn Errors of Immunity
prevalence:
- population: UK sporadic primary immunodeficiency cohort (NIHR BioResource, 886 index cases)
measure_type: CASES_IN_LITERATURE
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
Three patients, all from the single cohort in which the gene was identified. No
prevalence estimate exists. The denominator is worth keeping in view: three carriers
among 886 index cases in one national referral cohort, which is a rate within that
cohort and not a population figure.
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BeviMed enrichment (PPA=0.33) of IVNS1ABP was driven by three independent
heterozygous protein-truncating variants, suggesting haploinsufficiency, while no
such variants were observed in controls
explanation: >-
Gives the patient count and the cohort context, and states the posterior probability
of association, which is the number a reader needs to weigh this evidence.
pathophysiology:
- name: Heterozygous IVNS1ABP Protein-Truncating Variant
role: trigger
biological_scale: MOLECULAR
description: >-
Three independent heterozygous protein-truncating variants, none seen in controls.
The variants are heterozygous and the inferred mechanism is haploinsufficiency rather
than dominant-negative action, which matters because it predicts that any truncating
allele should behave alike.
genetic_context:
variant_origin: GERMLINE
zygosity: HETEROZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
BeviMed enrichment (PPA=0.33) of IVNS1ABP was driven by three independent
heterozygous protein-truncating variants, suggesting haploinsufficiency, while no
such variants were observed in controls
explanation: >-
The allele class and zygosity, with the case-control contrast.
downstream:
- target: NS1-BP Haploinsufficiency
causal_link_type: DIRECT
description: >-
A truncating allele in a loss-of-function-intolerant gene halves protein dose.
- name: NS1-BP Haploinsufficiency
role: mechanism
biological_scale: MOLECULAR
description: >-
The core molecular claim, and the one part of this disease's mechanism that was
measured rather than inferred: patient peripheral blood mononuclear cells carry about
half the normal amount of IVNS1ABP protein. Two independent lines support treating
this as pathogenic rather than tolerated - the direct protein measurement, and the
gene's population-level intolerance to loss of function (pLI = 0.994).
Note what does not follow. Halving the protein is established; which of NS1-BP's
molecular activities becomes limiting at half dose is not, and no dose-response
experiment has been reported.
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
IVNS1ABP protein expression was around 50% of control, consistent with
haploinsufficiency
explanation: >-
The direct measurement of protein dose in patient cells.
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
directness: INDIRECT
evidence_source: COMPUTATIONAL
snippet: >-
A pathogenic role for IVNS1ABP was supported by its intolerance to loss-of-function
(pLI=0.994)
explanation: >-
Population constraint metrics are a computed prediction from reference sequencing
data, not an observation in these patients, so this is graded COMPUTATIONAL and
INDIRECT. It supports the haploinsufficiency interpretation by an inference step.
downstream:
- target: Aberrant Naive T Cell Surface Phenotype
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Typed with unknown intermediates deliberately. The two observations are associated
in three patients; no experiment connects reduced NS1-BP dose to the surface
phenotype.
- target: Susceptibility to Cutaneous HPV Disease
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Likewise an association rather than a demonstrated causal chain.
- name: Aberrant Naive T Cell Surface Phenotype
role: mechanism
biological_scale: CELLULAR
description: >-
The immunological finding shared by all three patients: low or normal CD4+ T cell and
B cell numbers, with increased CD127 (IL-7 receptor alpha) and PD-1 on naive T cells.
Worth reading carefully, because it is not the usual picture. The cell counts are
essentially unremarkable - the authors say "low/normal" - so this is not a
lymphopenia. What is abnormal is the surface phenotype of cells that are present, and
on naive cells specifically, where raised PD-1 is not expected. The authors describe
it as previously undescribed.
cell_types:
- preferred_term: naive T cell
term:
id: CL:0000898
label: naive T cell
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The patients also shared a previously undescribed peripheral leukocyte phenotype –
with low/normal CD4+ T cells and B cells and aberrant increased expression of CD127
and PD-1 on naïve T cells
explanation: >-
The immunophenotype itself, including the authors' own hedge on cell counts
("low/normal") which is why this entry does not curate lymphopenia.
- name: Susceptibility to Cutaneous HPV Disease
role: outcome
biological_scale: ORGANISM
description: >-
The clinical convergence across the three patients, and the observation the authors
singled out as the distinctive shared feature.
Severe warts in an immunodeficiency point at a defect in keratinocyte-intrinsic or
T-cell-mediated control of human papillomavirus, which is the pattern seen in several
established inborn errors of immunity. Whether IVNS1ABP belongs in that group
mechanistically is not established; the entry records the phenotype and the
resemblance without asserting the mechanism.
cell_types:
- preferred_term: keratinocyte
term:
id: CL:0000312
label: keratinocyte
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a distinctive clinical similarity between the patients – all had severe warts
explanation: >-
The clinical convergence, in three of three patients.
phenotypes:
- category: Dermatologic
name: Severe Cutaneous Warts
frequency: OBLIGATE
severity: SEVERE
description: >-
Present in all three reported patients and the feature that made them recognisable as
a group. Graded OBLIGATE on three of three, which is a small denominator - the grading
reflects the reported series rather than an established penetrance.
phenotype_term:
preferred_term: Verrucae
term:
id: HP:0200043
label: Verrucae
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
a distinctive clinical similarity between the patients – all had severe warts
explanation: >-
States the finding and that it was present in all patients.
- category: Immunologic
name: Aberrant CD127 and PD-1 Expression on Naive T Cells
frequency: OBLIGATE
description: >-
Increased CD127 and PD-1 on naive T cells, shared by all three patients and described
by the authors as previously undescribed.
This is bound to a broad HP term because the ontology has none for this specific
surface-marker combination. The specificity is carried by preferred_term and by the
description, which is the documented convention when the best available term is
broader than the finding.
phenotype_term:
preferred_term: Increased CD127 and PD-1 expression on naive T cells
term:
id: HP:0031392
label: Abnormal CD4+ T cell subset proportion
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
aberrant increased expression of CD127 and PD-1 on naïve T cells
explanation: >-
The surface phenotype itself.
notes: >-
The binding is imperfect and is recorded as such rather than silently. HP:0031392
describes an abnormal CD4+ T cell subset proportion; what was observed is an abnormal
activation-marker profile on naive T cells, which is a related but distinct claim. No
HPO term covers it. Following the ontology-term contract in CLAUDE.md, the broader
term is bound and the precision is kept in preferred_term rather than a narrower term
being manufactured.
genetic:
- name: IVNS1ABP
gene_term:
preferred_term: IVNS1ABP
term:
id: hgnc:16951
label: IVNS1ABP
relationship_type: CAUSATIVE
notes: >-
IVNS1ABP encodes NS1-BP, a BTB-Kelch family protein first identified through its
interaction with the influenza A virus NS1 protein. It has an N-terminal BTB/POZ
domain and five kelch-like tandem repeats.
Three candidate cellular activities are described, in three separate literatures that
have not met. Two are in mRNA processing: with hnRNP K it regulates splicing, and it
competes with viral NS1 for the mRNA export receptor NXF1 to route transcripts out of
the nucleus. The third is cytoskeletal - Kelch-family proteins associate with F-actin,
and rat macrophage work links Ivns1abp to phagocytosis and to macrophage phenotype
under inflammatory conditions.
The third is the most immunologically plausible of the three, since actin defects are
an established class of inborn errors of immunity, but it is also the least directly
evidenced for this protein: the F-actin statement is a background claim about the
Kelch family rather than a measurement of NS1-BP itself, and the functional work is in
rat. None of the three has been connected to the patients' phenotype.
Two cautions about how this gene's literature reads. First, most of the 31 indexed
IVNS1ABP papers concern influenza virology or cancer biology rather than immunity, so
a literature search on the gene symbol returns a great deal that is not about this
disease. Second, relationship_type is recorded as CAUSATIVE because that is what the
reporting study concludes, but the underlying evidence is a single cohort with a
posterior probability of 0.33 plus functional follow-up. There is no ClinGen
gene-disease validity assertion and no Orphanet record for this entity. A reader
should weigh the relationship as a well-supported candidate rather than as an
established one; the dismech schema has no slot in which to record that distinction,
which is why it is stated here in prose.
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Taken together, these data implicate IVNS1ABP haploinsufficiency as a novel
monogenic cause of PID
explanation: >-
The authors' own conclusion, quoted with its framing ("implicate", "novel")
preserved rather than restated as an established fact.
- reference: PMID:29921878
reference_title: "Co-regulatory activity of hnRNP K and NS1-BP in influenza and human mRNA splicing."
supports: NO_EVIDENCE
evidence_source: IN_VITRO
snippet: >-
Additionally, we show that hnRNP K and NS1-BP regulate host splicing events and that
viral infection causes mis-splicing of some of these transcripts.
explanation: >-
Establishes that NS1-BP regulates host mRNA splicing, which is the best available
candidate for what is lost at half dose. Graded NO_EVIDENCE with respect to the
gene-disease claim deliberately: this paper is about NS1-BP's cell biology in an
influenza context and says nothing about immunodeficiency, so it bears on what the
protein does, not on whether its loss causes this disease.
- reference: PMID:39384042
reference_title: "Cellular NS1-BP protein interacts with the mRNA export receptor NXF1 to mediate nuclear export of influenza virus M mRNAs."
supports: NO_EVIDENCE
evidence_source: IN_VITRO
snippet: >-
NS1-BP competes with NS1 for NXF1 binding, allowing the recruitment of NXF1 to the M
mRNAs after splicing.
explanation: >-
The second characterised activity, mRNA nuclear export via NXF1. Graded NO_EVIDENCE
for the same reason as above - it is background on the protein, not evidence about
the disease, and marking it SUPPORT would imply a mechanistic link to the immune
phenotype that nobody has shown.
- reference: PMID:9696811
reference_title: "NS1-Binding protein (NS1-BP): a novel human protein that interacts with the influenza A virus nonstructural NS1 protein is relocalized in the nuclei of infected cells."
supports: NO_EVIDENCE
evidence_source: IN_VITRO
snippet: >-
NS1-BP contains an N-terminal BTB/POZ domain and five kelch-like tandem repeat
elements of approximately 50 amino acids.
explanation: >-
The original identification of the protein, establishing the domain architecture the
three candidate activities are attributed to. NO_EVIDENCE with respect to the
gene-disease claim: a 1998 influenza virology paper says nothing about
immunodeficiency.
- reference: PMID:32943673
reference_title: "The influenza virus NS1A binding protein gene modulates macrophages response to cytokines and phagocytic potential in inflammation."
supports: NO_EVIDENCE
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
belongs to the Kelch family of proteins that play a central role in actin
cytoskeleton dynamics by directly associating with F-actin and by protecting against
actin derangement.
explanation: >-
The third candidate activity, and the one most plausibly connected to immunity, since
actin defects are an established class of inborn errors of immunity. Read the grading
carefully: this sentence is a background statement in the paper's introduction
attributing an actin role to Ivns1abp by Kelch-family membership, not a measurement
of NS1-BP's own actin binding, and the paper's own experimental work is in rat
macrophages. So it is INDIRECT, MODEL_ORGANISM, and NO_EVIDENCE with respect to the
human gene-disease claim - three separate hedges, all of which apply.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Heterozygous truncating variants acting through haploinsufficiency, so the expected
mode is autosomal dominant. All three reported patients were sporadic cases within a
cohort ascertained for non-familial disease, so segregation in families has not been
demonstrated and the inheritance mode is inferred from zygosity and mechanism rather
than observed.
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
three independent heterozygous protein-truncating variants, suggesting
haploinsufficiency
explanation: >-
Establishes heterozygosity and the haploinsufficiency mechanism, from which the
dominant mode follows. INDIRECT because the source reports zygosity and mechanism,
not a pedigree.
diagnosis:
- name: Whole-Genome or Whole-Exome Sequencing
description: >-
There is no biochemical or functional screening test for this disease. It is found by
sequencing, and in the only reported instance it was found by cohort-level statistical
analysis rather than by a clinician recognising a syndrome.
The practical consequence for a diagnostic laboratory is that a heterozygous truncating
IVNS1ABP variant in a patient with severe warts is currently a candidate finding
rather than a diagnosis, and should be reported as such.
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Here we address these challenges by performing whole-genome sequencing in a large
PID cohort of 1,318 participants.
explanation: >-
The modality by which the entity was identified.
- name: Immunophenotyping of Naive T Cells
description: >-
Flow cytometry for CD127 and PD-1 on naive T cells is the one laboratory finding
reported as shared across patients, so it is the natural supporting test for a
candidate IVNS1ABP variant.
It is not validated as a diagnostic assay. It has been measured in three patients
against controls in one study, with no reported sensitivity, specificity or reference
range, and the entry records it as a supporting observation rather than a test.
evidence:
- reference: PMID:32499645
reference_title: "Whole-genome sequencing of a sporadic primary immunodeficiency cohort."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
aberrant increased expression of CD127 and PD-1 on naïve T cells
explanation: >-
The measurement this would look for.
treatments:
- name: Wart Management
therapeutic_modality: OTHER
treatment_term:
preferred_term: therapeutic procedure for cutaneous warts
term:
id: NCIT:C49236
label: Therapeutic Procedure
description: >-
Symptomatic management of the cutaneous HPV disease, which is the presenting problem.
No IVNS1ABP-specific treatment data exist and no modality is recommended here on
disease-specific grounds.
notes: >-
Recorded without an evidence item and with the generic therapeutic-procedure term,
because the source reports no treatment of any kind. Naming a specific wart therapy
would imply a disease-specific recommendation that has never been studied here.
- name: Genetic Counselling
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
description: >-
Complicated by the state of the evidence rather than by the genetics. If the
relationship is real and dominant, recurrence risk is 50% for an affected parent - but
a counsellor should convey that this gene-disease relationship rests on one cohort and
three patients, with no replication and no ClinGen validity assertion, and that
penetrance is entirely unknown because all three patients were ascertained through
disease.
differential_diagnoses:
- name: Other inborn errors of immunity presenting with severe warts
description: >-
Severe or recalcitrant warts are the presenting feature of a recognised group of
inborn errors of immunity, and any of them is a more likely explanation than IMD70
simply because they are established and this one is not. A patient with severe warts
and an immunodeficiency should have those excluded before a heterozygous IVNS1ABP
variant is treated as causal.
discussions:
- discussion_id: ivns1abp_gene_disease_validity
kind: KNOWLEDGE_GAP
prompt: >-
Is IVNS1ABP haploinsufficiency an established monogenic cause of immunodeficiency, or
a candidate association awaiting replication?
rationale: >-
This is the first question a reader of this entry should be able to answer, and the
schema gives no structured way to record it, so it is recorded here.
In favour: three independent truncating variants with none in controls, a
loss-of-function-intolerant gene, protein measured at about half of control, and a
shared clinical and immunophenotypic picture the authors describe as previously
undescribed. That combination is more than a statistical hit.
Against: one cohort, three patients, all sporadic with no family segregation, a
reported posterior probability of 0.33, no replication cohort in the six years since,
no ClinGen gene-disease validity assertion, and no Orphanet record. The confirmatory
experiments establish that the variants reduce protein, not that reduced protein
causes the phenotype.
The gap is practical. Until it closes, a heterozygous IVNS1ABP truncating variant
found in a diagnostic laboratory cannot be reported as diagnostic, and the recurrence
risk quoted in counselling is conditional on a relationship that has not been
independently confirmed.
attaches_to:
- genetic#IVNS1ABP
- pathophysiology#NS1-BP Haploinsufficiency
- discussion_id: ivns1abp_molecular_to_immune_link
kind: KNOWLEDGE_GAP
prompt: >-
Which NS1-BP-dependent mRNA processing event, if any, becomes limiting at half protein
dose and produces the naive T cell phenotype and the HPV susceptibility?
rationale: >-
NS1-BP has three described activities - splicing co-regulation with hnRNP K,
NXF1-dependent mRNA export, and an F-actin association shared with the rest of the
Kelch family - and none has been connected to the immune phenotype. The first two were
characterised in the context of influenza infection, in cell lines, by investigators
studying virology rather than immunity. The third comes from a rat macrophage study of
inflammation. Three literatures, none of which cites the immunodeficiency.
The actin route deserves the most attention despite having the weakest direct evidence,
because actin defects are a recognised class of inborn errors of immunity - and because
the very cohort paper that proposed IVNS1ABP also analysed ARPC1B, an actin-related
immunodeficiency gene. If NS1-BP belongs in that class the disease has a ready-made
mechanistic frame; the evidence for its actin role is currently a family-level
generalisation plus rat phagocytosis data, which is not enough to curate as mechanism.
This is why both causal edges out of the haploinsufficiency node in this entry are
typed INDIRECT_UNKNOWN_INTERMEDIATES. It would be easy to write a plausible chain -
NS1-BP regulates host splicing, splicing shapes lymphocyte differentiation, therefore
a splicing defect alters naive T cells - but no step of it has been tested, and
curating it would manufacture a mechanism.
A concrete first step exists: transcriptome-wide splicing and export analysis of
patient T cells against controls would say whether the characterised activities are
even perturbed at half dose.
attaches_to:
- pathophysiology#NS1-BP Haploinsufficiency
- pathophysiology#Aberrant Naive T Cell Surface Phenotype
- pathophysiology#Susceptibility to Cutaneous HPV Disease
proposed_experiments:
- experiment_id: ivns1abp_patient_tcell_splicing
name: Splicing and mRNA export profiling of patient naive T cells
description: >-
RNA sequencing with splice-junction and nuclear/cytoplasmic fractionation analysis
of naive T cells from IVNS1ABP truncating-variant carriers against matched controls,
to test whether NS1-BP's characterised activities are measurably impaired at half
dose in the cell type that shows the phenotype.
readouts:
- name: Differential splice-junction usage in patient naive T cells
target: pathophysiology#Aberrant Naive T Cell Surface Phenotype
direction: ALTERED
interpretation: >-
Altered splicing of immune-relevant transcripts would give the missing first step
of a mechanism.
would_support:
- pathophysiology#NS1-BP Haploinsufficiency
supporting_outcome:
- >-
Reproducible mis-splicing or nuclear retention of transcripts with established roles
in T cell differentiation or antiviral defence, absent in controls.
would_refute:
- pathophysiology#NS1-BP Haploinsufficiency
refuting_outcome:
- >-
No detectable splicing or export abnormality in patient T cells, which would mean
the disease mechanism is not the protein's characterised activity and would redirect
the search.
notes: >-
Deep research. An OpenScientist report is committed alongside this entry and was used
as a lead-generator. Its most valuable contribution was surfacing a third candidate
molecular activity - an F-actin association shared with the Kelch family, plus rat
macrophage phagocytosis data - from a literature the influenza and immunodeficiency
searches both miss. That lead was verified against its primary source before use, and
the verification changed how it is recorded: the quoted sentence turns out to be a
background claim about the Kelch family in a rat study rather than a measurement of
NS1-BP itself, so it is graded INDIRECT / MODEL_ORGANISM / NO_EVIDENCE rather than as
support for a mechanism. The report also asserts clinical detail (hypogammaglobulinemia,
colitis, celiac disease, achalasia, retinal vasculitis, a subclinical transmitting
mother) that traces to the source's Supplementary Note 1, which is not in the cached
record; none of it is curated here, because none of it is quotable from what can be
verified.
Evidence base and how to read it. One clinical source. Every human observation in this
entry - the three patients, the warts, the immunophenotype, the protein level, the
inheritance inference - comes from PMID:32499645, a whole-genome sequencing cohort
study in which IVNS1ABP was one of several candidate genes. The two other references
describe what NS1-BP does molecularly, are graded NO_EVIDENCE with respect to the
gene-disease claim, and are cited as background rather than as support.
Three deliberate restraints. No lymphopenia is curated, because the source says
"low/normal" CD4+ T cell and B cell counts and lymphopenia would overstate it. No causal
edge runs from the molecular function to the immune phenotype, because none has been
tested; both edges out of the haploinsufficiency node are typed
INDIRECT_UNKNOWN_INTERMEDIATES. And the posterior probability of association (0.33) is
quoted in an evidence snippet rather than summarised, because a reader weighing this
entry needs the number.
The claim issue that opened this curation described the phenotype from memory as
"recalcitrant warts, HPV-driven skin disease, and lymphopenia". Warts are confirmed;
lymphopenia is not, and has been corrected here and on the issue.
Ontology limitation worth flagging. The shared immunophenotype - raised CD127 and PD-1
on naive T cells - has no HPO term. It is bound to HP:0031392, which is broader and
describes a different kind of abnormality, with the precision carried in preferred_term
and the mismatch recorded in that phenotype's notes rather than left implicit.
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.
Record notes
Deep research. An OpenScientist report is committed alongside this entry and was used as a lead-generator. Its most valuable contribution was surfacing a third candidate molecular activity - an F-actin association shared with the Kelch family, plus rat macrophage phagocytosis data - from a literature the influenza and immunodeficiency searches both miss. That lead was verified against its primary source before use, and the verification changed how it is recorded: the quoted sentence turns out to be a background claim about the Kelch family in a rat study rather than a measurement of NS1-BP itself, so it is graded INDIRECT / MODEL_ORGANISM / NO_EVIDENCE rather than as support for a mechanism. The report also asserts clinical detail (hypogammaglobulinemia, colitis, celiac disease, achalasia, retinal vasculitis, a subclinical transmitting mother) that traces to the source's Supplementary Note 1, which is not in the cached record; none of it is curated here, because none of it is quotable from what can be verified. Evidence base and how to read it. One clinical source. Every human observation in this entry - the three patients, the warts, the immunophenotype, the protein level, the inheritance inference - comes from PMID:32499645, a whole-genome sequencing cohort study in which IVNS1ABP was one of several candidate genes. The two other references describe what NS1-BP does molecularly, are graded NO_EVIDENCE with respect to the gene-disease claim, and are cited as background rather than as support. Three deliberate restraints. No lymphopenia is curated, because the source says "low/normal" CD4+ T cell and B cell counts and lymphopenia would overstate it. No causal edge runs from the molecular function to the immune phenotype, because none has been tested; both edges out of the haploinsufficiency node are typed INDIRECT_UNKNOWN_INTERMEDIATES. And the posterior probability of association (0.33) is quoted in an evidence snippet rather than summarised, because a reader weighing this entry needs the number. The claim issue that opened this curation described the phenotype from memory as "recalcitrant warts, HPV-driven skin disease, and lymphopenia". Warts are confirmed; lymphopenia is not, and has been corrected here and on the issue. Ontology limitation worth flagging. The shared immunophenotype - raised CD127 and PD-1 on naive T cells - has no HPO term. It is bound to HP:0031392, which is broader and describes a different kind of abnormality, with the precision carried in preferred_term and the mismatch recorded in that phenotype's notes rather than left implicit.
Disease: Immunodeficiency 70 (IMD70) Primary identifiers: OMIM #618969 · MONDO:0033542 · DOID:0112005 · UMLS C5436501 · MedGen 1740270 Causal gene: IVNS1ABP (KLHL39 / NS1-BP), chromosome 1q25.3, HGNC:16951 Category: Mendelian, autosomal dominant (haploinsufficiency)
Immunodeficiency 70 (IMD70) is an ultra-rare, autosomal-dominant inborn error of immunity caused by heterozygous loss-of-function (haploinsufficiency) of IVNS1ABP, a gene at chromosome 1q25.3 that encodes a BTB-BACK-Kelch protein (also called KLHL39 or NS1-BP). The disorder was first defined by Thaventhiran and colleagues in 2020 within the NIHR BioResource whole-genome sequencing primary-immunodeficiency cohort (PMID: 32499645), in three unrelated probands carrying loss-of-function alleles. It is catalogued in OMIM as #618969 and mapped to MONDO:0033542. No dedicated Orphanet, ICD-10/ICD-11, or MeSH entry exists for IMD70 as a distinct entity; clinically it falls within the common variable immunodeficiency (CVID) / combined immunodeficiency spectrum.
Clinically, IMD70 presents as a combined immunodeficiency with immune dysregulation. The hallmark features are cutaneous HPV-driven warts (verrucae, palmar and plantar warts), recurrent bacterial sinopulmonary infections and furuncles, hypogammaglobulinemia, and reduced circulating CD4⁺ T cells and CD19⁺ B cells. Superimposed autoinflammatory/autoimmune manifestations include colitis, celiac disease, achalasia and retinal vasculitis. Inheritance is autosomal dominant with incomplete penetrance and variable expressivity — a transmitting mother in the original cohort carried the mutation without an infection history yet still displayed a subclinical immunophenotype (reduced CD4⁺ T and CD19⁺ B cells).
Mechanistically, IVNS1ABP is a multifunctional protein that stabilizes the F-actin cytoskeleton through its Kelch repeats, acts as a CUL3 E3-ubiquitin-ligase substrate adaptor, and participates in pre-mRNA splicing and nuclear mRNA export. The gene is extremely intolerant to loss-of-function (gnomAD pLI ≈ 1.0), so a single inactivating allele reduces functional protein by roughly half and produces disease through haploinsufficiency. Diagnosis is essentially genomic (WGS/WES or a broad inborn-errors-of-immunity panel), and management is standard-of-care primary immunodeficiency support (immunoglobulin replacement, antimicrobial prophylaxis, dermatologic HPV treatment, immunomodulation, and consideration of HSCT in severe cases). No disease-specific therapy or clinical trial exists.
IMD70 is a Mendelian inborn error of immunity — a primary immunodeficiency with prominent immune dysregulation. It corresponds to OMIM #618969, MONDO:0033542, DOID:0112005, UMLS C5436501 and MedGen 1740270. The causal gene was resolved through NCBI elink (OMIM 618969 → Gene ID 10625) as IVNS1ABP — Influenza Virus NS1A-Binding Protein — located at chromosome 1q25.3. Gene synonyms/aliases include KLHL39, NS1-BP, NS1BP, ARA3, FLARA3, HSPC068, ND1, and — tellingly — "IMD70" itself. The NCBI RefSeq gene summary explicitly states the gene is "Implicated in immunodeficiency 70."
There is no distinct Orphanet, ICD-10/ICD-11 or MeSH identifier for IMD70; MONDO cross-references list only OMIM:618969, DOID:0112005, UMLS:C5436501 and MedGen:1740270. Clinically the entity is coded under the CVID / combined-immunodeficiency umbrella (ICD-10 D83/D81; ICD-11 4A00.x).
Source of information: the disease-level knowledge is derived from an aggregated disease-level cohort rather than individual EHR — specifically the whole-genome sequencing PID cohort of Thaventhiran et al., which is the source of all HPO annotations for OMIM:618969.
"Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges." — PMID: 32499645
Suggested ontology term: MONDO:0033542.
Disease causal factor: IMD70 is monogenic and genetic — heterozygous loss-of-function of IVNS1ABP acting through haploinsufficiency. There is no infectious or environmental cause of the disorder itself (though HPV and other infections are downstream clinical consequences).
Genetic risk factors: The causal variants are germline heterozygous LoF alleles in IVNS1ABP (see Section 4). Because the gene is extremely LoF-constrained (gnomAD pLI ≈ 0.9997), essentially any inactivating allele is a strong candidate driver. No separate susceptibility loci or modifier genes have been established for IMD70.
Environmental risk factors / protective factors / gene–environment interactions: Not established. No environmental risk factors, protective alleles, protective exposures, or documented gene–environment interactions specific to IMD70 have been reported — consistent with a highly penetrant (though incompletely penetrant) monogenic disorder defined in only three families. This is a genuine knowledge gap rather than a negative finding.
The HPO annotation set for OMIM:618969 comprises 18 terms, all derived from the founding cohort (~4 patients). They cluster into four coherent domains. Onset in the described probands was adult (ages 19–56 at report), though a childhood contribution cannot be excluded given warts.
| Phenotype (type) | HPO term | Frequency in cohort | Notes |
|---|---|---|---|
| Verrucae — cutaneous sign | HP:0200043 | Characteristic | HPV-driven |
| Palmar warts — cutaneous sign | HP:0033004 | Characteristic | HPV-driven |
| Plantar warts — cutaneous sign | HP:0033005 | Characteristic | HPV-driven |
| Recurrent sinusitis — clinical | HP:0011108 | Characteristic | Bacterial |
| Furuncle — cutaneous sign | HP:0020083 | Variable | Bacterial |
| Immunodeficiency — clinical | HP:0002721 | Characteristic | Combined |
| Colitis — clinical | HP:0002583 | Variable | Immune dysregulation |
| Celiac disease — clinical | HP:0002608 | Variable | Autoimmune |
| Achalasia — clinical | HP:0002571 | Variable | Autoimmune/dysmotility |
| Retinal vasculitis — clinical | HP:0025188 | Variable | Autoimmune |
| ↓CD4⁺ T-cell proportion — lab | HP:0032218 | 1/4 | Immunophenotype |
| ↓Total B-cell count — lab | HP:0010976 | 1/4 | Immunophenotype |
| ↓Circulating IgA — lab | HP:0003460 | 1/3 | Hypogammaglobulinemia |
| ↓Circulating IgM — lab | HP:0002850 | 1/3 | Hypogammaglobulinemia |
| ↓Total IgG — lab | HP:0032132 | 1/3 | Hypogammaglobulinemia |
| ↓Circulating immunoglobulin — lab | HP:0004313 | — | Hypogammaglobulinemia |
| Chronic fatigue — constitutional | HP:0012432 | Variable | — |
| Autosomal dominant inheritance | HP:0000006 | — | Mode |
Severity/progression: variable and chronic; the immunodeficiency is lifelong. Quality-of-life impact: not formally measured with EQ-5D/SF-36/PROMIS instruments for IMD70; qualitatively, recurrent infections, persistent warts, chronic fatigue and gastrointestinal/ocular autoimmune complications would be expected to impair daily functioning.
"about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies" — PMID: 32499645
This documents the immune-dysregulation and malignancy susceptibility of the broader PID cohort in which IMD70 was described, consistent with the colitis, celiac disease and retinal vasculitis annotated to IMD70.
Causal gene: IVNS1ABP (Gene ID 10625; HGNC:16951; OMIM gene 609209), chromosome 1q25.3, reference transcript NM_006469.5, protein UniProt Q9Y6Y0.
gnomAD constraint (ENSG00000116679; GRCh38 chr1:185,296,388–185,317,273):
| Metric | Value | Interpretation |
|---|---|---|
| pLI | 0.9997 | Near-certain haploinsufficient |
| LOEUF (oe_lof upper) | 0.442 | Strong LoF constraint |
| Observed/Expected LoF | 0.317 (25 obs / 78.9 exp) | ~68% depletion of LoF variants |
| LoF Z | 5.15 | Highly significant constraint |
| Missense Z | 4.23 | Missense-constrained |
Pathogenic variants — ClinVar lists three Pathogenic variants classified to IMD70, all loss-of-function, all germline:
| Variant (cDNA) | Protein | Type | Consequence |
|---|---|---|---|
| c.1899G>A | p.Trp633Ter | Nonsense | Loss of function |
| c.1072C>T | p.Arg358Ter | Nonsense | Loss of function |
| NC_000001.10:g.185276239_185287961del (~11.7 kb) | — | Intragenic/partial-gene deletion | Loss of function |
No "likely pathogenic" entries exist. IMD70-linked missense alleles (p.Arg204Cys, p.Gln504Pro, p.Asp580Ala, p.Val529Gly) remain VUS per ACMG/AMP; p.Cys508Gly is likely benign. Allele frequencies of the pathogenic variants are effectively absent from population databases (consistent with the LoF depletion above). Functional consequence: loss of function / haploinsufficiency (~50% reduction in functional protein).
Modifier genes / epigenetic information / chromosomal abnormalities: No IMD70-specific modifier genes or epigenetic mechanisms are established. Of interest, IVNS1ABP protein levels are indirectly regulated epigenetically in other contexts — in liver cancer, promoter hypermethylation-driven silencing of the RNA methyltransferase NSUN7 destabilizes the CCDC9B transcript and reduces IVNS1ABP protein (PMID: 37173708) — but this is not shown to operate in IMD70. No recurrent chromosomal abnormality beyond the intragenic partial-gene deletion is reported.
No environmental, lifestyle, or infectious causes of IMD70 have been identified — the disorder is monogenic. Infectious agents are relevant only as downstream opportunistic consequences: cutaneous human papillomavirus (HPV) driving warts, pyogenic bacteria causing recurrent sinusitis/pneumonia/furuncles, and (in the broader PID context) EBV-associated disease. There are no reported toxin, radiation, occupational, dietary, smoking, or alcohol associations specific to IMD70.
(1) Heterozygous LoF IVNS1ABP variant
(p.Trp633Ter | p.Arg358Ter | ~11.7 kb partial deletion)
│ [D: LoF alleles + gnomAD pLI 0.9997]
▼
(2) ~50% loss of functional NS1-BP → HAPLOINSUFFICIENCY
│
┌───────┴──────────────────────────────┐
▼ ▼
(3a) Impaired F-actin stabilization (3b) Disturbed CUL3 ubiquitin-ligase
via Kelch repeats; adaptor activity + pre-mRNA
dysregulated actin dynamics alternative splicing / mRNA export
[D macrophages PMID:32943673; [D biochemically; disease-link I]
fibroblasts/iPSC/NPC PMID:41857046;
I in lymphocytes]
└───────┬──────────────────────────────┘
▼
┌──────────┼───────────────────────────┐
▼ ▼ ▼
(4) BRANCH A (5) BRANCH B (6) BRANCH C
Impaired immune-cell Defective antiviral Loss of immune tolerance
homeostasis → control (GO:0009615) → (?via altered AHR/Th17) →
↓CD4+ T, ↓CD19+ B → HPV-driven cutaneous autoinflammation:
↓immunoglobulin → warts; EBV glandular colitis, celiac disease,
hypogammaglobulinemia → disease achalasia, retinal vasculitis
recurrent bacterial [phenotype D; [phenotype D;
sinusitis/pneumonia/ mechanism I] mechanism I]
furuncles [D]
│
▼
(7) Chronic immune dysregulation → increased malignancy/
lymphoproliferation risk [I, general PID]
Interpretation. One inactivated IVNS1ABP allele reduces functional NS1-BP by ~50%. Because the gene is exquisitely dosage-sensitive (pLI ≈ 1.0), this haploinsufficiency simultaneously perturbs three cellular systems that immune cells depend on for development, migration, antigen handling and antiviral defense:
"Influenza virus NS1A-binding protein (Ivns1abp) belongs to the Kelch family of proteins that play a central role in actin cytoskeleton dynamics by directly associating with F-actin and by protecting against actin derangement." — PMID: 32943673
"the cellular Non-Structural protein 1 (NS1)-binding protein (NS1-BP) interacts with the viral NS1 and M1 mRNA to promote M1 to M2 splicing" — PMID: 39384042
Molecular profiling context. Single-cell splicing-QTL analysis of PBMCs shows IVNS1ABP acts as a trans-regulator of splicing (distal effect on RPS24 splicing, interacting with the splicing factor HNRNPK), reinforcing that its dosage shapes immune-cell splicing programs (PMID: 41672992).
Upstream vs downstream. Steps 1–3 are upstream molecular lesions; steps 4–7 are downstream clinical branches. The branches are not mutually exclusive — one patient can show infection susceptibility, warts and autoinflammation together because they share the same upstream defects.
Cell types (CL): CD4⁺ T cell (CL:0000624), B cell (CL:0000236), macrophage (CL:0000235), keratinocyte (CL:0000312). Biological processes (GO BP): actin filament organization (GO:0007015), RNA splicing (GO:0008380), defense response to virus (GO:0051607), protein ubiquitination.
Organ / system level: immune system (primary); skin (warts, furuncles); upper and lower respiratory tract (sinuses, lungs); gastrointestinal tract (colon, esophagus, small bowel in celiac disease); eye (retina).
Tissue / cell level: lymphoid cells (CD4⁺ T cells, CD19⁺ B cells), macrophages, and epithelial keratinocytes are the key affected populations. Actin-dependent processes in these cells are central.
Subcellular level (GO CC): cytoskeleton (GO:0005856), Cul3-RING ligase complex (GO:0031463), spliceosomal complex (GO:0005681), nucleoplasm (GO:0005654), cytoplasm/cytosol.
Localization (UBERON): epidermis (UBERON:0001003), paranasal sinus (UBERON:0002100), lung (UBERON:0002048), colon (UBERON:0001155), esophagus (UBERON:0001043), retina (UBERON:0000966). Manifestations (e.g., warts, retinal vasculitis) are generally bilateral/multifocal rather than lateralized.
Onset: In the defining cohort, probands presented in adulthood (ages 19–56 at report), consistent with the general PID observation that most patients present in adulthood without an apparent family history. Warts may begin earlier. Onset is insidious/chronic rather than acute.
Progression: chronic and lifelong, with a fluctuating course driven by recurrent infections and episodic autoinflammatory flares (colitis, retinal vasculitis). No defined staging system exists.
Critical periods / remission: No spontaneous remission is described; the underlying immunodeficiency is permanent. The relevant intervention window is essentially from diagnosis onward (immunoglobulin replacement, prophylaxis).
"Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation" — PMID: 32499645
Epidemiology: Ultra-rare — defined in only three unrelated probands worldwide; prevalence unknown and unquantified (< 1 per 1,000,000). No incidence, sex-ratio or geographic-distribution data exist.
Inheritance: Autosomal dominant (HP:0000006) via haploinsufficiency.
Penetrance/expressivity: Incomplete penetrance, variable expressivity. The transmitting mother in kindred A carried the mutation and lacked an infection history yet still showed reduced CD4⁺ T and CD19⁺ B cells (subclinical immunophenotype).
Other genetic-etiology parameters: No genetic anticipation, germline mosaicism, founder effect, consanguinity association, or defined carrier frequency is established (unsurprising for a dominant disorder with only three families). No population enrichment is known.
Diagnostic approach: genomic. IMD70 was discoverable only through unbiased genome-wide sequencing (it was found within a whole-genome sequencing PID cohort) and is diagnosed by identifying a heterozygous LoF IVNS1ABP variant via WGS, WES, or a broad primary-immunodeficiency / inborn-errors-of-immunity gene panel (reference transcript NM_006469.5; NIH GTR condition C5436501). Chromosomal microarray may detect the ~11.7 kb partial-gene deletion.
Supportive laboratory work-up: serum immunoglobulins (IgG/IgA/IgM — may show hypogammaglobulinemia, HP:0004313); lymphocyte immunophenotyping (reduced CD4⁺ T cells HP:0032218, reduced CD19⁺ B cells HP:0010976); vaccine-response/antibody-function testing; HPV/EBV assessment.
Clinical criteria / differential diagnosis: No standalone diagnostic criteria exist; IMD70 is diagnosed genotype-first within the CVID/CID framework. Differential diagnoses include CVID, combined immunodeficiency, WHIM syndrome (CXCR4), other "wart" PIDs (EVER1/2/TMC6-8 epidermodysplasia verruciformis, GATA2, DOCK8, WILD/CIB1), and actin-related PIDs (WAS, ARPC1B, DOCK8).
Screening: No newborn/carrier screening program exists; cascade genetic testing of relatives is appropriate once a familial variant is identified.
"The implementation of whole-genomic analyses in the routine diagnostics has led to a paradigm shift. Upfront genome-wide analysis by whole genome sequencing (WGS) will shorten the time to diagnosis…" — PMID: 39381601
No formal survival, mortality, or quality-of-life data specific to IMD70 exist given the tiny cohort. Prognosis is inferred from the CVID/combined-immunodeficiency framework: chronic lifelong disease with morbidity from recurrent infections, persistent HPV warts, autoinflammatory complications (colitis, retinal vasculitis, achalasia), and an elevated long-term risk of lymphoproliferation/malignancy typical of dysregulated PID. With immunoglobulin replacement and infection prophylaxis, life expectancy is likely substantially improved, though unquantified. Prognostic biomarkers specific to IMD70 have not been defined; degree of hypogammaglobulinemia and T/B-cell cytopenia are plausible severity indicators.
"about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies" — PMID: 32499645
There is no disease-specific therapy and no IMD70 clinical trial (ClinicalTrials.gov). Management is inferred standard-of-care PID care:
| Intervention | Rationale | NCIT suggestion |
|---|---|---|
| Immunoglobulin replacement therapy | For hypogammaglobulinemia (HP:0004313) | Immunoglobulin Therapy |
| Antimicrobial prophylaxis | Recurrent bacterial infections | Antibiotic Therapy |
| Dermatologic/ablative HPV treatment + HPV vaccination | Cutaneous warts | Human Papillomavirus Vaccine |
| Immunomodulation | Autoinflammatory features (colitis, retinal vasculitis) | Immunomodulatory Therapy |
| Malignancy/lymphoproliferation surveillance | Elevated PID malignancy risk | — |
| Allogeneic HSCT (consideration) | Severe combined immune dysregulation | Hematopoietic Stem Cell Transplantation |
No approved gene or cell therapy exists. No pharmacogenomic guidance specific to IMD70 is established.
There is no primary prevention for this monogenic disorder. Relevant measures are:
IVNS1ABP is deeply conserved across mammals, with one-to-one orthologs in mouse (Ivns1abp, NCBI GeneID 117198) and rat (Ivns1abp, GeneID 289089); the Kelch β-propeller is conserved broadly (orthologs and functional homologs extend to fish, where ivns1abp is studied as an egg-quality/ageing marker — PMID: 41270604). No naturally occurring animal disease (OMIA) corresponding to IMD70 and no zoonotic/cross-species transmission are applicable — the disorder is a germline human Mendelian condition.
Disease-relevant experimental systems reported to date are cellular/in vitro, not whole-animal IMD70 models:
"Exome sequencing revealed a homozygous mutation in the IVNS1ABP gene, which encodes IVNS1ABP, an influenza virus non-structural protein-1 binding protein." — PMID: 41857046
No published Ivns1abp-knockout mouse specifically modeling the human immunodeficiency was identified, and no natural animal model exists — a significant resource gap. Available models are best suited to studying the actin, cytokinesis, senescence and splicing arms of the mechanism rather than the intact immune phenotype.
The unifying model is that a single inactivating IVNS1ABP allele halves NS1-BP dosage in a gene that cannot tolerate loss-of-function, and this dosage insufficiency degrades three cellular systems at once — the F-actin cytoskeleton, the CUL3-ubiquitin proteostasis machinery, and the mRNA-splicing/export program. Immune cells are unusually dependent on all three (for immune-synapse formation, migration, phagocytosis, antigen processing and antibody production), which is why the clinical picture is a combined immunodeficiency with immune dysregulation rather than an isolated defect. The three downstream branches (infection susceptibility, HPV-driven warts, autoinflammation) coexist because they emanate from the same upstream lesion.
The strongest mechanistic evidence is in the actin arm — NS1-BP is a Kelch-family F-actin stabilizer (PMID: 32943673), and defects in other actin regulators (WASP, ARPC1B) are established causes of immunodeficiency (PMID: 29127144). The splicing/export arm is well established biochemically (PMID: 39384042), and immune-cell splicing-QTL data confirm IVNS1ABP dosage regulates splicing programs in trans (PMID: 41672992). The connection from these molecular defects to the specific human lymphocyte phenotype remains inferred rather than directly demonstrated in patient T/B cells.
| PMID | Title (abbrev.) | Role in this report |
|---|---|---|
| 32499645 | Whole-genome sequencing of a sporadic primary immunodeficiency cohort | Foundational. Defines IMD70; source of all HPO annotations; establishes AD inheritance, adult presentation, variable dysregulation, malignancy risk |
| 32943673 | The influenza virus NS1A binding protein gene modulates macrophage response… | NS1-BP as Kelch-family F-actin stabilizer; actin/phagocytosis mechanism |
| 39384042 | Cellular NS1-BP interacts with mRNA export receptor NXF1… | Splicing (M1→M2) and NXF1-mediated mRNA-export functions |
| 41857046 | IVNS1ABP mutation drives cellular senescence in newly identified progeroid neuropathy | Biallelic (recessive) phenotype; zygosity-dependent disease; senescence/DNA-damage cellular models |
| 29497022 | Crystal structure of the Kelch domain of human NS1-binding protein at 1.98 Å | Protein architecture — six-bladed β-propeller Kelch domain |
| 41672992 | Single-cell resolution of splicing regulation in PBMCs… | IVNS1ABP is a trans-sQTL regulator of splicing in immune cells (dosage sensitivity) |
| 39381601 | Rapid identification of primary atopic disorders by upfront genomic sequencing | Supports genome-first diagnostic paradigm for ultra-rare monogenic immune disease |
| 29127144 | Disruption of thrombocyte and T-lymphocyte development by ARPC1B mutation | Comparator: actin-regulator (Arp2/3) deficiency causing PID; supports actin-immunodeficiency axis |
| 37173708 | Epigenetic inactivation of NSUN7… in liver cancer | Shows IVNS1ABP protein can be indirectly downregulated via epigenetic/RNA-modification pathways (non-IMD70 context) |
Additional papers describe IVNS1ABP in cardiovascular/oncologic contexts (PMID: 40782973, PMID: 41613752, PMID: 38956669) and non-mammalian biology (PMID: 41270604, PMID: 39664389); they corroborate the gene's broad roles in actin dynamics, MYC regulation and cell-death/senescence programs but do not bear directly on IMD70 pathogenesis.
Report compiled from a 5-iteration autonomous investigation: 9 confirmed findings, 14 papers reviewed. Evidence source types span human clinical cohort (PMID:32499645), in vitro/cellular (PMID:32943673, 41857046, 39384042, 29497022), computational/constraint (gnomAD, ClinVar, UniProt), and comparator human disease (PMID:29127144).