HOIP Deficiency

Mendelian MONDO:0957981 Pathograph 46 Show in embeddings browser Primary Immunodeficiency Combined Immunodeficiency Autoinflammatory Syndrome

HOIP deficiency is an autosomal recessive inborn error of immunity caused by biallelic hypomorphic or loss-of-function variants in RNF31, which encodes HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC). LUBAC is the only ubiquitin ligase known to build head-to-tail (M1-linked, "linear") polyubiquitin chains, and it is HOIP that carries the catalytic RING-IBR-RING module; HOIL-1 (RBCK1) and SHARPIN are the other two subunits. Losing HOIP therefore does not merely remove one component: the whole ternary complex is destabilised, with HOIL-1 and SHARPIN protein falling alongside it, and linear ubiquitination in patient cells is essentially abolished. What makes the disease mechanistically interesting is that one molecular lesion produces two clinically opposite immune phenotypes at once. Linear ubiquitin chains on NEMO and RIPK1 are required both to activate canonical NF-kappa-B downstream of TNFR1, IL-1R, the TLRs and CD40, and to restrain the death-inducing complex II that assembles when those same receptors are engaged. Loss of the chains therefore gives immunodeficiency through the first arm - fibroblasts and B cells that cannot mount an NF-kappa-B response, failed CD40-driven B cell activation, absent germinal centres, poor antibody responses - and autoinflammation through the second, with patient cells sensitised to TNF-induced apoptosis and necroptosis. Cell type is the third variable: while patient fibroblasts are hyporesponsive to IL-1 beta, patient monocytes are hyperresponsive to it, which is the lineage-specific split the founding report proposed as the direct basis of the autoinflammation. The clinical syndrome is early-onset multiorgan autoinflammation (recurrent fever, raised CRP and ESR, arthritis, dermatitis) combined with recurrent bacterial, viral and fungal infection, and it may include subclinical amylopectinosis of skeletal muscle and systemic lymphangiectasia with protein-losing enteropathy. Fewer than ten patients have been published, and the four fully reported cases differ substantially from one another: only the founding case had lymphangiectasia and amylopectinosis, and the most recently reported patient died before the age of two. Two of the reported patients carry a type I interferon signature in blood, which is unexplained and is not, on the current evidence, enough to call the disease an interferonopathy.

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Classifications

Harrison's Part

IUIS Category

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Inheritance

Autosomal recessive HP:0000007

Reported patients are homozygous (p.L72P; a C-terminal frameshift) or compound heterozygous (splice-region variants; p.Q552Ter with p.H1013Pro) for RNF31 alleles that reduce HOIP protein. Parents and unaffected siblings are heterozygous carriers. Carrier status is clinically silent, but the asymptomatic mother in the second family carried the same type I interferon and TNF transcriptome signatures as her affected daughter, so haploinsufficiency has a measurable subclinical effect on mononuclear cells.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:26008899 SUPPORT Human Clinical

"Both parents and the healthy sibling of the patient were heterozygous for the mutation"

Segregation in the founding consanguineous kindred: the patient is homozygous and the obligate carriers are unaffected, which is the recessive pattern.

PMID:30936877 SUPPORT Human Clinical

"We demonstrated that these variants are inherited in trans by sub-cloning of the patient's genomic DNA"

Confirms biallelic (in trans) inheritance of the two variants in the second family, excluding a cis configuration on one chromosome.

PMID:30936877 SUPPORT Human Clinical

"Type I IFN and TNF-mediated inflammatory transcriptome signatures were also identified in the PBMCs of the asymptomatic mother"

The basis for describing carrier status as clinically silent but not transcriptionally silent.

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Mechanistic Hypotheses

Dual Lesion Model - Lost NF-kappa-B Activation Plus Released Cell-Death Brake

lubac_dual_lesion_model CANONICAL

Evidence balance 1 support

Linear ubiquitin chains at receptor signalling complexes both enable canonical NF-kappa-B activation and hold the complex out of its death-inducing configuration. Losing them therefore produces immunodeficiency and autoinflammation from one lesion: the first through failed NF-kappa-B output in fibroblasts, B cells and T cells, the second through TNF-driven apoptosis and necroptosis of tissue cells. The model is supported in humans by the patient allele that removes the catalytic domain and produces both effects in the same cells, and in mice by the TNFR1 rescue of the endothelial and epidermal phenotypes.

Show evidence (1 reference)

PMID:28469620 SUPPORT REVIEW SYNTHESIS Other

"Consequently, OTULIN or A20-deficient cells have an excess of Met1 or K63 Ub chains on NEMO, RIPK1, and other target substrates, which lead to constitutive activation of the NF-kB pathway."

The mirror-image diseases. OTULIN and A20 deficiency remove the enzymes that take ubiquitin chains off the same substrates, and produce constitutive NF-kappa-B rather than deficient NF-kappa-B - which is what places LUBAC deficiency in a class defined by the direction of the ubiquitin imbalance, and is the main differential diagnosis to hold in mind.

Lineage-Specific Myeloid IL-1 Hyperresponsiveness Model

myeloid_hyperresponsiveness_model ALTERNATIVE

The autoinflammation is driven not by cell death but by the paradoxical hyperresponsiveness of LUBAC-deficient monocytes to IL-1 beta, which the founding reports of both HOIL-1 and HOIP deficiency proposed. The mouse evidence pulls in the same direction: dendritic-cell-restricted Hoip deletion causes spontaneous inflammation that TNFR1 deletion fails to rescue and MyD88 deletion does. The two models are not exclusive and may operate in different tissues, but they predict different therapies - IL-1 blockade rather than TNF blockade - and no patient has been reported on IL-1 blockade.

Discussions and Knowledge Gaps

Is the autoinflammation of HOIP deficiency driven by TNF-induced cell death, or by MyD88-dependent TLR and IL-1R signalling in myeloid cells?

CONTROVERSY hoip_autoinflammation_tnf_versus_myd88

Attached to

pathophysiology#Systemic Autoinflammation pathophysiology#Monocyte Hyperresponsiveness to IL-1 beta pathophysiology#Sensitisation to TNFR1-Mediated Cell Death

The two candidate drivers have evidence of different kinds pointing in different directions. For TNF: patient colonic mucosa carries markers of RIPK1 kinase-dependent death, TNFR1 deletion rescues the endothelial and epidermal mouse phenotypes, and anti-TNF therapy produces clinical responses in patients - complete in a SHARPIN-deficient patient, partial and non-durable in a HOIP-deficient one. For MyD88: in the dendritic-cell-restricted Hoip knockout, which is the model built specifically to ask this question about autoinflammation, crossing to TNFR1-null mice did not rescue the inflammation while MyD88 deficiency did, and the patient monocyte phenotype that both founding reports proposed as the basis of autoinflammation is IL-1 beta hyperresponsiveness, which is MyD88-dependent. The question is not academic: it decides whether IL-1 blockade should be tried in a patient whose fever breaks through anti-TNF, and no reported patient has received it.

What produces the type I interferon signature in HOIP-deficient patients, and is it doing clinical work?

KNOWLEDGE GAP hoip_interferon_signature_mechanism

Attached to

pathophysiology#Type I Interferon Pathway Activation

Two unrelated patients with different genotypes carry an interferon-stimulated gene signature in blood, and a healthy carrier mother carries it too. The obvious candidate mechanism - LUBAC restraining type I interferon production by degrading TRIM25 - was tested in the second patient's PBMCs and TRIM25 was not increased. The signature appears to be T cell rather than monocyte driven, since excess STAT1 phosphorylation after interferon-alpha was found in naive CD4 and CD8 T cells but not in CD14-positive cells. Its therapeutic relevance is untested: no HOIP-deficient patient has received a JAK inhibitor, and the second patient's own authors decline to classify the disease as an interferonopathy on the available evidence.

Show evidence (2 references)

PMID:30936877 SUPPORT Human Clinical

"However, we did not observe increased expression of TRIM25 in unstimulated HOIP deficient patient's PBMCs, compared to control cells (Figure S8)."

The negative result that keeps this gap open: the TRIM25 route, which is the mechanism the literature proposed for LUBAC restraining type I interferon, was tested in a HOIP-deficient patient's own cells and not found.

PMID:30936877 SUPPORT Human Clinical

"At this point there is no strong evidence to categorize the HOIP deficiency as a new type I interferonopathy, and it is unclear whether these patients would benefit from treatment with JAK inhibitors."

The authors' own statement of the two open questions this gap records: the disease classification and whether JAK inhibition is indicated.

Why is amylopectinosis mild or absent in HOIP deficiency when it is early, severe and consistent in HOIL-1 deficiency, if both destabilise the same complex?

KNOWLEDGE GAP hoip_amylopectinosis_subunit_dependence

Attached to

pathophysiology#Amylopectin Accumulation in Skeletal Muscle

Both diseases abolish LUBAC assembly, yet the polyglucosan arm tracks with the HOIL-1 lesion rather than with LUBAC loss as such. The founding HOIP report offers two readings and does not choose between them: either the storage phenotype depends on a HOIL-1 function outside the complex, or the HOIP L72P allele is simply not fully loss-of-function. The distinction matters for whether these are two presentations of one mechanism or two mechanisms sharing a complex, and it is also the point at which the boundary between this entry and the RBCK1 disease would be redrawn if the answer were the first one.

Show evidence (1 reference)

PMID:23995275 SUPPORT REVIEW SYNTHESIS Other

"Polyglucosan body myopathy with cardiomyopathy has been associated with mutations in RBCK1, a ubiquitin ligase, which have also been reported in children with early-onset immune disorder."

States the two-faced character of the RBCK1 disease - a muscle glycogenosis and an immune disorder from the same gene - which is the contrast this gap is about, since the HOIP patients show the immune arm without a comparable storage myopathy.

Can mouse Hoip-null models speak to the human disease at all, given that complete HOIP loss is embryonic lethal in mice while patients survive into adult life?

HUMAN MODEL MISMATCH hoip_mouse_null_versus_human_hypomorph

Attached to

pathophysiology#Sensitisation to TNFR1-Mediated Cell Death pathophysiology#Lymphatic and Vascular Endothelial Injury

Every constitutive Hoip-null mouse dies at midgestation from TNFR1-driven endothelial death, so the entire murine literature on this gene is about complete loss, while every reported patient retains residual HOIP. This is not a reason to discard the models - the TNFR1 epistasis they establish is unobtainable in humans, and the colonic caspase-3 and pRIPK1 staining in a patient shows the same route is active - but it does mean the quantitative relationship between residual HOIP and phenotype severity is unaddressed by any model. It is a live clinical question, since the four reported patients differ widely in severity and the one who died before two years old carried a nonsense allele.

Proposed experiments

Graded hypomorphic Hoip allelic series

hoip_graded_hypomorphic_allelic_series

Generate a mouse allelic series producing defined residual HOIP levels, including knock-in of the human p.L72P and p.H1013Pro changes, and ask at what residual level embryonic lethality is escaped and which of the human arms - autoinflammation, antibody failure, lymphangiectasia, muscle polyglucosan - appear.

Would support

pathophysiology#Sensitisation to TNFR1-Mediated Cell Death

Supporting outcome

Surviving hypomorphic animals recapitulate autoinflammation and antibody failure at residual HOIP levels comparable with those measured in patient cells, with severity tracking residual protein.

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Pathophysiology

Biallelic RNF31 Loss-of-Function Variants

Reported alleles are spread across the protein and across variant classes: the homozygous p.L72P missense change at the start of the N-terminal PUB domain in the founding kindred; compound heterozygous splice-region variants (c.1197G>C and c.1737+3A>G) producing transcripts that skip exon 7 or exon 9 and so remove all or part of the UBA domain through which HOIP binds SHARPIN and HOIL-1; a homozygous C-terminal frameshift that deletes the catalytic domain outright; and a compound heterozygous nonsense plus missense pair (p.Q552Ter, p.H1013Pro). The alleles are hypomorphic rather than strictly null in most patients, which matters because complete Hoip loss is embryonic lethal in mice. p.L72P leaves no detectable protein on immunoblot yet is described by its own authors as at least severely hypomorphic rather than proven null.

RNF31 hgnc:16031 ⇓ LOSS OF FUNCTION

Genetic context variant_origin: GERMLINE allelic_event: MISSENSE_VARIANT allelic_event: FRAMESHIFT_VARIANT allelic_event: SPLICE_SITE_VARIANT allelic_event: NONSENSE_VARIANT functional_impact_category: LOSS_OF_FUNCTION

Germline biallelic RNF31 alleles. Missense, splice-region, nonsense and frameshift mechanisms are all represented, and all converge on reduced HOIP protein.

HOIP ubiquitin ligase activity GO:0061630 ⇓ LOSS OF FUNCTION

Downstream

LUBAC Complex Destabilisation Reduced or absent HOIP protein removes the scaffold on which the ternary complex assembles.

Show evidence (4 references)

PMID:26008899 SUPPORT Human Clinical

"The missense allele (L72P, in the PUB domain) is at least severely hypomorphic, as it impairs HOIP expression and destabilizes the whole LUBAC complex."

The founding allele, its domain position, and the authors' own careful statement that it is severely hypomorphic rather than demonstrably null.

PMID:30936877 SUPPORT Human Clinical

"Results: We identified biallelic variants in close proximity to splice sites (c.1197G>C and c.1737+3A>G) in the RNF31 gene."

The splice-region genotype of the second patient.

PMID:39009172 SUPPORT Human Clinical

"The variant causes a frameshift and generates a premature termination codon in messenger RNA, resulting in a C-terminal truncated HOIP mutant, that is, the loss of the linear ubiquitin chain-specific catalytic domain."

The one reported allele that removes the catalytic domain itself, which makes this patient the cleanest human evidence that it is HOIP's ligase activity that is lost.

+ 1 more reference

LUBAC Complex Destabilisation

LUBAC is a ternary complex and behaves as one: losing HOIP takes HOIL-1 and SHARPIN down with it, in patients as in mice. This has been shown in three unrelated patients with three different genotypes, in fibroblasts and EBV-transformed B cells in the first and in PBMCs in the second and fourth, so it is not a property of one allele. The consequence is that HOIP deficiency is functionally a whole-LUBAC deficiency rather than the loss of one enzymatic subunit from an otherwise intact complex. Which interaction is lost depends on the allele. The exon-9-skipping transcript of the second patient removes most of the UBA-1 module and loses binding to SHARPIN while keeping HOIL-1 binding; the exon-7-skipping transcript removes the whole UBA domain and binds neither.

fibroblast CL:0000057

LUBAC complex GO:0071797

Downstream

Loss of Linear (M1) Ubiquitination HOIP carries the catalytic RBR module, so a destabilised complex cannot conjugate M1-linked chains.

Show evidence (3 references)

PMID:26008899 SUPPORT In Vitro

"SHARPIN and HOIL-1 protein levels were lower in the cells from the patient than in control cells"

The direct measurement that the other two subunits fall when HOIP is lost, which is what makes this a whole-complex lesion.

PMID:30936877 SUPPORT In Vitro

"The protein expression of HOIP, as well as HOIL-1 and SHARPIN, were markedly diminished in the patient's PBMCs, suggesting the destabilization of the LUBAC (Figure 2A)."

Independent replication in a second patient with a different genotype, in PBMCs.

PMID:41026334 SUPPORT Human Clinical

"These mutations significantly reduced HOIP and LUBAC protein expression and altered the HOIP protein structure."

A third independent genotype giving the same complex-level result.

Loss of Linear (M1) Ubiquitination

LUBAC is the only ligase known to build head-to-tail M1-linked polyubiquitin, and its substrates sit inside the receptor signalling complexes of TNFR1, IL-1R, the TLRs and CD40 - NEMO and RIPK1 among them. The chains do two jobs at once at those complexes: they recruit and activate the IKK complex, and they hold the receptor signalling complex in its gene-activating configuration rather than letting it convert into the death-inducing cytosolic complex II. Removing them therefore subtracts a signal and releases a brake in the same step, which is the structural reason a single lesion here produces both immunodeficiency and autoinflammation downstream.

protein linear polyubiquitination GO:0097039 ↓ DECREASED

Downstream

Impaired Canonical NF-kappa-B Activation M1 chains on NEMO and RIPK1 are required for IKK recruitment and activation at the receptor signalling complex.

Sensitisation to TNFR1-Mediated Cell Death Without M1 chains the TNFR1 signalling complex converts into the death-inducing cytosolic complex II.

Monocyte Hyperresponsiveness to IL-1 beta The same loss of linear ubiquitination produces the opposite signalling outcome in monocytes, by a route that is not established.

Type I Interferon Pathway Activation Two of the four reported patients carry an interferon-stimulated gene signature in blood; the mechanism linking it to loss of linear ubiquitination is unknown.

Impaired TLR3-Dependent Antiviral Signalling LUBAC components sit in the TLR3 signalling complex and are required for it to activate genes rather than assemble a death complex, so the same loss of linear chains compromises the double-stranded-RNA sensing arm.

Amylopectin Accumulation in Skeletal Muscle Diastase-resistant polyglucosan accumulates in muscle of LUBAC-deficient patients. The route from the ubiquitination defect to the storage material is not established for HOIP.

Show evidence (3 references)

PMID:26008899 SUPPORT In Vitro

"Linear ubiquitination and NF-κB activation are impaired in the patient's fibroblasts stimulated by IL-1β or TNF."

Establishes in patient cells that the ubiquitination defect and the signalling defect travel together.

PMID:39009172 SUPPORT In Vitro

"The truncated HOIP mutant has impaired E3 ligase function in linear ubiquitination, leading to the suppression of canonical NF-κB signalling and increased TNF-induced multiple forms of cell death."

A patient allele that removes the catalytic domain reproduces both downstream arms, which is what licenses drawing both edges from this node.

PMID:22863777 SUPPORT In Vitro

"Here, we show that both LUBAC catalytic activity and LUBAC specificity for linear ubiquitin chain formation are embedded within the RING-IBR-RING (RBR) ubiquitin ligase subunit HOIP."

Establishes that it is HOIP itself that carries both the ligase activity and the linkage specificity, which is why losing this subunit abolishes M1 chains rather than merely reducing LUBAC output.

Impaired Canonical NF-kappa-B Activation

In patient fibroblasts, IKK phosphorylation is impaired and IkappaB-alpha degradation delayed after TNF or IL-1 beta, and IL-6 output falls sharply. The same defect is seen in patient PBMCs after TNF and in patient T and B cells after LPS. Reintroducing wild-type HOIP into the patient's fibroblasts restores IKK phosphorylation, IkappaB-alpha turnover and IL-6 production, which is what makes this a consequence of the HOIP lesion rather than a correlate of it. The defect is graded rather than absolute, and it is deeper for IL-1 beta than for TNF: NEMO puncta form normally after TNF in the same cells in which IL-1 beta fails to induce them.

fibroblast CL:0000057 B cell CL:0000236

canonical NF-kappa-B signal transduction GO:0007249 ↓ DECREASED

Downstream

Defective CD40-Driven B Cell Activation CD40 signals into the canonical NF-kappa-B pathway, and CD40-induced IKK activation is itself reduced in patient B cells.

Impaired T Cell Compartment T cell numbers and memory differentiation are abnormal in the reported patients, but the abnormalities vary between them and no experiment has traced them to the NF-kappa-B defect in human T cells.

Show evidence (3 references)

PMID:26008899 SUPPORT In Vitro

"The HOIP-mutated patient’s fibroblasts displayed impaired IKK phosphorylation and delayed IκBα degradation in response to TNF or IL-1β"

The primary measurement of the signalling defect in patient cells.

PMID:26008899 SUPPORT In Vitro

"cells from the patient complemented with the WT HOIP allele produced similar amounts of IL-6 to control cells in response to stimulation with TNF or IL-1β"

The genetic complementation that establishes the signalling defect as a consequence of the HOIP allele rather than of anything else in the patient's genome.

PMID:41026334 SUPPORT In Vitro

"In the patient’s cells, phosphorylation of NF-κB was significantly reduced compared to the healthy control"

Extends the defect to primary T and B cells after LPS stimulation in a fourth patient.

Defective CD40-Driven B Cell Activation

Patient B cells fail to upregulate CD80 and fail to differentiate into plasmablasts when stimulated with CD40 ligand plus IL-21 or IL-4, while responding normally to B cell receptor engagement. That dissociation - CD40 arm broken, BCR arm intact - was found in the first patient and reproduced in the second, and it localises the lesion to the CD40/NF-kappa-B axis rather than to B cell activation in general.

B cell CL:0000236 plasmablast CL:0000980

CD40 signaling pathway GO:0023035 ↓ DECREASED plasma cell differentiation GO:0002317 ↓ DECREASED

Downstream

Germinal Centre Failure and Impaired Antibody Production CD40-driven B cell activation is the step that seeds germinal centre reactions and plasmablast output.

Show evidence (3 references)

PMID:26008899 SUPPORT In Vitro

"However, the activation and differentiation of the patient's B cells are impaired in response to CD40 engagement."

The defect stated at the level of the claim this node makes.

PMID:26008899 SUPPORT In Vitro

"Nevertheless, they were able to respond to BCR stimulation (anti-IgM plus CpG ± BAFF), suggesting that BCR activation is only partially dependent on LUBAC"

The preserved BCR arm, which is what makes this a CD40-pathway node rather than a general B cell activation failure.

PMID:30936877 SUPPORT In Vitro

"Consistent with the previous report of HOIP deficiency, the patient's B cell proliferation and CD80 expression were impaired after CD40 ligand (CD40L) stimulation and preserved after B cell receptor stimulation"

Independent replication of both halves of the dissociation in a second patient.

Germinal Centre Failure and Impaired Antibody Production

The tissue-level consequence, shown directly in a HOIP-deficient patient's lymph node: lymphoid follicles are fewer and disorganised, germinal centres are lacking, apoptotic cells are increased within follicles, and somatic hypermutation in sorted memory B cells is defective. Circulating memory B cells are low across the reported patients. The result is poor antibody output even where total IgG is not frankly low - the second patient had normal immunoglobulins and still failed to respond to pneumococcal vaccination. Both arms of the molecular lesion converge here, since the excess follicular apoptosis is not explained by the CD40 signalling defect alone.

B cell CL:0000236

B cell activation GO:0042113 ↓ DECREASED

Downstream

Decreased circulating IgG concentration

Decreased specific antibody response to vaccination

Decreased memory B cell proportion

Recurrent bacterial infections Failure of protective antibody against encapsulated organisms is the route from the germinal centre defect to the infection phenotype.

Show evidence (3 references)

PMID:38609546 SUPPORT Human Clinical

"Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development."

Direct evidence in HOIP-deficient human secondary lymphoid tissue, not inferred from the SHARPIN patients alone.

PMID:38609546 SUPPORT Human Clinical

"As expected 6, there were fewer and disorganized lymphoid follicles (B cell zone) in a HOIP-deficient patient’s axillary lymph node."

The histological finding in the HOIP patient's own lymph node.

PMID:38609546 SUPPORT Human Clinical

"The SHM was clearly defective in the HOIP-deficient patient and was modestly diminished in the SHARPIN-deficient patient, indicating a genotype-phenotype correlation consistent with the ex-vivo functional data."

Somatic hypermutation measured in sorted memory B cells, and the observation that the HOIP lesion is the more severe of the two.

Sensitisation to TNFR1-Mediated Cell Death

The second arm of the lesion, and the one that best explains the autoinflammation. Without M1 chains holding the TNFR1 signalling complex together, the receptor's output shifts from gene activation towards the cytosolic complex II that drives RIPK1 kinase-dependent apoptosis and necroptosis. In human patients the evidence is histological rather than biochemical: colon biopsies from a HOIP-deficient patient carry excess cleaved caspase-3 and Ser166-phosphorylated RIPK1, the two markers of exactly that death route. The corresponding biochemistry comes from patient-derived and engineered cells and from mice.

tumor necrosis factor-mediated signaling pathway GO:0033209 ↕ DYSREGULATED programmed cell death GO:0012501 ↑ INCREASED

Animal models

Constitutive and endothelial Hoip knockout mouse Mouse recapitulates HOIP-deficient cells from this model show increased TNF- and lymphotoxin-alpha-induced death through aberrant complex II, and TNFR1 ablation prevents the in vivo consequence.

Downstream

Tissue Cell Death and Inflammatory Infiltration

Lymphatic and Vascular Endothelial Injury Endothelial cells are the cell type in which this sensitisation has the clearest in vivo consequence, established in mice rather than in patients.

Show evidence (2 references)

PMID:38609546 SUPPORT Human Clinical

"Remarkably, a significant increase of positive cells for cleaved caspase-3 (CC3), a marker of apoptosis, and Ser166 pRIPK1, a marker of RIPK1 kinase-dependent apoptosis and necroptosis, were found in colon biopsy samples from both SHARPIN-deficient P1 and a HOIP-deficient patient compared to a..."

The human tissue evidence for this node, and specifically for the RIPK1 kinase-dependent route rather than for cell death in general.

PMID:39009172 SUPPORT In Vitro

"The variant attenuates the canonical NF-κB and MAPK signalling cascades and increases the sensitivity of TNFα-induced diverse cell death and activation of mitochondrial apoptosis pathways."

A patient allele tested in cells, showing the signalling and death arms moving in opposite directions from the same lesion.

Monocyte Hyperresponsiveness to IL-1 beta

The counterintuitive half of the disease. In the same patient whose fibroblasts respond poorly to IL-1 beta, circulating monocytes respond to it more strongly than control monocytes, producing more IL-6 and IL-1 beta. The identical dissociation was described first in HOIL-1 deficiency, so it is a property of LUBAC loss rather than of one gene, and the authors of both reports propose it as the direct cellular basis of the clinical autoinflammation. The fourth patient's monocytes instead accumulated more intracellular TNF after IL-1 beta, so the cytokine that is overproduced is not fixed across patients, but the direction of the monocyte response is.

monocyte CL:0000576

interleukin-1-mediated signaling pathway GO:0070498 ↑ INCREASED

Downstream

Systemic Autoinflammation Excess myeloid proinflammatory cytokine output is the proposed driver of the clinical inflammatory syndrome. It is an authors' hypothesis rather than a demonstrated chain.

Show evidence (3 references)

PMID:26008899 SUPPORT In Vitro

"Upon IL-1β stimulation, the proportion of monocytes producing IL-6 and IL-1β was higher in the patient than in healthy controls"

The measurement in the patient's own monocytes.

PMID:26008899 SUPPORT Human Clinical

"At any rate, the unusual association of IL-1β hyporesponsiveness in fibroblasts and hyperresponsiveness in monocytes from HOIP- or HOIL-1–deficient patients may be responsible for autoinflammation."

The authors' proposal that this lineage split is what drives the autoinflammation, quoted as the hypothesis it is, which is why the downstream edge below is typed as having unknown intermediates.

PMID:23104095 SUPPORT PRIMARY RESULT In Vitro

"By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1β."

The original description of the dissociation, in HOIL-1-deficient patients. Cited here as evidence that it is a LUBAC-level property replicated across two of the three subunit diseases, not as evidence about HOIP patients specifically.

Tissue Cell Death and Inflammatory Infiltration

Where cells die in a LUBAC-deficient tissue, inflammation follows. In patients this is seen as perivascular chronic inflammation with dense CD4-positive infiltration in skin biopsy, and as caspase-3- and pRIPK1-positive cells in colonic mucosa. In conditional mouse models the same node is lethal on its own: deleting Rnf31 in epidermis kills the animals postnatally with severe skin inflammation, and deleting it in dendritic cells produces spontaneous systemic inflammation.

apoptotic process GO:0006915 ↑ INCREASED

Animal models

Epidermis-specific Rnf31 knockout mouse Mouse recapitulates Shows the whole chain within one tissue: HOIP loss, TNF-driven apoptosis, inflammatory infiltrate, and reversal of all of it by removing TNFR1.

Downstream

Systemic Autoinflammation

Show evidence (1 reference)

PMID:30936877 SUPPORT Human Clinical

"Skin biopsy demonstrated superficial perivascular chronic inflammation with dense infiltration of CD4+ and focal MPO+ cells"

The histological infiltrate in a HOIP-deficient patient's affected skin.

Type I Interferon Pathway Activation

Two unrelated patients, on two continents and with different genotypes, carry an interferon-stimulated gene signature in blood. In the second patient it is enriched in PBMCs rather than whole blood, tracks with excess STAT1 phosphorylation in naive CD4 and CD8 T cells but not in monocytes, and is present in the asymptomatic carrier mother as well. The mechanism is open. The obvious candidate - LUBAC degrading TRIM25, a positive regulator of type I interferon production - was tested directly in the patient's PBMCs and TRIM25 was not increased. The authors are explicit that the evidence does not yet make HOIP deficiency an interferonopathy, and that whether JAK inhibition would help is unknown.

type I interferon-mediated signaling pathway GO:0060337 ↑ INCREASED

Show evidence (2 references)

PMID:30936877 SUPPORT Human Clinical

"The type I IFN signature, as defined by the set of 28 genes upregulated in monogenic interferonopathies (14), was enriched in the patient's PBMCs (Figure 4F), and less remarkable in the whole blood (Figure S7C)."

The signature measured against a defined interferonopathy gene set.

PMID:41026334 SUPPORT Human Clinical

"The expression of the patient's interferon-stimulated gene (ISG) was markedly higher than that of healthy controls."

Independent replication in a fourth patient with a different genotype.

Impaired TLR3-Dependent Antiviral Signalling

LUBAC components are part of the TLR3 signalling complex, and without them TLR3 ligation activates fewer genes while assembling more of a death-inducing complex. Both halves of that shift point the same way clinically: less antiviral gene induction, and more double-stranded-RNA-driven cell death. The evidence is from LUBAC-deficient cells and mice rather than from HOIP patients, and no reported HOIP-deficient patient has had influenza A infection, so this arm is a mechanistic candidate for the viral susceptibility rather than a demonstrated cause of it.

toll-like receptor signaling pathway GO:0002224 ↓ DECREASED

Downstream

Recurrent viral infections Proposed route from the TLR3 signalling defect to the clinical viral susceptibility. No reported HOIP-deficient patient has had a TLR3-dependent infection characterised, so the link is inferred from the cellular and murine work rather than observed.

Show evidence (2 references)

PMID:27810922 SUPPORT Model Organism

"We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection."

The antiviral consequence of the LUBAC-TLR3 interaction, established in mice, which is the claim this node makes and the reason it is graded as model-organism evidence.

PMID:27810922 SUPPORT In Vitro

"Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death."

The second half of the shift: the same receptor that loses gene-activating output gains a death-inducing one, which is the TLR3 counterpart of the TNFR1 node above.

Impaired T Cell Compartment

The T cell arm is real but variable, and the variability is the point. The founding patient had severe T cell lymphopenia affecting the naive compartment with an impaired proliferative response to anti-CD3; the second patient had normal T cell counts and normal responses to T cell stimulation; the fourth had reduced CD4 and CD8 T cells with loss of central and effector memory CD8 subsets, fewer circulating T follicular helper cells and more Th17 cells. Mouse work shows LUBAC is required for late thymocyte differentiation and for regulatory T cell development and homeostasis, which gives a candidate mechanism the human data do not yet discriminate between. In the founding patient a second route is available and was raised by her own authors: systemic lymphangiectasia causes lymphatic leak, and lymphatic leak causes lymphopenia independently of any signalling defect.

T cell CL:0000084

Downstream

Decreased total T cell count

Recurrent viral infections Viral control fails through the T cell compartment rather than directly: the reduced T cell count and the impaired CD40-dependent B cell help it supports leave both cellular and antibody-mediated antiviral responses weakened. Those two steps are the known intermediates, and both are curated as their own nodes in this entry.

Show evidence (4 references)

PMID:26008899 SUPPORT Human Clinical

"Moreover, the HOIP-deficient patient had severe T cell lymphopenia, affecting the naive compartment in particular, accompanied by an increase in the proportions of effector memory CD4+ and TEMRA CD8+ cells."

The T cell phenotype in the founding patient.

PMID:41026334 SUPPORT Human Clinical

"Subset analysis of CD4 + T cells showed decreased T follicular helper cells (Tfh) and increased IL-17-producing T helper (Th17) cells."

The subset-level abnormalities in the fourth patient.

PMID:30936877 REFUTE Human Clinical

"However, these features were not observed in our patient, who showed normal T cell counts and normal response to T cell receptor-mediated stimulations, which might be attributed to her different genotype, her age, or other environmental factors."

A patient in whom the T cell arm is absent, which is why this node is curated as a variable consequence rather than a constant feature of the disease.

+ 1 more reference

Lymphatic and Vascular Endothelial Injury

Reported in one patient only, and the least mechanistically settled arm of the disease in humans. The founding patient had abnormal thoracic duct filling on lymphangiography, white-tipped thickened villi through most of the small bowel, and dilated lymphatic spaces in duodenal, small intestinal and colonic biopsies. Neither of the two subsequent patients assessed for it had lymphangiectasia. The case for connecting it to the cell-death arm rests on mouse work: constitutive and endothelium-restricted Hoip deletion kills embryos through TNFR1-mediated endothelial death with disrupted vasculature, and that is the model the founding report itself invoked for its patient's lymphatic phenotype.

endothelial cell of lymphatic vessel CL:0002138

lymph vessel development GO:0001945 ⚠ ABNORMAL

Animal models

Constitutive and endothelial Hoip knockout mouse Mouse partially recapitulates Endothelium-restricted deletion produces disrupted vasculature, the murine counterpart of the vascular and lymphatic phenotype in the founding patient.

Downstream

Intestinal lymphangiectasia

Show evidence (3 references)

PMID:26008899 SUPPORT Human Clinical

"An endoscopy with biopsies showed dilated lymphatic space in duodenal, small intestinal, and colonic mucosa."

The histological confirmation of lymphangiectasia in the founding patient.

PMID:26008899 SUPPORT INDIRECT Human Clinical

"Overall, the circulatory and lymph vessel phenotypes of Hoip-deficient mice and HOIP-deficient patients suggest that HOIP, alone or less likely as a subunit of LUBAC, may regulate these systems."

The authors' own reading of the mouse-to-human parallel, stated as a suggestion, which is the strength of claim this node carries.

PMID:30936877 REFUTE Human Clinical

"The clinical and histological absence of lymphangiectasia in our patient is noteworthy, because the vessel formation abnormality has been observed in the previous HOIP-deficient patient as well as in Rnf31-knock out mice (19)."

A second patient in whom the arm is absent on endoscopy and histology, which is why this node is not treated as a constant feature.

Amylopectin Accumulation in Skeletal Muscle

Patchy diastase-resistant, PAS-positive material in scattered skeletal muscle fibres - polyglucosan, chemically an amylopectin-like glucan - on sternocleidomastoid biopsy in the founding patient. It was subclinical: no electrographic or echographic sign of myopathy or cardiomyopathy, and normal creatine kinase. This is where HOIP and HOIL-1 deficiency differ most. In HOIL-1 disease amylopectinosis is early, severe and consistent, and it dominates the non-immunological phenotype; in the HOIP patient it was a biopsy finding, which led the founding authors to suggest the storage arm depends more on HOIL-1 than on HOIP or on LUBAC as a whole. Neither of the later patients assessed had it, although in both cases muscle was not biopsied.

skeletal muscle fiber CL:0008002

glycogen metabolic process GO:0005977 ⚠ ABNORMAL

Downstream

Abnormal muscle glycogen content

Show evidence (2 references)

PMID:26008899 SUPPORT Human Clinical

"Periodic Acid-Schiff staining of sternocleidomastoid muscular biopsy showed patches of granular or subsarcolemmal PAS-positive material that was resistant to treatment with diastase, consistent with amylopectinosis, but there were no clinical, electrographic, or echographic signs of skeletal..."

The histological finding and, in the same sentence, the absence of a clinical myopathy, which is why this node has no downstream weakness edge.

PMID:26008899 SUPPORT Human Clinical

"The milder amylopectinosis in the HOIP-deficient patient suggests that amylopectinosis may be more dependent on HOIL-1 than HOIP, LUBAC, and NF-κB."

The authors' subunit-level interpretation, which is why this entry does not treat the storage arm as a core feature of the HOIP disease.

Systemic Autoinflammation

The clinical syndrome that the myeloid hyperresponsiveness and the tissue cell death converge on: recurrent fever with no identified pathogen, persistently raised CRP and ESR, arthritis, dermatitis and splenomegaly, beginning in the neonatal period or in infancy in every reported patient. It is separable from the infection burden - the founding patient was treated for three years as familial Mediterranean fever before any immunological work was done - and it is what TNF blockade addresses.

Animal models

Dendritic cell-specific Hoip knockout mouse Mouse partially recapitulates Reproduces spontaneous systemic inflammation from a HOIP lesion restricted to one myeloid lineage, and assigns it to MyD88-dependent signalling.

Downstream

Recurrent fever

Elevated circulating C-reactive protein concentration

Elevated erythrocyte sedimentation rate

Polyarticular arthritis

Eczematoid dermatitis

Splenomegaly

Show evidence (2 references)

PMID:26008899 SUPPORT Human Clinical

"A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC."

The founding clinical description, which names the autoinflammation as multiorgan.

PMID:41026334 SUPPORT Human Clinical

"The patient experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period, requiring repeated hospitalizations."

The same syndrome in the most severely affected reported patient.

⬡

Pathograph

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

●

Phenotypes

Blood 4

Decreased circulating IgG concentration HP:0004315

Show evidence (2 references)

PMID:26008899 SUPPORT Human Clinical

"and hypogammaglobulinemia (IgG: 315 mg/dl), associated with nonprotective antibody responses to S. pneumoniae and H. influenzae, but with a good antibody response to tetanus toxoid."

The measured IgG in the founding patient, with the antibody-response pattern beside it - absent against polysaccharide antigens, preserved against a protein antigen.

PMID:30936877 REFUTE Human Clinical

"Although she did not demonstrate hypogammaglobulinemia (IgG 645, IgM 25, and IgA 965 mg/dl), she lacked response to pneumococcal antigens upon vaccination."

A patient without hypogammaglobulinaemia, which is what stops this being curated as a constant feature.

Decreased memory B cell proportion HP:0030374

Show evidence (2 references)

PMID:30936877 SUPPORT Human Clinical

"Immunophenotyping of leukocyte surface markers demonstrated low memory B cells (Table S2)."

The measurement in the second patient.

PMID:41026334 SUPPORT Human Clinical

"B cell analysis showed increased frequencies of total B and naive B cells, with reductions in memory and transitional B cell populations."

Replication with the reciprocal naive B cell excess in the fourth patient.

Decreased total T cell count HP:0005403

Show evidence (2 references)

PMID:26008899 SUPPORT Human Clinical

"showed T cell lymphopenia (CD3+: 776 cells/µl)"

The measured T cell count in the founding patient.

PMID:41026334 SUPPORT Human Clinical

"Immunophenotyping revealed a reduction in CD8 + T cells, central memory (CD8 CM) and effector memory (CD8 EM) T cells, and CD4 + T cells."

The T cell reduction in the fourth patient, with the memory subsets specified.

Anemia HP:0001903

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"anemia (Hb, 8.1 g/dl), iron deficiency (3.7 µmol/l)"

The measured haemoglobin and the coexisting iron deficiency.

Cardiovascular 2

Splenomegaly HP:0001744

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"During the neonatal period, she presented omphalitis, requiring antibiotic treatment, and splenomegaly."

Neonatal splenomegaly in the founding patient.

Intestinal lymphangiectasia HP:0002593

Sequelae: Chronic diarrhea Protein-losing enteropathy

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"videocapsule endoscopy, at the age of 16 yr, showed patchy areas of white-tipped thickened villi throughout most of the small bowel, consistent with intestinal lymphangiectasia"

The endoscopic finding that established the diagnosis in the founding patient.

Digestive 3

Hepatomegaly HP:0002240

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"After discharge, she had recurrent episodes of fever and persistent splenomegaly, associated with mild liver enlargement."

Records the liver enlargement in the founding patient, in the same sentence that records the fever and splenomegaly this entry already curates.

Chronic diarrhea HP:0002028

Temporal: CHRONIC

Show evidence (2 references)

PMID:41026334 SUPPORT Human Clinical

"The patient experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period, requiring repeated hospitalizations."

Chronic diarrhoea named as a presenting feature in the fourth patient.

PMID:26008899 SUPPORT Human Clinical

"At the age of 7 yr, the patient began to suffer from recurrent episodes of fatty diarrhea, associated with fever and oral ulcers."

The steatorrhoeic form in the founding patient, which tracks the lymphangiectasia.

Protein-losing enteropathy HP:0002243

Sequelae: Hypoalbuminemia Edema

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"Recurrent episodes of diarrhea and edema, requiring frequent infusions of albumin and furosemide, led to additional investigations."

The clinical consequence of enteric protein loss, and the reason the lymphatic investigations were undertaken.

Immune 4

Eczematoid dermatitis HP:0000964

Show evidence (1 reference)

PMID:30936877 SUPPORT Human Clinical

"On examination at the age of 7 years old she was noted to have eczematous dermatitis (Figure 1A), splenomegaly, and clubbing of her toes and fingers."

The dermatitis, splenomegaly and clubbing of the second patient in a single clinical description.

Recurrent bacterial infections HP:0002718

Temporal: RECURRENT

Show evidence (2 references)

PMID:41026334 SUPPORT Human Clinical

"He was diagnosed with diaper dermatitis, purulent meningitis, pneumonia, urinary tract infection, peritonitis, and growth retardation"

The range of bacterial infections in the fourth patient.

PMID:41608114 SUPPORT Other

The IUIS committee's summary row, which lists bacterial infection first among the clinical features of the disease.

Recurrent viral infections HP:0004429

Temporal: RECURRENT

Sequelae: Verrucae

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"a combined immunodeficiency manifesting as chronic diarrhea and recurrent viral and bacterial infections"

Recurrent viral infection as part of the presenting combined immunodeficiency.

Decreased specific antibody response to vaccination HP:0032140

Show evidence (2 references)

PMID:26008899 SUPPORT Human Clinical

"The HOIP-deficient patient has hypogammaglobulinemia and nonprotective antibody responses to Streptococcus pneumoniae and Haemophilus influenzae."

Names the organisms against which the antibody response fails.

PMID:30936877 SUPPORT Human Clinical

"she lacked response to pneumococcal antigens upon vaccination"

The same defect in a patient with normal immunoglobulins, which is why this phenotype is separated from IgG concentration.

Integument 1

Verrucae HP:0200043

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"She also developed persistent warts."

The wart phenotype recorded in the founding patient's case description.

Limbs 2

Clubbing HP:0001217

Show evidence (1 reference)

PMID:30936877 SUPPORT Human Clinical

"On examination at the age of 7 years old she was noted to have eczematous dermatitis (Figure 1A), splenomegaly, and clubbing of her toes and fingers."

The clubbing described on examination of the second patient at seven years.

Lower limb muscle weakness HP:0007340

Show evidence (2 references)

PMID:26008899 SUPPORT Human Clinical

"Moreover, the patient was suffering from muscular weakness, especially in the lower extremities."

The weakness as described in the founding patient.

PMID:26008899 SUPPORT Human Clinical

"However, motor and sensory conduction and needle electromyography were normal, and there was no evidence of cardiomyopathy at heart ultrasound."

The normal electrophysiology, which is why no causal edge is drawn from the muscle storage node to this phenotype.

Metabolism 6

Recurrent fever HP:0001954

Temporal: RECURRENT

Show evidence (2 references)

PMID:26008899 SUPPORT Human Clinical

"After discharge, she had recurrent episodes of fever and persistent splenomegaly, associated with mild liver enlargement."

Recurrent fever from the neonatal period in the founding patient.

PMID:30936877 SUPPORT Human Clinical

"At age 3, she developed recurrent fevers and suffered from severe bacterial, viral and fungal infections even after discontinuation of immunosuppressants"

The same feature in the second patient.

Elevated circulating C-reactive protein concentration HP:0011227

Show evidence (1 reference)

PMID:41026334 SUPPORT Human Clinical

"He initially presented with fever at 8 days of life, accompanied by elevated inflammatory markers (C-reactive protein(CRP) 57 mg/L)."

Raised CRP at presentation in the fourth patient.

Elevated erythrocyte sedimentation rate HP:0003565

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"elevated fluctuating but consistently high ESR (between 26 and 119 mm/h)"

The quantitative ESR range reported in the founding patient.

Hypoalbuminemia HP:0003073

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"Additional abnormalities identified in laboratory tests included hypoalbuminemia (2.6 g/dl), hypocalcemia (8.2 mg/dl), anemia (Hb, 8.1 g/dl)"

The measured albumin, with the coexisting hypocalcaemia and anaemia.

Edema HP:0000969

Temporal: RECURRENT

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"However, the episodes of systemic edema persisted, although at a lower frequency."

The oedema and its partial response to immunoglobulin replacement.

Abnormal muscle glycogen content HP:0012269

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"A patchy accumulation of PAS+diastase-resistant material in a scattered muscle fibers is shown in patient’ biopsy."

The histological description of the storage material in muscle.

Musculoskeletal 1

Polyarticular arthritis HP:0005764

Show evidence (1 reference)

PMID:30936877 SUPPORT Human Clinical

"At 7 months old she was diagnosed with polyarticular juvenile idiopathic arthritis after developing hip swelling and knee contracture."

The presenting feature of the second patient.

Prenatal and Birth 1

Neonatal omphalitis HP:0032435

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"During the neonatal period, she presented omphalitis, requiring antibiotic treatment"

The presenting infection of the founding patient.

Respiratory 1

Bronchiectasis HP:0002110

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"A chest CT scan at the age of 17 yr demonstrated mild bronchiectasis in the right middle and lower lobes."

The imaging finding in the founding patient.

Growth 1

Postnatal growth retardation HP:0008897

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"From early childhood, the growth of the patient was stunted."

The growth phenotype in the founding patient.

🧬

Genetic Associations

RNF31

Gene: RNF31 hgnc:16031 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:26008899 SUPPORT Human Clinical

"These variants included a homozygous T-to-C substitution at position 215 (c.215T>C) in exon 2 of HOIP (also known as RNF31), which was identified in the patient and confirmed by Sanger sequencing"

The gene-discovery result and the founding allele.

PMID:26008899 SUPPORT Human Clinical

"The HOIP L72P variant was not found in public databases (NCBI, UCSC, 1000 genomes, or ExAC, reaching a total of up to 60,706 individuals) or in our own WES database (2,212 individuals)."

Population-database absence, part of the case for pathogenicity of the founding allele.

PMID:41026334 SUPPORT Human Clinical

"These mutations were absent in population databases such as ExAC, 1000 Genomes, HGMD, and gnomAD."

The same argument for the fourth patient's two alleles.

Variants (3)

c.215T>C (p.Leu72Pro)

Homozygous missense change at the start of the PUB domain in the founding Kuwaiti kindred. Absent from public databases covering up to 60,706 individuals at the time of publication; no mutant protein detectable on immunoblot.

c.1197G>C and c.1737+3A>G

Compound heterozygous splice-region variants in the second patient, producing transcripts that skip exon 7 (out of frame, removing the whole UBA domain) or exon 9 (in frame, removing most of UBA-1 and with it SHARPIN binding).

c.1654C>T (p.Gln552Ter) and c.3038A>C (p.His1013Pro)

Compound heterozygous nonsense plus missense pair in the fourth patient, both absent from ExAC, 1000 Genomes, HGMD and gnomAD.

💊

Medical Actions

Immunoglobulin Replacement Therapy

Action: immunoglobulin replacement therapy Ontology label: Intravenous Immunoglobulin Therapy NCIT:C121331

Agent: human immunoglobulin G NCIT:C80829

Platform: Protein replacement

Intravenous or subcutaneous immunoglobulin, given in every reported patient. It replaces the antibody the failed germinal centre cannot produce, and improves IgG trough levels and infection burden; in the second patient it was sufficient on its own to keep her stable with minimal inflammation. It does not address the autoinflammatory arm, and in the founding patient systemic oedema continued after it was started.

Mechanism Target:

BYPASSES Germinal Centre Failure and Impaired Antibody Production — Supplies pooled donor antibody rather than repairing the germinal centre defect, which is why it is curated as bypassing rather than inhibiting the node.

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"Treatment with intravenous immunoglobulins was initiated, leading to an improvement in IgG trough levels."

The measured effect on the humoral deficit in the founding patient.

Show evidence (1 reference)

PMID:30936877 SUPPORT Human Clinical

"Currently, the patient is stable with minimal inflammation on subcutaneous immunoglobulin supplementation."

The subcutaneous route, and the observation that it was sufficient as sole therapy in one patient.

TNF Blockade

Action: Pharmacotherapy NCIT:C15986

Agent: adalimumab NCIT:C65216 etanercept NCIT:C2381

Etanercept and adalimumab have both been used in HOIP-deficient patients, and the rationale is the cell-death arm: if TNF signalling through a LUBAC-deficient TNFR1 complex is what kills cells and drives inflammation, blocking TNF should quieten it. The clinical picture is of real but incomplete and non-durable benefit - arthritis improved on etanercept in the second patient, and in the fourth each adalimumab dose produced defervescence and a CRP fall lasting fifteen to twenty-five days before fever returned. That patient died during a relapse. The strongest evidence for the strategy in a LUBAC disease comes from a SHARPIN-deficient patient, in whom anti-TNF produced complete clinical and transcriptomic resolution.

Mechanism Target:

INHIBITS Sensitisation to TNFR1-Mediated Cell Death — Removing the ligand prevents engagement of the TNFR1 complex that, without linear ubiquitin chains, converts into the death-inducing complex II.

Show evidence (1 reference)

PMID:38609546 SUPPORT INDIRECT Human Clinical

"The remarkable efficacy of anti-TNF therapy in one patient, supported by genetic dissection of joint inflammation using murine models, suggests that TNF-mediated cell death contributes to the autoinflammation."

The authors' inference from treatment response to mechanism, in a LUBAC-deficient patient. That patient is SHARPIN- rather than HOIP-deficient, which is why this is graded indirect and why the entry does not present the mechanism as established for HOIP.

Show evidence (3 references)

PMID:41026334 SUPPORT Human Clinical

"A second dose on November 23 led to rapid defervescence and a significant drop in CRP(Fig. 1G)."

Adalimumab in a HOIP-deficient patient: a clear but time-limited response, which is the basis for describing the benefit as incomplete.

PMID:30936877 SUPPORT Human Clinical

"She was treated with corticosteroids, methotrexate, and eventually improved on TNF blockade with etanercept."

Etanercept for the arthritis of the second patient, before her genetic diagnosis.

PMID:38609546 SUPPORT Human Clinical

"Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation."

The best response reported in any LUBAC deficiency, in the sibling SHARPIN disease rather than in a HOIP patient.

Antibiotic Prophylaxis

Action: antibiotic prophylaxis Ontology label: Antibiotic Prophylaxis NCIT:C51993

Agent: trimethoprim-sulfamethoxazole NCIT:C909

Platform: Small molecule

Continuous antibacterial prophylaxis, cotrimoxazole in the founding patient and sulfamethoxazole in the fourth, alongside immunoglobulin replacement. It addresses the consequence of the antibody defect rather than any mechanism.

Target Phenotypes: Recurrent bacterial infections HP:0002718

Show evidence (2 references)

PMID:26008899 SUPPORT Human Clinical

"Prophylaxis with cotrimoxazole was initiated."

Antibacterial prophylaxis in the founding patient.

PMID:41026334 SUPPORT Human Clinical

"the patient started a regimen of intravenous immunoglobulin (IVIG) (400-600 mg/kg monthly) and sulfamethoxazole (SMZ) for infection prophylaxis"

The same strategy, with doses, in the fourth patient.

Low-Fat High-Protein Diet

Action: low-fat high-protein diet Ontology label: Dietary Intervention NCIT:C15447

Platform: Behavioral / lifestyle

Dietary management of intestinal lymphangiectasia: restricting long-chain fat reduces intestinal lymph flow and so reduces enteric protein loss. Partially effective in the founding patient, who continued to have fatty diarrhoea and poor weight gain on it.

Target Phenotypes: Protein-losing enteropathy HP:0002243

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"The patient was placed on a low-fat, high-protein diet, with some improvement, but she continued to suffer from fatty diarrhea, with poor weight gain and impaired linear growth."

Both the intervention and the honest statement of its partial effect, in the one patient who needed it.

Octreotide

Action: Pharmacotherapy NCIT:C15986

Agent: octreotide NCIT:C711

Platform: Peptide

A somatostatin analogue, started in the founding patient for refractory intestinal lymphangiectasia after diet, albumin infusions and immunoglobulin replacement had left her with continuing lymphatic leak. Reported as started rather than as having an assessed outcome.

Target Phenotypes: Intestinal lymphangiectasia HP:0002593

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"The patient is still on antibiotic prophylaxis, a low-fat and high-protein diet, iron and vitamin D supplementation, and immunoglobulin replacement therapy, and has started treatment with octreotide."

Records that octreotide was started. The report does not state an outcome, and none is claimed here.

🔬

Diagnosis

RNF31 sequencing

Molecular confirmation by sequencing RNF31, reached in the published patients by whole-exome sequencing or by a targeted inborn-errors-of-immunity panel. The clinical trigger is the combination that defines the disease: early-onset autoinflammation with recurrent bacterial infection and poor antibody responses. Note that two of the four reported patients were labelled common variable immunodeficiency before the genetic diagnosis was made.

whole exome sequencing NCIT:C101295

Show evidence (2 references)

PMID:41026334 SUPPORT Human Clinical

"Whole-exome sequencing (WES) was performed, and HOIP mutations were confirmed by Sanger sequencing."

The diagnostic route taken in the fourth patient.

PMID:30936877 SUPPORT Human Clinical

"Methods: Targeted next generation sequencing of 352 immune-related genes was performed."

The panel route, which is how the second patient was diagnosed after a clinical label of common variable immunodeficiency.

LUBAC subunit immunoblot

Immunoblotting patient fibroblasts or PBMCs for HOIP, HOIL-1 and SHARPIN. This is the functional confirmation step: all three subunits fall together, which both demonstrates that the variant is destabilising and distinguishes a real LUBAC deficiency from a variant of uncertain significance in RNF31. It was applied in each of the reported patients.

western blotting of LUBAC subunits NCIT:C16357

Show evidence (1 reference)

PMID:41026334 SUPPORT Human Clinical

"Western blot analysis of the patient’s PBMCs revealed significantly reduced expression of HOIP, HOIL-1, and SHARPIN compared to healthy controls (Fig. 2D)."

The assay, and the result pattern that confirms a destabilising RNF31 allele.

Lymphocyte immunophenotyping

Flow cytometric enumeration of T and B cell subsets. The findings that recur are low memory B cells with a naive B cell excess, and variable T cell lymphopenia with loss of CD8 memory subsets; IUIS records normal total T cell numbers with decreased memory B cells as the laboratory signature of the disease.

flow cytometry NCIT:C16585

Show evidence (1 reference)

PMID:41026334 SUPPORT Human Clinical

"Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry to assess T and B cell subsets under unstimulated condition."

The assay as applied in the most recently reported patient.

Muscle biopsy with periodic acid-Schiff staining

Periodic acid-Schiff staining with and without diastase pretreatment on skeletal muscle. Persistence of PAS-positive material after diastase is what identifies polyglucosan rather than ordinary glycogen. Worth doing where the storage arm is suspected, but note that in the one HOIP patient biopsied the finding was subclinical and the muscle was electrophysiologically normal.

muscle biopsy NCIT:C51895

Show evidence (1 reference)

PMID:26008899 SUPPORT Human Clinical

"The presence of amylopectinosis was documented by persistence of PAS-positive material in diastase-treated sections."

The criterion that distinguishes polyglucosan from glycogen on this stain.

📊

Prevalence

Worldwide, published cases

Cases In Literature Ultra Rare

Four patients fully reported in the English-language literature as of January 2025, plus one further HOIP-deficient patient contributing laboratory data without a separate clinical report. No incidence or prevalence estimate exists and none is computable from a cohort this size.

Show evidence (1 reference)

PMID:41026334 SUPPORT Human Clinical

"Here, we present the clinical and immunological features of a Chinese boy with novel compound heterozygous HOIP mutations, the fourth reported case globally."

A 2025 report whose authors reviewed the HOIP literature through January 2025 and count their patient as the fourth case, which is the basis for the ULTRA_RARE band.

🐁

Animal Models

Constitutive and endothelial Hoip knockout mouse

Germline and endothelium-restricted Hoip deletion. Both are lethal at midgestation from aberrant endothelial cell death and defective vascularisation, and both are rescued by concurrent deletion of TNFR1. This is the cleanest in vivo demonstration that the TNFR1 death route, rather than the loss of NF-kappa-B output, is what kills LUBAC-deficient endothelium.

Species

Mouse

Genotype

Hoip-/- ; Hoip fl/fl Tie2-Cre

Publication

PMID:25284787

Pathograph links

Sensitisation to TNFR1-Mediated Cell Death recapitulates fidelity: high observes: cellular HOIP-deficient cells from this model show increased TNF- and lymphotoxin-alpha-induced death through aberrant complex II, and TNFR1 ablation prevents the in vivo consequence.

Limitations: The rescue experiment that establishes the TNFR1 dependence is only possible in mice; in patients the corresponding evidence is caspase-3 and pRIPK1 staining of colonic mucosa, which shows the death route is active but not that it is necessary.

Show evidence (1 reference)

PMID:25284787 SUPPORT Model Organism

"Ablation of tumor necrosis factor receptor 1 (TNFR1) prevents cell death, vascularization defects, and death at midgestation."

The genetic epistasis that establishes TNFR1 as the route.

Lymphatic and Vascular Endothelial Injury partially recapitulates fidelity: moderate observes: tissue Endothelium-restricted deletion produces disrupted vasculature, the murine counterpart of the vascular and lymphatic phenotype in the founding patient.

Limitations: The mouse dies in utero from a blood-vessel defect, while the human phenotype is postnatal lymphangiectasia in one of four patients and explicitly absent in another. The model therefore speaks to endothelial vulnerability to TNFR1-driven death rather than to the human lymphatic syndrome, and complete HOIP loss is lethal in mouse where the human alleles are hypomorphic.

Show evidence (1 reference)

PMID:25284787 SUPPORT Model Organism

"Hence, LUBAC and its linear-ubiquitin-forming activity are required for maintaining vascular integrity during embryogenesis by preventing TNFR1-mediated endothelial cell death."

The authors' conclusion, which is the claim this link makes at tissue scale.

Show evidence (1 reference)

PMID:29695863 SUPPORT Model Organism

"Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity."

Independent replication of the model's central result, and the qualification that the death is only partly RIPK1 kinase-dependent.

Dendritic cell-specific Hoip knockout mouse

Conditional Hoip deletion in dendritic cells, the model that separates the autoinflammatory arm from the TNF arm. These mice develop spontaneous systemic inflammation; crossing them to TNFR1-null mice does not rescue it, whereas MyD88 deficiency does and antibiotics reduce it, pointing at TLR/IL-1R rather than TNFR1 signalling as the driver of the inflammatory phenotype.

Species

Mouse

Genotype

Hoip fl/fl CD11c-Cre

Publication

PMID:34253576

Pathograph links

Systemic Autoinflammation partially recapitulates fidelity: moderate observes: organism Reproduces spontaneous systemic inflammation from a HOIP lesion restricted to one myeloid lineage, and assigns it to MyD88-dependent signalling.

Limitations: The lesion is dendritic-cell-restricted and complete, whereas patients are hypomorphic in every cell. The MyD88 dependence is a mouse epistasis result with no human counterpart, and it sits awkwardly beside the clinical observation that anti-TNF therapy controls the autoinflammation in LUBAC-deficient patients.

Show evidence (2 references)

PMID:34253576 SUPPORT Model Organism

"In this study, we found that dendritic cell (DC)-specific deletion of HOIP resulted in spontaneous inflammation, indicating the essential role of HOIP in maintaining DC homeostasis."

The phenotype this link records.

+ 1 more reference

Epidermis-specific Rnf31 knockout mouse

Keratinocyte-restricted Rnf31 deletion, lethal in the early postnatal period from severe skin inflammation driven by TNF-induced keratinocyte apoptosis and rescued by TNFR1 deletion. Included because it is the tissue-level demonstration that LUBAC loss converts a normal TNF signal into a cell-death signal in a differentiated epithelium.

Species

Mouse

Genotype

Rnf31 fl/fl K14-Cre

Publication

PMID:29728512

Pathograph links

Tissue Cell Death and Inflammatory Infiltration recapitulates fidelity: moderate observes: tissue Shows the whole chain within one tissue: HOIP loss, TNF-driven apoptosis, inflammatory infiltrate, and reversal of all of it by removing TNFR1.

Limitations: The severe inflammatory dermatitis of this model and of Sharpin-null mice has no close counterpart in HOIP-deficient patients, whose dermatological findings are eczematous rather than the fulminant skin disease seen here. Species differences in keratinocyte TNF sensitivity, and the fact that the mouse allele is a complete deletion, both bear on that gap.

Show evidence (1 reference)

PMID:29728512 SUPPORT Model Organism

"Consistently, deleting TNF receptor 1 could rescue the lethality of RNF31 epidermis-specific KO mice and also the skin inflammation."

The TNFR1 rescue that makes this a demonstration of the cell-death-to-inflammation step rather than of skin inflammation in general.

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Source YAML

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name: HOIP Deficiency
creation_date: "2026-09-29T21:00:00Z"
category: Mendelian
synonyms:
- immunodeficiency 115 with autoinflammation
- IMD115
- RNF31 deficiency
- LUBAC deficiency due to HOIP mutation
disease_term:
  preferred_term: HOIP deficiency
  term:
    id: MONDO:0957981
    label: immunodeficiency 115 with autoinflammation
parents:
- Primary Immunodeficiency
- Combined Immunodeficiency
- Autoinflammatory Syndrome
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
  iuis_category:
    classification_value: combined immunodeficiency with syndromic features
    notes: >-
      The IUIS 2024 update lists HOIP deficiency in Table 2, "CIDs with associated or
      syndromic features", in the same "Other defects" sub-section as its sibling HOIL1
      deficiency. The placement is the committee's, not an inference from the phenotype.
      The quoted row comes from the classification tables in the cached full text rather
      than from the abstract.
    evidence:
    - reference: PMID:41608114
      reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        HOIP deficiency | RNF31 | AR | 612487 | Normal numbers | Normal, decreased memory B cells | Decreased | Bacterial infections; autoinflammation; amylopectinosis; lymphangiectasia
      explanation: >-
        The committee's own row for HOIP deficiency, naming the gene, autosomal recessive
        inheritance, normal T cell numbers with decreased memory B cells, and the four
        cardinal clinical features.
description: >-
  HOIP deficiency is an autosomal recessive inborn error of immunity caused by biallelic
  hypomorphic or loss-of-function variants in RNF31, which encodes HOIP, the catalytic
  subunit of the linear ubiquitin chain assembly complex (LUBAC). LUBAC is the only
  ubiquitin ligase known to build head-to-tail (M1-linked, "linear") polyubiquitin chains,
  and it is HOIP that carries the catalytic RING-IBR-RING module; HOIL-1 (RBCK1) and
  SHARPIN are the other two subunits. Losing HOIP therefore does not merely remove one
  component: the whole ternary complex is destabilised, with HOIL-1 and SHARPIN protein
  falling alongside it, and linear ubiquitination in patient cells is essentially
  abolished.

  What makes the disease mechanistically interesting is that one molecular lesion produces
  two clinically opposite immune phenotypes at once. Linear ubiquitin chains on NEMO and
  RIPK1 are required both to activate canonical NF-kappa-B downstream of TNFR1, IL-1R, the
  TLRs and CD40, and to restrain the death-inducing complex II that assembles when those
  same receptors are engaged. Loss of the chains therefore gives immunodeficiency through
  the first arm - fibroblasts and B cells that cannot mount an NF-kappa-B response, failed
  CD40-driven B cell activation, absent germinal centres, poor antibody responses - and
  autoinflammation through the second, with patient cells sensitised to TNF-induced
  apoptosis and necroptosis. Cell type is the third variable: while patient fibroblasts are
  hyporesponsive to IL-1 beta, patient monocytes are hyperresponsive to it, which is the
  lineage-specific split the founding report proposed as the direct basis of the
  autoinflammation.

  The clinical syndrome is early-onset multiorgan autoinflammation (recurrent fever, raised
  CRP and ESR, arthritis, dermatitis) combined with recurrent bacterial, viral and fungal
  infection, and it may include subclinical amylopectinosis of skeletal muscle and systemic
  lymphangiectasia with protein-losing enteropathy. Fewer than ten patients have been
  published, and the four fully reported cases differ substantially from one another: only
  the founding case had lymphangiectasia and amylopectinosis, and the most recently reported
  patient died before the age of two. Two of the reported patients carry a type I interferon
  signature in blood, which is unexplained and is not, on the current evidence, enough to
  call the disease an interferonopathy.
notes: >-
  Scope and lump/split. This entry is the RNF31/HOIP disease only. The sibling LUBAC
  disorders - HOIL-1 deficiency (RBCK1; the MONDO concept "polyglucosan body myopathy 1 with
  or without immunodeficiency", MONDO:0014389) and SHARPIN deficiency - are separate MONDO
  concepts with separate genes and are deliberately not merged here, although their cellular
  phenotypes overlap almost completely and the literature routinely reports them together.
  RBCK1 disease additionally has a large non-immunological arm (progressive myopathy and
  cardiomyopathy with polyglucosan storage) that has no counterpart in the reported HOIP
  patients. Papers about HOIL-1 or SHARPIN are cited here only where they report data on
  HOIP patients or HOIP-deficient cells, and each such evidence item says which.

  Patient count. Four patients are fully reported in English as of the literature review in
  PMID:41026334, which covered HOIP cases through January 2025: Boisson 2015 (Kuwaiti woman,
  homozygous p.L72P), Oda 2019 (girl with compound heterozygous splice-region variants), a
  Chinese patient with a homozygous C-terminal frameshift (PMID:39009172), and the Chongqing
  boy with compound heterozygous p.Q552Ter and p.H1013Pro. A further HOIP-deficient patient
  contributes cell and tissue data to PMID:38609546 without a separate clinical report.
  Counts in this entry are counts of patients, and `frequency` is deliberately left unset
  throughout rather than computed from four cases.

  No GeneReviews chapter exists. PubMed with
  `term=(HOIP[TI] OR RNF31[TI] OR LUBAC[TI]) AND genereviews[book]` returns 0 records, and
  `just check-genereviews` reports NO_CHAPTER against the committed Bookshelf index with the
  synonyms above present.

  Haematopoietic stem cell transplantation is not curated as a treatment because no report
  of it in a HOIP-deficient patient was found. The PubMed searches run were
  `HOIL-1 deficiency hematopoietic stem cell transplantation` (0 records),
  `LUBAC deficiency transplantation RBCK1 HSCT` (0 records) and
  `(RNF31 OR HOIP) AND (anakinra OR transplantation OR tocilizumab OR JAK)` (12 records,
  none of them a transplant report in a patient). The published management is supportive:
  immunoglobulin replacement, antibiotic prophylaxis, TNF blockade, and diet plus octreotide
  for the lymphangiectasia. Colchicine was given for three years to the founding patient on
  a presumptive diagnosis of familial Mediterranean fever with no clinical benefit; that is
  left in the cited case description rather than curated as a treatment, because it is a
  failed empirical trial under a mistaken diagnosis rather than a therapy for this disease.

  No `conforms_to` is declared. `just list-modules` was searched for inflammatory,
  necroptosis/cell-death and NF-kappa-B module families; the nearest candidates
  (`nlrp3_inflammasome_activation`, `cytokine_storm_hyperinflammation`) describe a different
  chain - inflammasome priming, and IL-6-driven capillary leak and multiorgan shock - and
  neither matches a node here. A LUBAC/M1-ubiquitin module, or a TNFR1 complex-II
  cell-death module, would be the right conformance target and does not yet exist; this
  entry and the SHARPIN and HOIL-1 diseases would be its first conformers.

  Six phenotypes are deliberately left unwired to the pathograph: neonatal omphalitis,
  clubbing, anaemia, postnatal growth retardation, bronchiectasis and lower limb muscle
  weakness. Each has a textbook explanation - infection in an antibody deficiency, chronic
  inflammation, enteric loss, recurrent respiratory infection - and none of them has a source
  that makes the causal claim about a HOIP-deficient patient. The muscle weakness case is the
  clearest: the patient with the muscle polyglucosan had normal electromyography and normal
  creatine kinase in the same paragraph, so the obvious edge is the one the source excludes.

  Deep-research provenance. An OpenScientist report
  (`research/HOIP_Deficiency-deep-research-openscientist.md`) is committed alongside this
  entry. `just preflight-dr` returns WARN on two counts, both resolved on inspection: TNF is
  mentioned more often than RNF31 because TNF signalling is this disease's own mechanism
  rather than a second disease, and the OMIM number the report cites (612487) is RNF31's
  gene MIM where MONDO xrefs the phenotype MIM 620632. Its reference validation is 15/15
  resolved with 11/11 quotes matching; its term validation reports three mislabelled CURIEs,
  none of which is used here. One of those is worth naming: the report offers `GO:1990592`
  for "protein linear polyubiquitination", which GO calls protein K69-linked ufmylation. The
  term bound in this entry, `GO:0097039`, was looked up independently.

  Pyroptosis is deliberately not modelled. The deep-research report proposes a
  pyroptotic arm from LUBAC and caspase-1 cross-regulation (PMID:32122970),
  but that work is in cell lines and mouse macrophages and no HOIP patient
  phenotype has been attributed to it, so there is no node for it here and the
  reference is not cited.

  Evidence grading rule used throughout: an assay on the patient's own cells
  performed in culture, including ex vivo stimulation of fibroblasts,
  monocytes, B cells or PBMCs, is graded IN_VITRO, following the CLAUDE.md
  rule that cultured cells are in vitro whether human or animal. Only clinical
  observations, histology of patient biopsies and flow counts of unstimulated
  blood are graded HUMAN_CLINICAL. Review round 1 on PR #13204 found seven
  items that broke this rule and they were regraded.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Reported patients are homozygous (p.L72P; a C-terminal frameshift) or compound
    heterozygous (splice-region variants; p.Q552Ter with p.H1013Pro) for RNF31 alleles that
    reduce HOIP protein. Parents and unaffected siblings are heterozygous carriers. Carrier
    status is clinically silent, but the asymptomatic mother in the second family carried the
    same type I interferon and TNF transcriptome signatures as her affected daughter, so
    haploinsufficiency has a measurable subclinical effect on mononuclear cells.
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both parents and the healthy sibling of the patient were heterozygous for the mutation"
    explanation: >-
      Segregation in the founding consanguineous kindred: the patient is homozygous and the
      obligate carriers are unaffected, which is the recessive pattern.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrated that these variants are inherited in trans by sub-cloning of the patient's genomic DNA"
    explanation: >-
      Confirms biallelic (in trans) inheritance of the two variants in the second family,
      excluding a cis configuration on one chromosome.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Type I IFN and TNF-mediated inflammatory transcriptome signatures were also identified in the PBMCs of the asymptomatic mother"
    explanation: >-
      The basis for describing carrier status as clinically silent but not transcriptionally
      silent.
prevalence:
- population: Worldwide, published cases
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Four patients fully reported in the English-language literature as of January 2025, plus
    one further HOIP-deficient patient contributing laboratory data without a separate
    clinical report. No incidence or prevalence estimate exists and none is computable from a
    cohort this size.
  evidence:
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we present the clinical and immunological features of a Chinese boy with novel compound heterozygous HOIP mutations, the fourth reported case globally."
    explanation: >-
      A 2025 report whose authors reviewed the HOIP literature through January 2025 and count
      their patient as the fourth case, which is the basis for the ULTRA_RARE band.

pathophysiology:

- name: Biallelic RNF31 Loss-of-Function Variants
  role: trigger
  biological_scale: MOLECULAR
  description: >-
    Reported alleles are spread across the protein and across variant classes: the homozygous
    p.L72P missense change at the start of the N-terminal PUB domain in the founding kindred;
    compound heterozygous splice-region variants (c.1197G>C and c.1737+3A>G) producing
    transcripts that skip exon 7 or exon 9 and so remove all or part of the UBA domain
    through which HOIP binds SHARPIN and HOIL-1; a homozygous C-terminal frameshift that
    deletes the catalytic domain outright; and a compound heterozygous nonsense plus missense
    pair (p.Q552Ter, p.H1013Pro).

    The alleles are hypomorphic rather than strictly null in most patients, which matters
    because complete Hoip loss is embryonic lethal in mice. p.L72P leaves no detectable
    protein on immunoblot yet is described by its own authors as at least severely hypomorphic
    rather than proven null.
  genes:
  - preferred_term: RNF31
    term:
      id: hgnc:16031
      label: RNF31
    modifier: LOSS_OF_FUNCTION
  molecular_functions:
  - preferred_term: HOIP ubiquitin ligase activity
    term:
      id: GO:0061630
      label: ubiquitin protein ligase activity
    modifier: LOSS_OF_FUNCTION
  notes: >-
    On the term choice. `GO:0061630` is bound here rather than a linkage-specific one because
    GO has no molecular function for Met1/linear-linkage ubiquitin *ligase* activity: the
    linkage-specific terms it does carry are `GO:0061815` Met1-linked polyubiquitin
    deubiquitinase activity, which is the reverse reaction and OTULIN's activity rather than
    HOIP's, and `GO:1990450` linear polyubiquitin binding, which is a binding rather than a
    catalytic function (`runoak -i ols:go search` on "Met1", "linear polyubiquitin" and
    "ubiquitin ligase activity" returns those three and nothing nearer). The positive reason
    for `GO:0061630` is that its own GO definition already covers this reaction: it ends
    "or, in the linear extension of ubiquitin chains, a peptide bond the between the
    C-terminal glycine and N-terminal methionine of ubiquitin residues". The `preferred_term`
    carries the HOIP-specific reading the ontology label leaves out.

    The activity is annotated on this node rather than on `Loss of Linear (M1)
    Ubiquitination` so that the entry states the GO ladder once and in order - gene
    (`RNF31`) to molecular function (ligase activity, lost) to biological process
    (`GO:0097039` protein linear polyubiquitination, decreased, two nodes downstream).
  genetic_context:
    description: >-
      Germline biallelic RNF31 alleles. Missense, splice-region, nonsense and frameshift
      mechanisms are all represented, and all converge on reduced HOIP protein.
    allelic_events:
    - MISSENSE_VARIANT
    - FRAMESHIFT_VARIANT
    - SPLICE_SITE_VARIANT
    - NONSENSE_VARIANT
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The missense allele (L72P, in the PUB domain) is at least severely hypomorphic, as it impairs HOIP expression and destabilizes the whole LUBAC complex."
    explanation: >-
      The founding allele, its domain position, and the authors' own careful statement that it
      is severely hypomorphic rather than demonstrably null.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Results: We identified biallelic variants in close proximity to splice sites (c.1197G>C and c.1737+3A>G) in the RNF31 gene."
    explanation: The splice-region genotype of the second patient.
  - reference: PMID:39009172
    reference_title: "A novel HOIP frameshift variant alleviates NF-kappaB signalling and sensitizes cells to TNF-induced death."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variant causes a frameshift and generates a premature termination codon in messenger RNA, resulting in a C-terminal truncated HOIP mutant, that is, the loss of the linear ubiquitin chain-specific catalytic domain."
    explanation: >-
      The one reported allele that removes the catalytic domain itself, which makes this
      patient the cleanest human evidence that it is HOIP's ligase activity that is lost.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted gene sequencing identified novel compound heterozygous mutations in HOIP (c.1654 C > T, p.Gln552Ter; c.3038 A > C, p.His1013Pro)."
    explanation: The fourth patient's genotype, extending the allelic spectrum to nonsense alleles.
  downstream:
  - target: LUBAC Complex Destabilisation
    causal_link_type: DIRECT
    description: >-
      Reduced or absent HOIP protein removes the scaffold on which the ternary complex
      assembles.
    evidence:
    - reference: PMID:26008899
      reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Thus, the L72P mutation destabilizes the HOIP protein and, consequently, the overall LUBAC complex."
      explanation: >-
        States the causal step from the variant to complex destabilisation, measured in the
        patient's own fibroblasts and EBV-B cells.

- name: LUBAC Complex Destabilisation
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    LUBAC is a ternary complex and behaves as one: losing HOIP takes HOIL-1 and SHARPIN down
    with it, in patients as in mice. This has been shown in three unrelated patients with
    three different genotypes, in fibroblasts and EBV-transformed B cells in the first and in
    PBMCs in the second and fourth, so it is not a property of one allele. The consequence is
    that HOIP deficiency is functionally a whole-LUBAC deficiency rather than the loss of one
    enzymatic subunit from an otherwise intact complex.

    Which interaction is lost depends on the allele. The exon-9-skipping transcript of the
    second patient removes most of the UBA-1 module and loses binding to SHARPIN while
    keeping HOIL-1 binding; the exon-7-skipping transcript removes the whole UBA domain and
    binds neither.
  protein_complexes:
  - preferred_term: LUBAC complex
    term:
      id: GO:0071797
      label: LUBAC complex
    modifier: DECREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SHARPIN and HOIL-1 protein levels were lower in the cells from the patient than in control cells"
    explanation: >-
      The direct measurement that the other two subunits fall when HOIP is lost, which is what
      makes this a whole-complex lesion.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The protein expression of HOIP, as well as HOIL-1 and SHARPIN, were markedly diminished in the patient's PBMCs, suggesting the destabilization of the LUBAC (Figure 2A)."
    explanation: Independent replication in a second patient with a different genotype, in PBMCs.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations significantly reduced HOIP and LUBAC protein expression and altered the HOIP protein structure."
    explanation: A third independent genotype giving the same complex-level result.
  downstream:
  - target: Loss of Linear (M1) Ubiquitination
    causal_link_type: DIRECT
    description: >-
      HOIP carries the catalytic RBR module, so a destabilised complex cannot conjugate
      M1-linked chains.
    evidence:
    - reference: PMID:26008899
      reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we detected linear polyubiquitin aggregates in TNF- and IL-1β–treated control cells, but almost none in the patient's cells"
      explanation: >-
        The direct demonstration in patient fibroblasts that the destabilised complex no longer
        produces linear chains on stimulation.

- name: Loss of Linear (M1) Ubiquitination
  role: central_effector
  biological_scale: MOLECULAR
  description: >-
    LUBAC is the only ligase known to build head-to-tail M1-linked polyubiquitin, and its
    substrates sit inside the receptor signalling complexes of TNFR1, IL-1R, the TLRs and
    CD40 - NEMO and RIPK1 among them. The chains do two jobs at once at those complexes: they
    recruit and activate the IKK complex, and they hold the receptor signalling complex in
    its gene-activating configuration rather than letting it convert into the death-inducing
    cytosolic complex II. Removing them therefore subtracts a signal and releases a brake in
    the same step, which is the structural reason a single lesion here produces both
    immunodeficiency and autoinflammation downstream.
  biological_processes:
  - preferred_term: protein linear polyubiquitination
    term:
      id: GO:0097039
      label: protein linear polyubiquitination
    modifier: DECREASED
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Linear ubiquitination and NF-κB activation are impaired in the patient's fibroblasts stimulated by IL-1β or TNF."
    explanation: >-
      Establishes in patient cells that the ubiquitination defect and the signalling defect
      travel together.
  - reference: PMID:39009172
    reference_title: "A novel HOIP frameshift variant alleviates NF-kappaB signalling and sensitizes cells to TNF-induced death."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The truncated HOIP mutant has impaired E3 ligase function in linear ubiquitination, leading to the suppression of canonical NF-κB signalling and increased TNF-induced multiple forms of cell death."
    explanation: >-
      A patient allele that removes the catalytic domain reproduces both downstream arms,
      which is what licenses drawing both edges from this node.
  - reference: PMID:22863777
    reference_title: "The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that both LUBAC catalytic activity and LUBAC specificity for linear ubiquitin chain formation are embedded within the RING-IBR-RING (RBR) ubiquitin ligase subunit HOIP."
    explanation: >-
      Establishes that it is HOIP itself that carries both the ligase activity and the
      linkage specificity, which is why losing this subunit abolishes M1 chains rather than
      merely reducing LUBAC output.
  downstream:
  - target: Impaired Canonical NF-kappa-B Activation
    causal_link_type: DIRECT
    description: >-
      M1 chains on NEMO and RIPK1 are required for IKK recruitment and activation at the
      receptor signalling complex.
    evidence:
    - reference: PMID:26008899
      reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "we found that the IL-1 β–induced formation of NEMO-containing structures was almost entirely abolished in HOIP L72P-expressing fibroblasts"
      explanation: >-
        The step between the two nodes measured directly: without linear chains, NEMO does not
        assemble into the punctate structures that mark early NF-kappa-B activation.
  - target: Sensitisation to TNFR1-Mediated Cell Death
    causal_link_type: DIRECT
    description: >-
      Without M1 chains the TNFR1 signalling complex converts into the death-inducing
      cytosolic complex II.
    evidence:
    - reference: PMID:25284787
      reference_title: "HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "HOIP-deficient cells are more sensitive to death induction by both tumor necrosis factor (TNF) and lymphotoxin-α (LT-α), and aberrant complex-II formation is responsible for sensitization to TNFR1-mediated cell death in the absence of HOIP."
      explanation: >-
        Names complex II as the intermediate between loss of HOIP and TNFR1-driven death, which
        is the claim this edge makes.
  - target: Monocyte Hyperresponsiveness to IL-1 beta
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The same loss of linear ubiquitination produces the opposite signalling outcome in
      monocytes, by a route that is not established.
    evidence:
    - reference: PMID:26008899
      reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In contrast, the patient's monocytes respond to IL-1β more vigorously than control monocytes."
      explanation: >-
        The observation the edge encodes. It is typed as indirect with unknown intermediates
        because the paper reports the lineage-specific reversal without establishing what
        mediates it.
  - target: Type I Interferon Pathway Activation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Two of the four reported patients carry an interferon-stimulated gene signature in
      blood; the mechanism linking it to loss of linear ubiquitination is unknown.
    evidence:
    - reference: PMID:30936877
      reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "RNA sequencing of whole blood RNA and PBMCs demonstrated a marked transcriptome wide change including differential expression of type I interferon regulated genes."
      explanation: >-
        The observation behind the edge. The authors tested and excluded the proposed TRIM25
        route, so the intermediates are recorded as unknown.
  - target: Impaired TLR3-Dependent Antiviral Signalling
    causal_link_type: DIRECT
    description: >-
      LUBAC components sit in the TLR3 signalling complex and are required for it to activate
      genes rather than assemble a death complex, so the same loss of linear chains
      compromises the double-stranded-RNA sensing arm.
    evidence:
    - reference: PMID:27810922
      reference_title: "--LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "On the biochemical level, we identify LUBAC components as interacting with the TLR3-signaling complex (SC), thereby enabling TLR3-mediated gene activation."
      explanation: >-
        Places LUBAC inside the TLR3 signalling complex and makes gene activation there
        LUBAC-dependent, which is the step this edge asserts.
  - target: Amylopectin Accumulation in Skeletal Muscle
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Diastase-resistant polyglucosan accumulates in muscle of LUBAC-deficient patients. The
      route from the ubiquitination defect to the storage material is not established for
      HOIP.
    evidence:
    - reference: PMID:38609546
      reference_title: "Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Individuals with HOIP and HOIL-1 deficiencies present with severe immunodeficiency, autoinflammation and glycogen storage disease."
      explanation: >-
        Groups the glycogen-storage arm with the LUBAC lesion across both diseases. It
        establishes the association, not the intermediates, which is why the edge is typed as
        having unknown ones.

- name: Impaired Canonical NF-kappa-B Activation
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    In patient fibroblasts, IKK phosphorylation is impaired and IkappaB-alpha degradation
    delayed after TNF or IL-1 beta, and IL-6 output falls sharply. The same defect is seen in
    patient PBMCs after TNF and in patient T and B cells after LPS. Reintroducing wild-type
    HOIP into the patient's fibroblasts restores IKK phosphorylation, IkappaB-alpha turnover
    and IL-6 production, which is what makes this a consequence of the HOIP lesion rather
    than a correlate of it.

    The defect is graded rather than absolute, and it is deeper for IL-1 beta than for TNF:
    NEMO puncta form normally after TNF in the same cells in which IL-1 beta fails to induce
    them.
  biological_processes:
  - preferred_term: canonical NF-kappa-B signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: DECREASED
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The HOIP-mutated patient’s fibroblasts displayed impaired IKK phosphorylation and delayed IκBα degradation in response to TNF or IL-1β"
    explanation: The primary measurement of the signalling defect in patient cells.
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cells from the patient complemented with the WT HOIP allele produced similar amounts of IL-6 to control cells in response to stimulation with TNF or IL-1β"
    explanation: >-
      The genetic complementation that establishes the signalling defect as a consequence of
      the HOIP allele rather than of anything else in the patient's genome.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In the patient’s cells, phosphorylation of NF-κB was significantly reduced compared to the healthy control"
    explanation: Extends the defect to primary T and B cells after LPS stimulation in a fourth patient.
  downstream:
  - target: Defective CD40-Driven B Cell Activation
    causal_link_type: DIRECT
    description: >-
      CD40 signals into the canonical NF-kappa-B pathway, and CD40-induced IKK activation is
      itself reduced in patient B cells.
    evidence:
    - reference: PMID:26008899
      reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We found reduced IκBα degradation and impaired phosphorylation of IKKs in HOIP-mutated cells, when compared with abolished signalization in CD40-deficient cells and normal signalization in control cells"
      explanation: >-
        Measures the NF-kappa-B step specifically under CD40 ligation in patient B cells, which
        is the link this edge asserts.
  - target: Impaired T Cell Compartment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      T cell numbers and memory differentiation are abnormal in the reported patients, but the
      abnormalities vary between them and no experiment has traced them to the NF-kappa-B
      defect in human T cells.

- name: Defective CD40-Driven B Cell Activation
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    Patient B cells fail to upregulate CD80 and fail to differentiate into plasmablasts when
    stimulated with CD40 ligand plus IL-21 or IL-4, while responding normally to B cell
    receptor engagement. That dissociation - CD40 arm broken, BCR arm intact - was found in
    the first patient and reproduced in the second, and it localises the lesion to the
    CD40/NF-kappa-B axis rather than to B cell activation in general.
  biological_processes:
  - preferred_term: CD40 signaling pathway
    term:
      id: GO:0023035
      label: CD40 signaling pathway
    modifier: DECREASED
  - preferred_term: plasma cell differentiation
    term:
      id: GO:0002317
      label: plasma cell differentiation
    modifier: DECREASED
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: plasmablast
    term:
      id: CL:0000980
      label: plasmablast
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, the activation and differentiation of the patient's B cells are impaired in response to CD40 engagement."
    explanation: The defect stated at the level of the claim this node makes.
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Nevertheless, they were able to respond to BCR stimulation (anti-IgM plus CpG ± BAFF), suggesting that BCR activation is only partially dependent on LUBAC"
    explanation: >-
      The preserved BCR arm, which is what makes this a CD40-pathway node rather than a general
      B cell activation failure.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Consistent with the previous report of HOIP deficiency, the patient's B cell proliferation and CD80 expression were impaired after CD40 ligand (CD40L) stimulation and preserved after B cell receptor stimulation"
    explanation: Independent replication of both halves of the dissociation in a second patient.
  downstream:
  - target: Germinal Centre Failure and Impaired Antibody Production
    causal_link_type: DIRECT
    description: >-
      CD40-driven B cell activation is the step that seeds germinal centre reactions and
      plasmablast output.
    evidence:
    - reference: PMID:26008899
      reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "the proportion of CD19+ B cells that were also CD27hi CD38hi (identifying plasmablasts) was markedly lower for the patient than for the control"
      explanation: >-
        Measures the output step downstream of CD40 ligation, connecting the activation defect
        to failed generation of antibody-secreting cells.

- name: Germinal Centre Failure and Impaired Antibody Production
  role: consequence
  biological_scale: TISSUE
  description: >-
    The tissue-level consequence, shown directly in a HOIP-deficient patient's lymph node:
    lymphoid follicles are fewer and disorganised, germinal centres are lacking, apoptotic
    cells are increased within follicles, and somatic hypermutation in sorted memory B cells
    is defective. Circulating memory B cells are low across the reported patients. The result
    is poor antibody output even where total IgG is not frankly low - the second patient had
    normal immunoglobulins and still failed to respond to pneumococcal vaccination.

    Both arms of the molecular lesion converge here, since the excess follicular apoptosis is
    not explained by the CD40 signalling defect alone.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: B cell activation
    term:
      id: GO:0042113
      label: B cell activation
    modifier: DECREASED
  evidence:
  - reference: PMID:38609546
    reference_title: "Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both SHARPIN-deficient and HOIP-deficient individuals showed a substantial reduction of secondary lymphoid germinal center B cell development."
    explanation: >-
      Direct evidence in HOIP-deficient human secondary lymphoid tissue, not inferred from the
      SHARPIN patients alone.
  - reference: PMID:38609546
    reference_title: "Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As expected 6, there were fewer and disorganized lymphoid follicles (B cell zone) in a HOIP-deficient patient’s axillary lymph node."
    explanation: The histological finding in the HOIP patient's own lymph node.
  - reference: PMID:38609546
    reference_title: "Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The SHM was clearly defective in the HOIP-deficient patient and was modestly diminished in the SHARPIN-deficient patient, indicating a genotype-phenotype correlation consistent with the ex-vivo functional data."
    explanation: >-
      Somatic hypermutation measured in sorted memory B cells, and the observation that the
      HOIP lesion is the more severe of the two.
  downstream:
  - target: Decreased circulating IgG concentration
    causal_link_type: DIRECT
  - target: Decreased specific antibody response to vaccination
    causal_link_type: DIRECT
  - target: Decreased memory B cell proportion
    causal_link_type: DIRECT
  - target: Recurrent bacterial infections
    causal_link_type: DIRECT
    description: >-
      Failure of protective antibody against encapsulated organisms is the route from the
      germinal centre defect to the infection phenotype.
    evidence:
    - reference: PMID:26008899
      reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The HOIP-deficient patient has hypogammaglobulinemia and nonprotective antibody responses to Streptococcus pneumoniae and Haemophilus influenzae."
      explanation: >-
        Names the specific organisms against which antibody protection fails, which is the
        mechanistic content of this edge.

- name: Sensitisation to TNFR1-Mediated Cell Death
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    The second arm of the lesion, and the one that best explains the autoinflammation.
    Without M1 chains holding the TNFR1 signalling complex together, the receptor's output
    shifts from gene activation towards the cytosolic complex II that drives RIPK1
    kinase-dependent apoptosis and necroptosis. In human patients the evidence is
    histological rather than biochemical: colon biopsies from a HOIP-deficient patient carry
    excess cleaved caspase-3 and Ser166-phosphorylated RIPK1, the two markers of exactly that
    death route. The corresponding biochemistry comes from patient-derived and engineered
    cells and from mice.
  biological_processes:
  - preferred_term: tumor necrosis factor-mediated signaling pathway
    term:
      id: GO:0033209
      label: tumor necrosis factor-mediated signaling pathway
    modifier: DYSREGULATED
  - preferred_term: programmed cell death
    term:
      id: GO:0012501
      label: programmed cell death
    modifier: INCREASED
  evidence:
  - reference: PMID:38609546
    reference_title: "Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Remarkably, a significant increase of positive cells for cleaved caspase-3 (CC3), a marker of apoptosis, and Ser166 pRIPK1, a marker of RIPK1 kinase-dependent apoptosis and necroptosis, were found in colon biopsy samples from both SHARPIN-deficient P1 and a HOIP-deficient patient compared to a control donor sample"
    explanation: >-
      The human tissue evidence for this node, and specifically for the RIPK1 kinase-dependent
      route rather than for cell death in general.
  - reference: PMID:39009172
    reference_title: "A novel HOIP frameshift variant alleviates NF-kappaB signalling and sensitizes cells to TNF-induced death."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The variant attenuates the canonical NF-κB and MAPK signalling cascades and increases the sensitivity of TNFα-induced diverse cell death and activation of mitochondrial apoptosis pathways."
    explanation: >-
      A patient allele tested in cells, showing the signalling and death arms moving in
      opposite directions from the same lesion.
  downstream:
  - target: Tissue Cell Death and Inflammatory Infiltration
    causal_link_type: DIRECT
  - target: Lymphatic and Vascular Endothelial Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Endothelial cells are the cell type in which this sensitisation has the clearest in vivo
      consequence, established in mice rather than in patients.
    evidence:
    - reference: PMID:25284787
      reference_title: "HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we show that both constitutive and Tie2-Cre-driven HOIP deletion lead to aberrant endothelial cell death, resulting in defective vascularization and embryonic lethality at midgestation."
      explanation: >-
        Endothelium-restricted deletion reproduces the vascular phenotype, which makes this an
        endothelial-intrinsic consequence rather than a systemic one.

- name: Monocyte Hyperresponsiveness to IL-1 beta
  role: central_effector
  biological_scale: CELLULAR
  description: >-
    The counterintuitive half of the disease. In the same patient whose fibroblasts respond
    poorly to IL-1 beta, circulating monocytes respond to it more strongly than control
    monocytes, producing more IL-6 and IL-1 beta. The identical dissociation was described
    first in HOIL-1 deficiency, so it is a property of LUBAC loss rather than of one gene,
    and the authors of both reports propose it as the direct cellular basis of the clinical
    autoinflammation. The fourth patient's monocytes instead accumulated more intracellular
    TNF after IL-1 beta, so the cytokine that is overproduced is not fixed across patients,
    but the direction of the monocyte response is.
  cell_types:
  - preferred_term: monocyte
    term:
      id: CL:0000576
      label: monocyte
  biological_processes:
  - preferred_term: interleukin-1-mediated signaling pathway
    term:
      id: GO:0070498
      label: interleukin-1-mediated signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Upon IL-1β stimulation, the proportion of monocytes producing IL-6 and IL-1β was higher in the patient than in healthy controls"
    explanation: The measurement in the patient's own monocytes.
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At any rate, the unusual association of IL-1β hyporesponsiveness in fibroblasts and hyperresponsiveness in monocytes from HOIP- or HOIL-1–deficient patients may be responsible for autoinflammation."
    explanation: >-
      The authors' proposal that this lineage split is what drives the autoinflammation, quoted
      as the hypothesis it is, which is why the downstream edge below is typed as having
      unknown intermediates.
  - reference: PMID:23104095
    reference_title: "Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: "By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1β."
    explanation: >-
      The original description of the dissociation, in HOIL-1-deficient patients. Cited here as
      evidence that it is a LUBAC-level property replicated across two of the three subunit
      diseases, not as evidence about HOIP patients specifically.
  downstream:
  - target: Systemic Autoinflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Excess myeloid proinflammatory cytokine output is the proposed driver of the clinical
      inflammatory syndrome. It is an authors' hypothesis rather than a demonstrated chain.

- name: Tissue Cell Death and Inflammatory Infiltration
  role: consequence
  biological_scale: TISSUE
  description: >-
    Where cells die in a LUBAC-deficient tissue, inflammation follows. In patients this is
    seen as perivascular chronic inflammation with dense CD4-positive infiltration in skin
    biopsy, and as caspase-3- and pRIPK1-positive cells in colonic mucosa. In conditional
    mouse models the same node is lethal on its own: deleting Rnf31 in epidermis kills the
    animals postnatally with severe skin inflammation, and deleting it in dendritic cells
    produces spontaneous systemic inflammation.
  biological_processes:
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
    modifier: INCREASED
  evidence:
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skin biopsy demonstrated superficial perivascular chronic inflammation with dense infiltration of CD4+ and focal MPO+ cells"
    explanation: The histological infiltrate in a HOIP-deficient patient's affected skin.
  downstream:
  - target: Systemic Autoinflammation
    causal_link_type: DIRECT

- name: Type I Interferon Pathway Activation
  role: modifier
  biological_scale: CELLULAR
  description: >-
    Two unrelated patients, on two continents and with different genotypes, carry an
    interferon-stimulated gene signature in blood. In the second patient it is enriched in
    PBMCs rather than whole blood, tracks with excess STAT1 phosphorylation in naive CD4 and
    CD8 T cells but not in monocytes, and is present in the asymptomatic carrier mother as
    well.

    The mechanism is open. The obvious candidate - LUBAC degrading TRIM25, a positive
    regulator of type I interferon production - was tested directly in the patient's PBMCs and
    TRIM25 was not increased. The authors are explicit that the evidence does not yet make
    HOIP deficiency an interferonopathy, and that whether JAK inhibition would help is
    unknown.
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: INCREASED
  evidence:
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The type I IFN signature, as defined by the set of 28 genes upregulated in monogenic interferonopathies (14), was enriched in the patient's PBMCs (Figure 4F), and less remarkable in the whole blood (Figure S7C)."
    explanation: The signature measured against a defined interferonopathy gene set.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The expression of the patient's interferon-stimulated gene (ISG) was markedly higher than that of healthy controls."
    explanation: Independent replication in a fourth patient with a different genotype.

- name: Impaired TLR3-Dependent Antiviral Signalling
  role: consequence
  biological_scale: CELLULAR
  description: >-
    LUBAC components are part of the TLR3 signalling complex, and without them TLR3 ligation
    activates fewer genes while assembling more of a death-inducing complex. Both halves of
    that shift point the same way clinically: less antiviral gene induction, and more
    double-stranded-RNA-driven cell death. The evidence is from LUBAC-deficient cells and
    mice rather than from HOIP patients, and no reported HOIP-deficient patient has had
    influenza A infection, so this arm is a mechanistic candidate for the viral
    susceptibility rather than a demonstrated cause of it.
  biological_processes:
  - preferred_term: toll-like receptor signaling pathway
    term:
      id: GO:0002224
      label: toll-like receptor signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:27810922
    reference_title: "--LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We identify a pivotal role of LUBAC in TLR3 signaling and discover a functional interaction between LUBAC components and TLR3 as crucial for immunity to influenza A virus infection."
    explanation: >-
      The antiviral consequence of the LUBAC-TLR3 interaction, established in mice, which is
      the claim this node makes and the reason it is graded as model-organism evidence.
  - reference: PMID:27810922
    reference_title: "--LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Absence of LUBAC components increases formation of a previously unrecognized TLR3-induced death-inducing SC, leading to enhanced cell death."
    explanation: >-
      The second half of the shift: the same receptor that loses gene-activating output gains
      a death-inducing one, which is the TLR3 counterpart of the TNFR1 node above.
  downstream:
  - target: Recurrent viral infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed route from the TLR3 signalling defect to the clinical viral susceptibility. No
      reported HOIP-deficient patient has had a TLR3-dependent infection characterised, so
      the link is inferred from the cellular and murine work rather than observed.

- name: Impaired T Cell Compartment
  role: consequence
  biological_scale: CELLULAR
  description: >-
    The T cell arm is real but variable, and the variability is the point. The founding
    patient had severe T cell lymphopenia affecting the naive compartment with an impaired
    proliferative response to anti-CD3; the second patient had normal T cell counts and
    normal responses to T cell stimulation; the fourth had reduced CD4 and CD8 T cells with
    loss of central and effector memory CD8 subsets, fewer circulating T follicular helper
    cells and more Th17 cells. Mouse work shows LUBAC is required for late thymocyte
    differentiation and for regulatory T cell development and homeostasis, which gives a
    candidate mechanism the human data do not yet discriminate between.

    In the founding patient a second route is available and was raised by her own authors:
    systemic lymphangiectasia causes lymphatic leak, and lymphatic leak causes lymphopenia
    independently of any signalling defect.
  cell_types:
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, the HOIP-deficient patient had severe T cell lymphopenia, affecting the naive compartment in particular, accompanied by an increase in the proportions of effector memory CD4+ and TEMRA CD8+ cells."
    explanation: The T cell phenotype in the founding patient.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subset analysis of CD4 + T cells showed decreased T follicular helper cells (Tfh) and increased IL-17-producing T helper (Th17) cells."
    explanation: The subset-level abnormalities in the fourth patient.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, these features were not observed in our patient, who showed normal T cell counts and normal response to T cell receptor-mediated stimulations, which might be attributed to her different genotype, her age, or other environmental factors."
    explanation: >-
      A patient in whom the T cell arm is absent, which is why this node is curated as a
      variable consequence rather than a constant feature of the disease.
  - reference: PMID:27857075
    reference_title: "Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show that the LUBAC components HOIP, HOIL-1 and SHARPIN have essential roles in late thymocyte differentiation, FOXP3+ regulatory T (Treg)-cell development and Treg cell homeostasis."
    explanation: >-
      The candidate murine mechanism for a T cell defect downstream of LUBAC loss, which the
      human data are not yet able to confirm or exclude.
  downstream:
  - target: Decreased total T cell count
    causal_link_type: DIRECT
  - target: Recurrent viral infections
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Viral control fails through the T cell compartment rather than directly:
      the reduced T cell count and the impaired CD40-dependent B cell help it
      supports leave both cellular and antibody-mediated antiviral responses
      weakened. Those two steps are the known intermediates, and both are
      curated as their own nodes in this entry.
    intermediate_mechanisms:
    - Reduced circulating T cell numbers available for antiviral effector responses
    - Impaired CD40-dependent B cell activation, curated as its own node, which limits the antibody response to viral antigen

- name: Lymphatic and Vascular Endothelial Injury
  role: consequence
  biological_scale: TISSUE
  description: >-
    Reported in one patient only, and the least mechanistically settled arm of the disease in
    humans. The founding patient had abnormal thoracic duct filling on lymphangiography,
    white-tipped thickened villi through most of the small bowel, and dilated lymphatic
    spaces in duodenal, small intestinal and colonic biopsies. Neither of the two subsequent
    patients assessed for it had lymphangiectasia.

    The case for connecting it to the cell-death arm rests on mouse work: constitutive and
    endothelium-restricted Hoip deletion kills embryos through TNFR1-mediated endothelial
    death with disrupted vasculature, and that is the model the founding report itself
    invoked for its patient's lymphatic phenotype.
  cell_types:
  - preferred_term: endothelial cell of lymphatic vessel
    term:
      id: CL:0002138
      label: endothelial cell of lymphatic vessel
  biological_processes:
  - preferred_term: lymph vessel development
    term:
      id: GO:0001945
      label: lymph vessel development
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An endoscopy with biopsies showed dilated lymphatic space in duodenal, small intestinal, and colonic mucosa."
    explanation: The histological confirmation of lymphangiectasia in the founding patient.
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Overall, the circulatory and lymph vessel phenotypes of Hoip-deficient mice and HOIP-deficient patients suggest that HOIP, alone or less likely as a subunit of LUBAC, may regulate these systems."
    explanation: >-
      The authors' own reading of the mouse-to-human parallel, stated as a suggestion, which is
      the strength of claim this node carries.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical and histological absence of lymphangiectasia in our patient is noteworthy, because the vessel formation abnormality has been observed in the previous HOIP-deficient patient as well as in Rnf31-knock out mice (19)."
    explanation: >-
      A second patient in whom the arm is absent on endoscopy and histology, which is why this
      node is not treated as a constant feature.
  downstream:
  - target: Intestinal lymphangiectasia
    causal_link_type: DIRECT

- name: Amylopectin Accumulation in Skeletal Muscle
  role: consequence
  biological_scale: TISSUE
  description: >-
    Patchy diastase-resistant, PAS-positive material in scattered skeletal muscle fibres -
    polyglucosan, chemically an amylopectin-like glucan - on sternocleidomastoid biopsy in the
    founding patient. It was subclinical: no electrographic or echographic sign of myopathy or
    cardiomyopathy, and normal creatine kinase.

    This is where HOIP and HOIL-1 deficiency differ most. In HOIL-1 disease amylopectinosis is
    early, severe and consistent, and it dominates the non-immunological phenotype; in the
    HOIP patient it was a biopsy finding, which led the founding authors to suggest the storage
    arm depends more on HOIL-1 than on HOIP or on LUBAC as a whole. Neither of the later
    patients assessed had it, although in both cases muscle was not biopsied.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: glycogen metabolic process
    term:
      id: GO:0005977
      label: glycogen metabolic process
    modifier: ABNORMAL
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Periodic Acid-Schiff staining of sternocleidomastoid muscular biopsy showed patches of granular or subsarcolemmal PAS-positive material that was resistant to treatment with diastase, consistent with amylopectinosis, but there were no clinical, electrographic, or echographic signs of skeletal myopathy or cardiomyopathy"
    explanation: >-
      The histological finding and, in the same sentence, the absence of a clinical myopathy,
      which is why this node has no downstream weakness edge.
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The milder amylopectinosis in the HOIP-deficient patient suggests that amylopectinosis may be more dependent on HOIL-1 than HOIP, LUBAC, and NF-κB."
    explanation: >-
      The authors' subunit-level interpretation, which is why this entry does not treat the
      storage arm as a core feature of the HOIP disease.
  downstream:
  - target: Abnormal muscle glycogen content
    causal_link_type: DIRECT

- name: Systemic Autoinflammation
  role: consequence
  biological_scale: ORGANISM
  description: >-
    The clinical syndrome that the myeloid hyperresponsiveness and the tissue cell death
    converge on: recurrent fever with no identified pathogen, persistently raised CRP and ESR,
    arthritis, dermatitis and splenomegaly, beginning in the neonatal period or in infancy in
    every reported patient. It is separable from the infection burden - the founding patient
    was treated for three years as familial Mediterranean fever before any immunological work
    was done - and it is what TNF blockade addresses.
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A patient with multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia, is homozygous for a mutation in HOIP, the gene encoding the catalytic component of LUBAC."
    explanation: The founding clinical description, which names the autoinflammation as multiorgan.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period, requiring repeated hospitalizations."
    explanation: The same syndrome in the most severely affected reported patient.
  downstream:
  - target: Recurrent fever
    causal_link_type: DIRECT
  - target: Elevated circulating C-reactive protein concentration
    causal_link_type: DIRECT
  - target: Elevated erythrocyte sedimentation rate
    causal_link_type: DIRECT
  - target: Polyarticular arthritis
    causal_link_type: DIRECT
  - target: Eczematoid dermatitis
    causal_link_type: DIRECT
  - target: Splenomegaly
    causal_link_type: DIRECT

phenotypes:

- name: Recurrent fever
  category: Inflammatory
  description: >-
    Recurrent, often irregular fever without an identified pathogen, present from the neonatal
    period or infancy in each reported patient.
  phenotype_term:
    preferred_term: Recurrent fever
    term:
      id: HP:0001954
      label: Recurrent fever
    temporality: RECURRENT
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After discharge, she had recurrent episodes of fever and persistent splenomegaly, associated with mild liver enlargement."
    explanation: Recurrent fever from the neonatal period in the founding patient.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At age 3, she developed recurrent fevers and suffered from severe bacterial, viral and fungal infections even after discontinuation of immunosuppressants"
    explanation: The same feature in the second patient.

- name: Elevated circulating C-reactive protein concentration
  category: Laboratory
  description: >-
    Raised CRP between inflammatory episodes as well as during them, ranging from 9.3 to
    258.3 mg/L in the most severely affected patient.
  phenotype_term:
    preferred_term: Elevated circulating C-reactive protein concentration
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He initially presented with fever at 8 days of life, accompanied by elevated inflammatory markers (C-reactive protein(CRP) 57 mg/L)."
    explanation: Raised CRP at presentation in the fourth patient.

- name: Elevated erythrocyte sedimentation rate
  category: Laboratory
  description: >-
    Markedly and persistently raised ESR, fluctuating between 26 and 119 mm/h in the founding
    patient.
  phenotype_term:
    preferred_term: Elevated erythrocyte sedimentation rate
    term:
      id: HP:0003565
      label: Elevated erythrocyte sedimentation rate
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "elevated fluctuating but consistently high ESR (between 26 and 119 mm/h)"
    explanation: The quantitative ESR range reported in the founding patient.

- name: Polyarticular arthritis
  category: Musculoskeletal
  description: >-
    Inflammatory polyarthritis, presenting as polyarticular juvenile idiopathic arthritis at
    seven months in the second patient and as severe hip, knee and ankle pain in the founding
    patient at fifteen years.
  phenotype_term:
    preferred_term: Polyarticular arthritis
    term:
      id: HP:0005764
      label: Polyarticular arthritis
  evidence:
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 7 months old she was diagnosed with polyarticular juvenile idiopathic arthritis after developing hip swelling and knee contracture."
    explanation: The presenting feature of the second patient.

- name: Eczematoid dermatitis
  category: Dermatological
  description: >-
    Eczematous dermatitis with a superficial perivascular lymphocytic infiltrate on biopsy.
    Note that the severe inflammatory dermatitis of Sharpin-deficient mice has no close
    counterpart in the reported HOIP patients.
  phenotype_term:
    preferred_term: Eczematoid dermatitis
    term:
      id: HP:0000964
      label: Eczematoid dermatitis
  evidence:
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On examination at the age of 7 years old she was noted to have eczematous dermatitis (Figure 1A), splenomegaly, and clubbing of her toes and fingers."
    explanation: >-
      The dermatitis, splenomegaly and clubbing of the second patient in a single clinical
      description.

- name: Splenomegaly
  category: Hematological
  description: Splenomegaly, present from the neonatal period in the founding patient.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the neonatal period, she presented omphalitis, requiring antibiotic treatment, and splenomegaly."
    explanation: Neonatal splenomegaly in the founding patient.

- name: Hepatomegaly
  category: Gastrointestinal
  description: >-
    Mild liver enlargement, described alongside the persistent splenomegaly in
    the founding patient. Reported once and not quantified.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After discharge, she had recurrent episodes of fever and persistent splenomegaly, associated with mild liver enlargement."
    explanation: >-
      Records the liver enlargement in the founding patient, in the same
      sentence that records the fever and splenomegaly this entry already
      curates.

- name: Clubbing
  category: Other
  description: Digital clubbing of fingers and toes, reported in the second patient.
  phenotype_term:
    preferred_term: Clubbing
    term:
      id: HP:0001217
      label: Clubbing
  evidence:
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "On examination at the age of 7 years old she was noted to have eczematous dermatitis (Figure 1A), splenomegaly, and clubbing of her toes and fingers."
    explanation: The clubbing described on examination of the second patient at seven years.

- name: Neonatal omphalitis
  category: Infectious
  description: >-
    Omphalitis in the neonatal period requiring antibiotic treatment, the first clinical event
    in the founding patient.
  phenotype_term:
    preferred_term: Neonatal omphalitis
    term:
      id: HP:0032435
      label: Neonatal omphalitis
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the neonatal period, she presented omphalitis, requiring antibiotic treatment"
    explanation: The presenting infection of the founding patient.

- name: Recurrent bacterial infections
  category: Infectious
  description: >-
    Recurrent and often invasive bacterial infection from infancy: meningitis, pneumonia,
    urinary tract infection, peritonitis, suppurative lymphadenitis, and Salmonella and
    Streptococcus pneumoniae bacteraemia in the most severely affected patient.
  phenotype_term:
    preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was diagnosed with diaper dermatitis, purulent meningitis, pneumonia, urinary tract infection, peritonitis, and growth retardation"
    explanation: The range of bacterial infections in the fourth patient.
  - reference: PMID:41608114
    reference_title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      HOIP deficiency | RNF31 | AR | 612487 | Normal numbers | Normal, decreased memory B cells | Decreased | Bacterial infections; autoinflammation; amylopectinosis; lymphangiectasia
    explanation: >-
      The IUIS committee's summary row, which lists bacterial infection first among the
      clinical features of the disease.

- name: Recurrent viral infections
  category: Infectious
  description: >-
    Severe and recurrent viral infection, including persistent cutaneous warts in the founding
    patient.
  phenotype_term:
    preferred_term: Recurrent viral infections
    term:
      id: HP:0004429
      label: Recurrent viral infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a combined immunodeficiency manifesting as chronic diarrhea and recurrent viral and bacterial infections"
    explanation: Recurrent viral infection as part of the presenting combined immunodeficiency.
  sequelae:
  - target: Verrucae
    causal_link_type: DIRECT
    description: >-
      Warts are a cutaneous papillomavirus infection, so the persistent warts are one
      manifestation of the viral susceptibility rather than a separate finding.

- name: Verrucae
  category: Dermatological
  description: Persistent cutaneous warts in the founding patient.
  phenotype_term:
    preferred_term: Verrucae
    term:
      id: HP:0200043
      label: Verrucae
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also developed persistent warts."
    explanation: The wart phenotype recorded in the founding patient's case description.

- name: Decreased circulating IgG concentration
  category: Immunological
  description: >-
    Hypogammaglobulinaemia in the founding patient (IgG 315 mg/dL). Not universal: the second
    patient had normal immunoglobulin concentrations and still failed to respond to
    pneumococcal vaccination, which is why the antibody-response phenotype is curated
    separately from the concentration.
  phenotype_term:
    preferred_term: Decreased circulating IgG concentration
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and hypogammaglobulinemia (IgG: 315 mg/dl), associated with nonprotective antibody responses to S. pneumoniae and H. influenzae, but with a good antibody response to tetanus toxoid."
    explanation: >-
      The measured IgG in the founding patient, with the antibody-response pattern beside it -
      absent against polysaccharide antigens, preserved against a protein antigen.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Although she did not demonstrate hypogammaglobulinemia (IgG 645, IgM 25, and IgA 965 mg/dl), she lacked response to pneumococcal antigens upon vaccination."
    explanation: >-
      A patient without hypogammaglobulinaemia, which is what stops this being curated as a
      constant feature.

- name: Decreased specific antibody response to vaccination
  category: Immunological
  description: >-
    Failure to make protective antibody against polysaccharide antigens, specifically
    Streptococcus pneumoniae and Haemophilus influenzae. Present in both of the first two
    patients, including the one with normal immunoglobulin concentrations, so it is the more
    reliable humoral finding.
  phenotype_term:
    preferred_term: Decreased specific antibody response to vaccination
    term:
      id: HP:0032140
      label: Decreased specific antibody response to vaccination
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The HOIP-deficient patient has hypogammaglobulinemia and nonprotective antibody responses to Streptococcus pneumoniae and Haemophilus influenzae."
    explanation: Names the organisms against which the antibody response fails.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she lacked response to pneumococcal antigens upon vaccination"
    explanation: >-
      The same defect in a patient with normal immunoglobulins, which is why this phenotype is
      separated from IgG concentration.

- name: Decreased memory B cell proportion
  category: Immunological
  description: >-
    Low circulating memory B cells with a relative excess of naive B cells, found in the
    second and fourth patients and listed by IUIS as a defining laboratory feature.
  phenotype_term:
    preferred_term: Decreased memory B cell proportion
    term:
      id: HP:0030374
      label: Decreased memory B cell proportion
  evidence:
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunophenotyping of leukocyte surface markers demonstrated low memory B cells (Table S2)."
    explanation: The measurement in the second patient.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "B cell analysis showed increased frequencies of total B and naive B cells, with reductions in memory and transitional B cell populations."
    explanation: Replication with the reciprocal naive B cell excess in the fourth patient.

- name: Decreased total T cell count
  category: Immunological
  description: >-
    T cell lymphopenia, severe in the founding patient (CD3+ 776 cells/uL) with the naive
    compartment most affected, and present with loss of CD8 memory subsets in the fourth.
    Absent in the second patient.
  phenotype_term:
    preferred_term: Decreased total T cell count
    term:
      id: HP:0005403
      label: Decreased total T cell count
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "showed T cell lymphopenia (CD3+: 776 cells/µl)"
    explanation: The measured T cell count in the founding patient.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunophenotyping revealed a reduction in CD8 + T cells, central memory (CD8 CM) and effector memory (CD8 EM) T cells, and CD4 + T cells."
    explanation: The T cell reduction in the fourth patient, with the memory subsets specified.

- name: Chronic diarrhea
  category: Gastrointestinal
  description: >-
    Chronic diarrhoea from infancy. In the founding patient it was fatty (steatorrhoeic) and
    attributable to intestinal lymphangiectasia; in the fourth it was part of the multisystem
    infectious and inflammatory picture from the neonatal period.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient experienced recurrent fever, multiple site infections, and chronic diarrhea from the neonatal period, requiring repeated hospitalizations."
    explanation: Chronic diarrhoea named as a presenting feature in the fourth patient.
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At the age of 7 yr, the patient began to suffer from recurrent episodes of fatty diarrhea, associated with fever and oral ulcers."
    explanation: The steatorrhoeic form in the founding patient, which tracks the lymphangiectasia.

- name: Intestinal lymphangiectasia
  category: Gastrointestinal
  description: >-
    Dilated intestinal lymphatics on videocapsule endoscopy and on duodenal, small intestinal
    and colonic biopsy, with abnormal thoracic duct filling on lymphangiography. Reported in
    the founding patient only, and explicitly absent in the second.
  phenotype_term:
    preferred_term: Intestinal lymphangiectasia
    term:
      id: HP:0002593
      label: Intestinal lymphangiectasia
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "videocapsule endoscopy, at the age of 16 yr, showed patchy areas of white-tipped thickened villi throughout most of the small bowel, consistent with intestinal lymphangiectasia"
    explanation: The endoscopic finding that established the diagnosis in the founding patient.
  sequelae:
  - target: Chronic diarrhea
    causal_link_type: DIRECT
    description: >-
      The founding patient's diarrhoea was fatty and improved on a low-fat diet, which is the
      pattern of lymphangiectasia-driven fat malabsorption. The link holds for that patient;
      the fourth patient's diarrhoea belongs to his infectious and inflammatory picture and
      has no lymphangiectasia behind it.
  - target: Protein-losing enteropathy
    causal_link_type: DIRECT
    description: >-
      Lymphatic leak into the bowel lumen drains protein, which is the mechanism connecting
      this phenotype to the hypoalbuminaemia and oedema below.
    evidence:
    - reference: PMID:26008899
      reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Further evidence of lymph vessel abnormalities was provided by a lymphangiogram (showing abnormal filling of the thoracic duct), high α-1-antitrypsin antibody, and triglyceride concentrations."
      explanation: >-
        Raised alpha-1-antitrypsin is the standard marker of enteric protein loss, and is what
        connects the lymphangiectasia to the protein-losing state in this patient.

- name: Protein-losing enteropathy
  category: Gastrointestinal
  description: >-
    Enteric protein loss secondary to intestinal lymphangiectasia, managed with a low-fat,
    high-protein diet and repeated albumin infusions.
  phenotype_term:
    preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent episodes of diarrhea and edema, requiring frequent infusions of albumin and furosemide, led to additional investigations."
    explanation: >-
      The clinical consequence of enteric protein loss, and the reason the lymphatic
      investigations were undertaken.
  sequelae:
  - target: Hypoalbuminemia
    causal_link_type: DIRECT
  - target: Edema
    causal_link_type: DIRECT

- name: Hypoalbuminemia
  category: Laboratory
  description: Hypoalbuminaemia (2.6 g/dL) secondary to enteric protein loss.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additional abnormalities identified in laboratory tests included hypoalbuminemia (2.6 g/dl), hypocalcemia (8.2 mg/dl), anemia (Hb, 8.1 g/dl)"
    explanation: The measured albumin, with the coexisting hypocalcaemia and anaemia.

- name: Edema
  category: Other
  description: >-
    Recurrent systemic oedema requiring albumin infusion and diuresis, persisting at lower
    frequency after immunoglobulin replacement was started.
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
    temporality: RECURRENT
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the episodes of systemic edema persisted, although at a lower frequency."
    explanation: The oedema and its partial response to immunoglobulin replacement.

- name: Anemia
  category: Hematological
  description: >-
    Anaemia (haemoglobin 8.1 g/dL) with coexisting iron and vitamin D deficiency, in the
    context of chronic inflammation and enteric loss.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anemia (Hb, 8.1 g/dl), iron deficiency (3.7 µmol/l)"
    explanation: The measured haemoglobin and the coexisting iron deficiency.

- name: Postnatal growth retardation
  category: Growth
  description: >-
    Stunted growth from early childhood with poor weight gain, sufficiently severe that
    recombinant growth hormone was tried; that trial was stopped after femoral fractures.
  phenotype_term:
    preferred_term: Postnatal growth retardation
    term:
      id: HP:0008897
      label: Postnatal growth retardation
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From early childhood, the growth of the patient was stunted."
    explanation: The growth phenotype in the founding patient.

- name: Bronchiectasis
  category: Respiratory
  description: >-
    Mild bronchiectasis of the right middle and lower lobes on CT at seventeen years, the
    expected structural consequence of recurrent respiratory infection in an antibody
    deficiency.
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A chest CT scan at the age of 17 yr demonstrated mild bronchiectasis in the right middle and lower lobes."
    explanation: The imaging finding in the founding patient.

- name: Lower limb muscle weakness
  category: Musculoskeletal
  description: >-
    Weakness of the lower extremities with diffuse muscular atrophy and fatty infiltration of
    gluteal and adductor muscles on MRI, but with normal nerve conduction, normal needle
    electromyography and normal creatine kinase. It is curated here without a causal edge from
    the amylopectinosis node, because the same report that documents the muscle storage
    material states there were no electrographic signs of myopathy.
  phenotype_term:
    preferred_term: Lower limb muscle weakness
    term:
      id: HP:0007340
      label: Lower limb muscle weakness
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moreover, the patient was suffering from muscular weakness, especially in the lower extremities."
    explanation: The weakness as described in the founding patient.
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, motor and sensory conduction and needle electromyography were normal, and there was no evidence of cardiomyopathy at heart ultrasound."
    explanation: >-
      The normal electrophysiology, which is why no causal edge is drawn from the muscle
      storage node to this phenotype.

- name: Abnormal muscle glycogen content
  category: Histopathological
  description: >-
    Diastase-resistant PAS-positive (polyglucosan) material in scattered skeletal muscle
    fibres on biopsy, without clinical myopathy. Subclinical in the founding patient and not
    assessed by biopsy in the later ones.
  phenotype_term:
    preferred_term: Abnormal muscle glycogen content
    term:
      id: HP:0012269
      label: Abnormal muscle glycogen content
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A patchy accumulation of PAS+diastase-resistant material in a scattered muscle fibers is shown in patient’ biopsy."
    explanation: The histological description of the storage material in muscle.

genetic:
- name: RNF31
  gene_term:
    preferred_term: RNF31
    term:
      id: hgnc:16031
      label: RNF31
  relationship_type: CAUSATIVE
  notes: >-
    RNF31 encodes HOIP (HOIL-1-interacting protein), the catalytic RBR E3 ligase subunit of
    LUBAC, at 14q12. The gene was reached in the founding kindred by combining genome-wide
    linkage with whole-exome sequencing after known autoinflammation, immunodeficiency and
    lymphangiectasia genes had been excluded. HOIP has no paralogue that substitutes for it:
    it is the only ligase component of the only complex known to make M1-linked chains.
  variants:
  - name: "c.215T>C (p.Leu72Pro)"
    description: >-
      Homozygous missense change at the start of the PUB domain in the founding Kuwaiti
      kindred. Absent from public databases covering up to 60,706 individuals at the time of
      publication; no mutant protein detectable on immunoblot.
  - name: "c.1197G>C and c.1737+3A>G"
    description: >-
      Compound heterozygous splice-region variants in the second patient, producing transcripts
      that skip exon 7 (out of frame, removing the whole UBA domain) or exon 9 (in frame,
      removing most of UBA-1 and with it SHARPIN binding).
  - name: "c.1654C>T (p.Gln552Ter) and c.3038A>C (p.His1013Pro)"
    description: >-
      Compound heterozygous nonsense plus missense pair in the fourth patient, both absent from
      ExAC, 1000 Genomes, HGMD and gnomAD.
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These variants included a homozygous T-to-C substitution at position 215 (c.215T>C) in exon 2 of HOIP (also known as RNF31), which was identified in the patient and confirmed by Sanger sequencing"
    explanation: The gene-discovery result and the founding allele.
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The HOIP L72P variant was not found in public databases (NCBI, UCSC, 1000 genomes, or ExAC, reaching a total of up to 60,706 individuals) or in our own WES database (2,212 individuals)."
    explanation: >-
      Population-database absence, part of the case for pathogenicity of the founding allele.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These mutations were absent in population databases such as ExAC, 1000 Genomes, HGMD, and gnomAD."
    explanation: The same argument for the fourth patient's two alleles.

animal_models:

- name: Constitutive and endothelial Hoip knockout mouse
  species: Mouse
  genotype: Hoip-/- ; Hoip fl/fl Tie2-Cre
  publication: PMID:25284787
  description: >-
    Germline and endothelium-restricted Hoip deletion. Both are lethal at midgestation from
    aberrant endothelial cell death and defective vascularisation, and both are rescued by
    concurrent deletion of TNFR1. This is the cleanest in vivo demonstration that the TNFR1
    death route, rather than the loss of NF-kappa-B output, is what kills LUBAC-deficient
    endothelium.
  modeled_mechanisms:
  - target: Sensitisation to TNFR1-Mediated Cell Death
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      HOIP-deficient cells from this model show increased TNF- and lymphotoxin-alpha-induced
      death through aberrant complex II, and TNFR1 ablation prevents the in vivo consequence.
    limitations: >-
      The rescue experiment that establishes the TNFR1 dependence is only possible in mice; in
      patients the corresponding evidence is caspase-3 and pRIPK1 staining of colonic mucosa,
      which shows the death route is active but not that it is necessary.
    evidence:
    - reference: PMID:25284787
      reference_title: "HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ablation of tumor necrosis factor receptor 1 (TNFR1) prevents cell death, vascularization defects, and death at midgestation."
      explanation: The genetic epistasis that establishes TNFR1 as the route.
  - target: Lymphatic and Vascular Endothelial Injury
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Endothelium-restricted deletion produces disrupted vasculature, the murine counterpart of
      the vascular and lymphatic phenotype in the founding patient.
    limitations: >-
      The mouse dies in utero from a blood-vessel defect, while the human phenotype is
      postnatal lymphangiectasia in one of four patients and explicitly absent in another. The
      model therefore speaks to endothelial vulnerability to TNFR1-driven death rather than to
      the human lymphatic syndrome, and complete HOIP loss is lethal in mouse where the human
      alleles are hypomorphic.
    evidence:
    - reference: PMID:25284787
      reference_title: "HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Hence, LUBAC and its linear-ubiquitin-forming activity are required for maintaining vascular integrity during embryogenesis by preventing TNFR1-mediated endothelial cell death."
      explanation: The authors' conclusion, which is the claim this link makes at tissue scale.
  evidence:
  - reference: PMID:29695863
    reference_title: "LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity."
    explanation: >-
      Independent replication of the model's central result, and the qualification that the
      death is only partly RIPK1 kinase-dependent.

- name: Dendritic cell-specific Hoip knockout mouse
  species: Mouse
  genotype: Hoip fl/fl CD11c-Cre
  publication: PMID:34253576
  description: >-
    Conditional Hoip deletion in dendritic cells, the model that separates the autoinflammatory
    arm from the TNF arm. These mice develop spontaneous systemic inflammation; crossing them
    to TNFR1-null mice does not rescue it, whereas MyD88 deficiency does and antibiotics reduce
    it, pointing at TLR/IL-1R rather than TNFR1 signalling as the driver of the inflammatory
    phenotype.
  modeled_mechanisms:
  - target: Systemic Autoinflammation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reproduces spontaneous systemic inflammation from a HOIP lesion restricted to one myeloid
      lineage, and assigns it to MyD88-dependent signalling.
    limitations: >-
      The lesion is dendritic-cell-restricted and complete, whereas patients are hypomorphic in
      every cell. The MyD88 dependence is a mouse epistasis result with no human counterpart,
      and it sits awkwardly beside the clinical observation that anti-TNF therapy controls the
      autoinflammation in LUBAC-deficient patients.
    evidence:
    - reference: PMID:34253576
      reference_title: "MyD88-Dependent Signaling Is Required for HOIP Deficiency-Induced Autoinflammation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In this study, we found that dendritic cell (DC)-specific deletion of HOIP resulted in spontaneous inflammation, indicating the essential role of HOIP in maintaining DC homeostasis."
      explanation: The phenotype this link records.
    - reference: PMID:34253576
      reference_title: "MyD88-Dependent Signaling Is Required for HOIP Deficiency-Induced Autoinflammation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Importantly, MyD88 deficiency rescued the inflammatory phenotype in HoipDC KO mice."
      explanation: >-
        The epistasis result behind the limitation recorded above, and the reason this model is
        curated as partially rather than fully recapitulating.

- name: Epidermis-specific Rnf31 knockout mouse
  species: Mouse
  genotype: Rnf31 fl/fl K14-Cre
  publication: PMID:29728512
  description: >-
    Keratinocyte-restricted Rnf31 deletion, lethal in the early postnatal period from severe
    skin inflammation driven by TNF-induced keratinocyte apoptosis and rescued by TNFR1
    deletion. Included because it is the tissue-level demonstration that LUBAC loss converts a
    normal TNF signal into a cell-death signal in a differentiated epithelium.
  modeled_mechanisms:
  - target: Tissue Cell Death and Inflammatory Infiltration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Shows the whole chain within one tissue: HOIP loss, TNF-driven apoptosis, inflammatory
      infiltrate, and reversal of all of it by removing TNFR1.
    limitations: >-
      The severe inflammatory dermatitis of this model and of Sharpin-null mice has no close
      counterpart in HOIP-deficient patients, whose dermatological findings are eczematous
      rather than the fulminant skin disease seen here. Species differences in keratinocyte TNF
      sensitivity, and the fact that the mouse allele is a complete deletion, both bear on that
      gap.
    evidence:
    - reference: PMID:29728512
      reference_title: "RNF31 Regulates Skin Homeostasis by Protecting Epidermal Keratinocytes from Cell Death."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Consistently, deleting TNF receptor 1 could rescue the lethality of RNF31 epidermis-specific KO mice and also the skin inflammation."
      explanation: >-
        The TNFR1 rescue that makes this a demonstration of the cell-death-to-inflammation step
        rather than of skin inflammation in general.

diagnosis:

- name: RNF31 sequencing
  description: >-
    Molecular confirmation by sequencing RNF31, reached in the published patients by
    whole-exome sequencing or by a targeted inborn-errors-of-immunity panel. The clinical
    trigger is the combination that defines the disease: early-onset autoinflammation with
    recurrent bacterial infection and poor antibody responses. Note that two of the four
    reported patients were labelled common variable immunodeficiency before the genetic
    diagnosis was made.
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing (WES) was performed, and HOIP mutations were confirmed by Sanger sequencing."
    explanation: The diagnostic route taken in the fourth patient.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Methods: Targeted next generation sequencing of 352 immune-related genes was performed."
    explanation: >-
      The panel route, which is how the second patient was diagnosed after a clinical label of
      common variable immunodeficiency.

- name: LUBAC subunit immunoblot
  description: >-
    Immunoblotting patient fibroblasts or PBMCs for HOIP, HOIL-1 and SHARPIN. This is the
    functional confirmation step: all three subunits fall together, which both demonstrates
    that the variant is destabilising and distinguishes a real LUBAC deficiency from a variant
    of uncertain significance in RNF31. It was applied in each of the reported patients.
  diagnosis_term:
    preferred_term: western blotting of LUBAC subunits
    term:
      id: NCIT:C16357
      label: Western Blotting
  evidence:
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Western blot analysis of the patient’s PBMCs revealed significantly reduced expression of HOIP, HOIL-1, and SHARPIN compared to healthy controls (Fig. 2D)."
    explanation: The assay, and the result pattern that confirms a destabilising RNF31 allele.

- name: Lymphocyte immunophenotyping
  description: >-
    Flow cytometric enumeration of T and B cell subsets. The findings that recur are low memory
    B cells with a naive B cell excess, and variable T cell lymphopenia with loss of CD8 memory
    subsets; IUIS records normal total T cell numbers with decreased memory B cells as the
    laboratory signature of the disease.
  diagnosis_term:
    preferred_term: flow cytometry
    term:
      id: NCIT:C16585
      label: Flow Cytometry
  evidence:
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry to assess T and B cell subsets under unstimulated condition."
    explanation: The assay as applied in the most recently reported patient.

- name: Muscle biopsy with periodic acid-Schiff staining
  description: >-
    Periodic acid-Schiff staining with and without diastase pretreatment on skeletal muscle.
    Persistence of PAS-positive material after diastase is what identifies polyglucosan rather
    than ordinary glycogen. Worth doing where the storage arm is suspected, but note that in
    the one HOIP patient biopsied the finding was subclinical and the muscle was
    electrophysiologically normal.
  diagnosis_term:
    preferred_term: muscle biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of amylopectinosis was documented by persistence of PAS-positive material in diastase-treated sections."
    explanation: The criterion that distinguishes polyglucosan from glycogen on this stain.

treatments:

- name: Immunoglobulin Replacement Therapy
  description: >-
    Intravenous or subcutaneous immunoglobulin, given in every reported patient. It replaces
    the antibody the failed germinal centre cannot produce, and improves IgG trough levels and
    infection burden; in the second patient it was sufficient on its own to keep her stable
    with minimal inflammation. It does not address the autoinflammatory arm, and in the
    founding patient systemic oedema continued after it was started.
  treatment_term:
    preferred_term: immunoglobulin replacement therapy
    term:
      id: NCIT:C121331
      label: Intravenous Immunoglobulin Therapy
    therapeutic_agent:
    - preferred_term: human immunoglobulin G
      term:
        id: NCIT:C80829
        label: Human Immunoglobulin G
  therapeutic_modality: PROTEIN_REPLACEMENT
  target_mechanisms:
  - target: Germinal Centre Failure and Impaired Antibody Production
    treatment_effect: BYPASSES
    description: >-
      Supplies pooled donor antibody rather than repairing the germinal centre defect, which is
      why it is curated as bypassing rather than inhibiting the node.
    evidence:
    - reference: PMID:26008899
      reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Treatment with intravenous immunoglobulins was initiated, leading to an improvement in IgG trough levels."
      explanation: The measured effect on the humoral deficit in the founding patient.
  evidence:
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Currently, the patient is stable with minimal inflammation on subcutaneous immunoglobulin supplementation."
    explanation: >-
      The subcutaneous route, and the observation that it was sufficient as sole therapy in one
      patient.

- name: TNF Blockade
  description: >-
    Etanercept and adalimumab have both been used in HOIP-deficient patients, and the rationale
    is the cell-death arm: if TNF signalling through a LUBAC-deficient TNFR1 complex is what
    kills cells and drives inflammation, blocking TNF should quieten it. The clinical picture
    is of real but incomplete and non-durable benefit - arthritis improved on etanercept in the
    second patient, and in the fourth each adalimumab dose produced defervescence and a CRP
    fall lasting fifteen to twenty-five days before fever returned. That patient died during a
    relapse. The strongest evidence for the strategy in a LUBAC disease comes from a
    SHARPIN-deficient patient, in whom anti-TNF produced complete clinical and transcriptomic
    resolution.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: adalimumab
      term:
        id: NCIT:C65216
        label: Adalimumab
    - preferred_term: etanercept
      term:
        id: NCIT:C2381
        label: Etanercept
  target_mechanisms:
  - target: Sensitisation to TNFR1-Mediated Cell Death
    treatment_effect: INHIBITS
    description: >-
      Removing the ligand prevents engagement of the TNFR1 complex that, without linear
      ubiquitin chains, converts into the death-inducing complex II.
    evidence:
    - reference: PMID:38609546
      reference_title: "Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: "The remarkable efficacy of anti-TNF therapy in one patient, supported by genetic dissection of joint inflammation using murine models, suggests that TNF-mediated cell death contributes to the autoinflammation."
      explanation: >-
        The authors' inference from treatment response to mechanism, in a LUBAC-deficient
        patient. That patient is SHARPIN- rather than HOIP-deficient, which is why this is
        graded indirect and why the entry does not present the mechanism as established for
        HOIP.
  evidence:
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A second dose on November 23 led to rapid defervescence and a significant drop in CRP(Fig. 1G)."
    explanation: >-
      Adalimumab in a HOIP-deficient patient: a clear but time-limited response, which is the
      basis for describing the benefit as incomplete.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was treated with corticosteroids, methotrexate, and eventually improved on TNF blockade with etanercept."
    explanation: Etanercept for the arthritis of the second patient, before her genetic diagnosis.
  - reference: PMID:38609546
    reference_title: "Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment of one SHARPIN-deficient individual with anti-TNF therapies led to complete clinical and transcriptomic resolution of autoinflammation."
    explanation: >-
      The best response reported in any LUBAC deficiency, in the sibling SHARPIN disease rather
      than in a HOIP patient.

- name: Antibiotic Prophylaxis
  description: >-
    Continuous antibacterial prophylaxis, cotrimoxazole in the founding patient and
    sulfamethoxazole in the fourth, alongside immunoglobulin replacement. It addresses the
    consequence of the antibody defect rather than any mechanism.
  treatment_term:
    preferred_term: antibiotic prophylaxis
    term:
      id: NCIT:C51993
      label: Antibiotic Prophylaxis
    therapeutic_agent:
    - preferred_term: trimethoprim-sulfamethoxazole
      term:
        id: NCIT:C909
        label: Trimethoprim-Sulfamethoxazole
  therapeutic_modality: SMALL_MOLECULE
  target_phenotypes:
  - preferred_term: Recurrent bacterial infections
    term:
      id: HP:0002718
      label: Recurrent bacterial infections
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prophylaxis with cotrimoxazole was initiated."
    explanation: Antibacterial prophylaxis in the founding patient.
  - reference: PMID:41026334
    reference_title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient started a regimen of intravenous immunoglobulin (IVIG) (400-600 mg/kg monthly) and sulfamethoxazole (SMZ) for infection prophylaxis"
    explanation: The same strategy, with doses, in the fourth patient.

- name: Low-Fat High-Protein Diet
  description: >-
    Dietary management of intestinal lymphangiectasia: restricting long-chain fat reduces
    intestinal lymph flow and so reduces enteric protein loss. Partially effective in the
    founding patient, who continued to have fatty diarrhoea and poor weight gain on it.
  treatment_term:
    preferred_term: low-fat high-protein diet
    term:
      id: NCIT:C15447
      label: Dietary Intervention
  therapeutic_modality: BEHAVIORAL
  target_phenotypes:
  - preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient was placed on a low-fat, high-protein diet, with some improvement, but she continued to suffer from fatty diarrhea, with poor weight gain and impaired linear growth."
    explanation: >-
      Both the intervention and the honest statement of its partial effect, in the one patient
      who needed it.

- name: Octreotide
  description: >-
    A somatostatin analogue, started in the founding patient for refractory intestinal
    lymphangiectasia after diet, albumin infusions and immunoglobulin replacement had left her
    with continuing lymphatic leak. Reported as started rather than as having an assessed
    outcome.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: octreotide
      term:
        id: NCIT:C711
        label: Octreotide
  therapeutic_modality: PEPTIDE
  target_phenotypes:
  - preferred_term: Intestinal lymphangiectasia
    term:
      id: HP:0002593
      label: Intestinal lymphangiectasia
  evidence:
  - reference: PMID:26008899
    reference_title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient is still on antibiotic prophylaxis, a low-fat and high-protein diet, iron and vitamin D supplementation, and immunoglobulin replacement therapy, and has started treatment with octreotide."
    explanation: >-
      Records that octreotide was started. The report does not state an outcome, and none is
      claimed here.

mechanistic_hypotheses:
- hypothesis_group_id: lubac_dual_lesion_model
  hypothesis_label: Dual Lesion Model - Lost NF-kappa-B Activation Plus Released Cell-Death Brake
  status: CANONICAL
  description: >-
    Linear ubiquitin chains at receptor signalling complexes both enable canonical NF-kappa-B
    activation and hold the complex out of its death-inducing configuration. Losing them
    therefore produces immunodeficiency and autoinflammation from one lesion: the first through
    failed NF-kappa-B output in fibroblasts, B cells and T cells, the second through TNF-driven
    apoptosis and necroptosis of tissue cells. The model is supported in humans by the patient
    allele that removes the catalytic domain and produces both effects in the same cells, and
    in mice by the TNFR1 rescue of the endothelial and epidermal phenotypes.
  evidence:
  - reference: PMID:28469620
    reference_title: "NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Consequently, OTULIN or A20-deficient cells have an excess of Met1 or K63 Ub chains on NEMO, RIPK1, and other target substrates, which lead to constitutive activation of the NF-kB pathway."
    explanation: >-
      The mirror-image diseases. OTULIN and A20 deficiency remove the enzymes that take
      ubiquitin chains off the same substrates, and produce constitutive NF-kappa-B rather
      than deficient NF-kappa-B - which is what places LUBAC deficiency in a class defined by
      the direction of the ubiquitin imbalance, and is the main differential diagnosis to
      hold in mind.
- hypothesis_group_id: myeloid_hyperresponsiveness_model
  hypothesis_label: Lineage-Specific Myeloid IL-1 Hyperresponsiveness Model
  status: ALTERNATIVE
  description: >-
    The autoinflammation is driven not by cell death but by the paradoxical hyperresponsiveness
    of LUBAC-deficient monocytes to IL-1 beta, which the founding reports of both HOIL-1 and
    HOIP deficiency proposed. The mouse evidence pulls in the same direction:
    dendritic-cell-restricted Hoip deletion causes spontaneous inflammation that TNFR1 deletion
    fails to rescue and MyD88 deletion does. The two models are not exclusive and may operate
    in different tissues, but they predict different therapies - IL-1 blockade rather than TNF
    blockade - and no patient has been reported on IL-1 blockade.

discussions:

- discussion_id: hoip_autoinflammation_tnf_versus_myd88
  kind: CONTROVERSY
  prompt: >-
    Is the autoinflammation of HOIP deficiency driven by TNF-induced cell death, or by
    MyD88-dependent TLR and IL-1R signalling in myeloid cells?
  attaches_to:
  - pathophysiology#Systemic Autoinflammation
  - pathophysiology#Monocyte Hyperresponsiveness to IL-1 beta
  - pathophysiology#Sensitisation to TNFR1-Mediated Cell Death
  rationale: >-
    The two candidate drivers have evidence of different kinds pointing in different
    directions. For TNF: patient colonic mucosa carries markers of RIPK1 kinase-dependent
    death, TNFR1 deletion rescues the endothelial and epidermal mouse phenotypes, and anti-TNF
    therapy produces clinical responses in patients - complete in a SHARPIN-deficient patient,
    partial and non-durable in a HOIP-deficient one. For MyD88: in the
    dendritic-cell-restricted Hoip knockout, which is the model built specifically to ask this
    question about autoinflammation, crossing to TNFR1-null mice did not rescue the
    inflammation while MyD88 deficiency did, and the patient monocyte phenotype that both
    founding reports proposed as the basis of autoinflammation is IL-1 beta
    hyperresponsiveness, which is MyD88-dependent. The question is not academic: it decides
    whether IL-1 blockade should be tried in a patient whose fever breaks through anti-TNF, and
    no reported patient has received it.
- discussion_id: hoip_interferon_signature_mechanism
  kind: KNOWLEDGE_GAP
  prompt: >-
    What produces the type I interferon signature in HOIP-deficient patients, and is it doing
    clinical work?
  attaches_to:
  - pathophysiology#Type I Interferon Pathway Activation
  rationale: >-
    Two unrelated patients with different genotypes carry an interferon-stimulated gene
    signature in blood, and a healthy carrier mother carries it too. The obvious candidate
    mechanism - LUBAC restraining type I interferon production by degrading TRIM25 - was tested
    in the second patient's PBMCs and TRIM25 was not increased. The signature appears to be T
    cell rather than monocyte driven, since excess STAT1 phosphorylation after interferon-alpha
    was found in naive CD4 and CD8 T cells but not in CD14-positive cells. Its therapeutic
    relevance is untested: no HOIP-deficient patient has received a JAK inhibitor, and the
    second patient's own authors decline to classify the disease as an interferonopathy on the
    available evidence.
  evidence:
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, we did not observe increased expression of TRIM25 in unstimulated HOIP deficient patient's PBMCs, compared to control cells (Figure S8)."
    explanation: >-
      The negative result that keeps this gap open: the TRIM25 route, which is the mechanism
      the literature proposed for LUBAC restraining type I interferon, was tested in a
      HOIP-deficient patient's own cells and not found.
  - reference: PMID:30936877
    reference_title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At this point there is no strong evidence to categorize the HOIP deficiency as a new type I interferonopathy, and it is unclear whether these patients would benefit from treatment with JAK inhibitors."
    explanation: >-
      The authors' own statement of the two open questions this gap records: the disease
      classification and whether JAK inhibition is indicated.
- discussion_id: hoip_amylopectinosis_subunit_dependence
  kind: KNOWLEDGE_GAP
  prompt: >-
    Why is amylopectinosis mild or absent in HOIP deficiency when it is early, severe and
    consistent in HOIL-1 deficiency, if both destabilise the same complex?
  attaches_to:
  - pathophysiology#Amylopectin Accumulation in Skeletal Muscle
  rationale: >-
    Both diseases abolish LUBAC assembly, yet the polyglucosan arm tracks with the HOIL-1
    lesion rather than with LUBAC loss as such. The founding HOIP report offers two readings
    and does not choose between them: either the storage phenotype depends on a HOIL-1 function
    outside the complex, or the HOIP L72P allele is simply not fully loss-of-function. The
    distinction matters for whether these are two presentations of one mechanism or two
    mechanisms sharing a complex, and it is also the point at which the boundary between this
    entry and the RBCK1 disease would be redrawn if the answer were the first one.
  evidence:
  - reference: PMID:23995275
    reference_title: "New insights in the field of muscle glycogenoses."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Polyglucosan body myopathy with cardiomyopathy has been associated with mutations in RBCK1, a ubiquitin ligase, which have also been reported in children with early-onset immune disorder."
    explanation: >-
      States the two-faced character of the RBCK1 disease - a muscle glycogenosis and an
      immune disorder from the same gene - which is the contrast this gap is about, since the
      HOIP patients show the immune arm without a comparable storage myopathy.
- discussion_id: hoip_mouse_null_versus_human_hypomorph
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Can mouse Hoip-null models speak to the human disease at all, given that complete HOIP loss
    is embryonic lethal in mice while patients survive into adult life?
  attaches_to:
  - pathophysiology#Sensitisation to TNFR1-Mediated Cell Death
  - pathophysiology#Lymphatic and Vascular Endothelial Injury
  rationale: >-
    Every constitutive Hoip-null mouse dies at midgestation from TNFR1-driven endothelial
    death, so the entire murine literature on this gene is about complete loss, while every
    reported patient retains residual HOIP. This is not a reason to discard the models - the
    TNFR1 epistasis they establish is unobtainable in humans, and the colonic caspase-3 and
    pRIPK1 staining in a patient shows the same route is active - but it does mean the
    quantitative relationship between residual HOIP and phenotype severity is unaddressed by
    any model. It is a live clinical question, since the four reported patients differ widely in
    severity and the one who died before two years old carried a nonsense allele.
  proposed_experiments:
  - experiment_id: hoip_graded_hypomorphic_allelic_series
    name: Graded hypomorphic Hoip allelic series
    description: >-
      Generate a mouse allelic series producing defined residual HOIP levels, including
      knock-in of the human p.L72P and p.H1013Pro changes, and ask at what residual level
      embryonic lethality is escaped and which of the human arms - autoinflammation, antibody
      failure, lymphangiectasia, muscle polyglucosan - appear.
    would_support:
    - pathophysiology#Sensitisation to TNFR1-Mediated Cell Death
    supporting_outcome:
    - >-
      Surviving hypomorphic animals recapitulate autoinflammation and antibody failure at
      residual HOIP levels comparable with those measured in patient cells, with severity
      tracking residual protein.

references:
- reference: PMID:26008899
  title: "Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia."
- reference: PMID:30936877
  title: "Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC."
- reference: PMID:39009172
  title: "A novel HOIP frameshift variant alleviates NF-kappaB signalling and sensitizes cells to TNF-induced death."
- reference: PMID:41026334
  title: "Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency."
- reference: PMID:38609546
  title: "Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency."
- reference: PMID:23104095
  title: "Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency."
- reference: PMID:25284787
  title: "HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death."
- reference: PMID:29695863
  title: "LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis."
- reference: PMID:34253576
  title: "MyD88-Dependent Signaling Is Required for HOIP Deficiency-Induced Autoinflammation."
- reference: PMID:29728512
  title: "RNF31 Regulates Skin Homeostasis by Protecting Epidermal Keratinocytes from Cell Death."
- reference: PMID:27857075
  title: "Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis."
- reference: PMID:27810922
  title: "--LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation."
- reference: PMID:22863777
  title: "The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension."
- reference: PMID:28469620
  title: "NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases."
- reference: PMID:23995275
  title: "New insights in the field of muscle glycogenoses."
- reference: PMID:41608114
  title: "Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee."

📚

References & Deep Research

References

PMID:26008899

Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia.

No top-level findings curated for this source.

PMID:30936877

Second Case of HOIP Deficiency Expands Clinical Features and Defines Inflammatory Transcriptome Regulated by LUBAC.

No top-level findings curated for this source.

PMID:39009172

A novel HOIP frameshift variant alleviates NF-kappaB signalling and sensitizes cells to TNF-induced death.

No top-level findings curated for this source.

PMID:41026334

Novel Compound Heterozygous Mutations in HOIP Result in Autoinflammation and Immunodeficiency.

No top-level findings curated for this source.

PMID:38609546

Biallelic human SHARPIN loss of function induces autoinflammation and immunodeficiency.

No top-level findings curated for this source.

PMID:23104095

Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency.

No top-level findings curated for this source.

PMID:25284787

HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death.

No top-level findings curated for this source.

PMID:29695863

LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis.

No top-level findings curated for this source.

PMID:34253576

MyD88-Dependent Signaling Is Required for HOIP Deficiency-Induced Autoinflammation.

No top-level findings curated for this source.

PMID:29728512

RNF31 Regulates Skin Homeostasis by Protecting Epidermal Keratinocytes from Cell Death.

No top-level findings curated for this source.

PMID:27857075

Linear ubiquitin chain assembly complex coordinates late thymic T-cell differentiation and regulatory T-cell homeostasis.

No top-level findings curated for this source.

PMID:27810922

--LUBAC deficiency perturbs TLR3 signaling to cause immunodeficiency and autoinflammation.

No top-level findings curated for this source.

PMID:22863777

The E3 ligase HOIP specifies linear ubiquitin chain assembly through its RING-IBR-RING domain and the unique LDD extension.

No top-level findings curated for this source.

PMID:28469620

NF-κB Pathway in Autoinflammatory Diseases: Dysregulation of Protein Modifications by Ubiquitin Defines a New Category of Autoinflammatory Diseases.

No top-level findings curated for this source.

PMID:23995275

New insights in the field of muscle glycogenoses.

No top-level findings curated for this source.

PMID:41608114

Human inborn errors of immunity: 2024 update on the classification from the International Union of Immunological Societies Expert Committee.

No top-level findings curated for this source.

Deep Research

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

Evaluations and curation notes (2)

Record notes

Scope and lump/split. This entry is the RNF31/HOIP disease only. The sibling LUBAC disorders - HOIL-1 deficiency (RBCK1; the MONDO concept "polyglucosan body myopathy 1 with or without immunodeficiency", MONDO:0014389) and SHARPIN deficiency - are separate MONDO concepts with separate genes and are deliberately not merged here, although their cellular phenotypes overlap almost completely and the literature routinely reports them together. RBCK1 disease additionally has a large non-immunological arm (progressive myopathy and cardiomyopathy with polyglucosan storage) that has no counterpart in the reported HOIP patients. Papers about HOIL-1 or SHARPIN are cited here only where they report data on HOIP patients or HOIP-deficient cells, and each such evidence item says which. Patient count. Four patients are fully reported in English as of the literature review in PMID:41026334, which covered HOIP cases through January 2025: Boisson 2015 (Kuwaiti woman, homozygous p.L72P), Oda 2019 (girl with compound heterozygous splice-region variants), a Chinese patient with a homozygous C-terminal frameshift (PMID:39009172), and the Chongqing boy with compound heterozygous p.Q552Ter and p.H1013Pro. A further HOIP-deficient patient contributes cell and tissue data to PMID:38609546 without a separate clinical report. Counts in this entry are counts of patients, and `frequency` is deliberately left unset throughout rather than computed from four cases. No GeneReviews chapter exists. PubMed with `term=(HOIP[TI] OR RNF31[TI] OR LUBAC[TI]) AND genereviews[book]` returns 0 records, and `just check-genereviews` reports NO_CHAPTER against the committed Bookshelf index with the synonyms above present. Haematopoietic stem cell transplantation is not curated as a treatment because no report of it in a HOIP-deficient patient was found. The PubMed searches run were `HOIL-1 deficiency hematopoietic stem cell transplantation` (0 records), `LUBAC deficiency transplantation RBCK1 HSCT` (0 records) and `(RNF31 OR HOIP) AND (anakinra OR transplantation OR tocilizumab OR JAK)` (12 records, none of them a transplant report in a patient). The published management is supportive: immunoglobulin replacement, antibiotic prophylaxis, TNF blockade, and diet plus octreotide for the lymphangiectasia. Colchicine was given for three years to the founding patient on a presumptive diagnosis of familial Mediterranean fever with no clinical benefit; that is left in the cited case description rather than curated as a treatment, because it is a failed empirical trial under a mistaken diagnosis rather than a therapy for this disease. No `conforms_to` is declared. `just list-modules` was searched for inflammatory, necroptosis/cell-death and NF-kappa-B module families; the nearest candidates (`nlrp3_inflammasome_activation`, `cytokine_storm_hyperinflammation`) describe a different chain - inflammasome priming, and IL-6-driven capillary leak and multiorgan shock - and neither matches a node here. A LUBAC/M1-ubiquitin module, or a TNFR1 complex-II cell-death module, would be the right conformance target and does not yet exist; this entry and the SHARPIN and HOIL-1 diseases would be its first conformers. Six phenotypes are deliberately left unwired to the pathograph: neonatal omphalitis, clubbing, anaemia, postnatal growth retardation, bronchiectasis and lower limb muscle weakness. Each has a textbook explanation - infection in an antibody deficiency, chronic inflammation, enteric loss, recurrent respiratory infection - and none of them has a source that makes the causal claim about a HOIP-deficient patient. The muscle weakness case is the clearest: the patient with the muscle polyglucosan had normal electromyography and normal creatine kinase in the same paragraph, so the obvious edge is the one the source excludes. Deep-research provenance. An OpenScientist report (`research/HOIP_Deficiency-deep-research-openscientist.md`) is committed alongside this entry. `just preflight-dr` returns WARN on two counts, both resolved on inspection: TNF is mentioned more often than RNF31 because TNF signalling is this disease's own mechanism rather than a second disease, and the OMIM number the report cites (612487) is RNF31's gene MIM where MONDO xrefs the phenotype MIM 620632. Its reference validation is 15/15 resolved with 11/11 quotes matching; its term validation reports three mislabelled CURIEs, none of which is used here. One of those is worth naming: the report offers `GO:1990592` for "protein linear polyubiquitination", which GO calls protein K69-linked ufmylation. The term bound in this entry, `GO:0097039`, was looked up independently. Pyroptosis is deliberately not modelled. The deep-research report proposes a pyroptotic arm from LUBAC and caspase-1 cross-regulation (PMID:32122970), but that work is in cell lines and mouse macrophages and no HOIP patient phenotype has been attributed to it, so there is no node for it here and the reference is not cited. Evidence grading rule used throughout: an assay on the patient's own cells performed in culture, including ex vivo stimulation of fibroblasts, monocytes, B cells or PBMCs, is graded IN_VITRO, following the CLAUDE.md rule that cultured cells are in vitro whether human or animal. Only clinical observations, histology of patient biopsies and flow counts of unstimulated blood are graded HUMAN_CLINICAL. Review round 1 on PR #13204 found seven items that broke this rule and they were regraded.

Create: HOIP_Deficiency · 2026-09-29T21:29:27Z · View source

New entry for HOIP deficiency (immunodeficiency 115 with autoinflammation, MONDO:0957981), the RNF31/HOIP arm of LUBAC deficiency. Curated from the four fully reported patients (PMID:26008899 Boisson 2015, PMID:30936877 Oda 2019, PMID:39009172, PMID:41026334) plus the HOIP-deficient patient whose cell and tissue data appear in the SHARPIN report (PMID:38609546), and from the mouse literature on Hoip and Rnf31 conditional knockouts. Pathograph. Fifteen pathophysiology nodes running from the biallelic RNF31 variant through LUBAC destabilisation and loss of M1-linked ubiquitination, which branches into the NF-kappa-B/antibody arm, the TNFR1 cell-death arm, the paradoxical monocyte IL-1 beta hyperresponsiveness, the TLR3 antiviral arm, the type I interferon signature, and the lymphatic and muscle-storage arms. Nineteen of twenty-five phenotypes are causally connected. Six are deliberately left unwired and the entry's notes say which and why; the muscle weakness is the clearest case, since the same paragraph that documents the muscle polyglucosan records normal electromyography and creatine kinase. Deep research. An OpenScientist run is committed with the entry. Its reference validation is 15/15 resolved with 11/11 quotes matching; term validation flags three mislabelled CURIEs and needs_review is true. just preflight-dr returns WARN on two counts, both checked and resolved: TNF outweighs RNF31 in mention count because TNF signalling is this disease's own mechanism rather than a second disease, and the OMIM number the report cites (612487) is the RNF31 gene MIM where MONDO xrefs the phenotype MIM 620632 (confirmed against NCBI Gene 55072). The report contributed PMID:22863777 (HOIP RBR carries the catalytic activity and linkage specificity), PMID:27810922 (the TLR3 arm), PMID:28469620 (the OTULIN/A20 mirror-image differential) and PMID:23995275 (the RBCK1 polyglucosan sibling). Its suggested GO:1990592 for protein linear polyubiquitination was not used: GO calls that term protein K69-linked ufmylation, and the entry binds GO:0097039, looked up independently. Its claim that all patients are homozygous was not used either, since two of the four are compound heterozygous. Not taken from the report: the IL-1 blockade and JAK inhibition rows of its treatment table, which are cited to a general inflammasomopathy review rather than to any HOIP patient, and its HSCT row, which it labels theoretical. No HOIP-deficient patient has received any of the three. The IL-1 and JAK questions are recorded in discussions and mechanistic_hypotheses instead of as treatments. Verification. All snippets were re-verified against the fetched reference cache rather than taken from the report. just validate reports 119/119 snippets verified and 135 titles checked with no issues; term validation passes; entity refs, causal targets, duplicate keys, qualifier terms and the coarse-phenotype gate are clean. just check-genereviews reports NO_CHAPTER with synonyms present, and the entry's notes record the PubMed genereviews[book] query behind that. The absence of an HSCT report is recorded in notes with the three PubMed queries run and their result counts.

OpenScientist ▸

HOIP Deficiency (Immunodeficiency-115 with Autoinflammation): A Comprehensive Disease Characteristics Report

openscientist-autonomous 15 citations 2026-09-29T21:09:04.351089

HOIP Deficiency (Immunodeficiency-115 with Autoinflammation): A Comprehensive Disease Characteristics Report

Target disease: HOIP Deficiency · MONDO: MONDO:0957981 · Gene: RNF31 (HOIP) · Category: Mendelian, autosomal recessive inborn error of immunity

Summary

HOIP deficiency is an ultra-rare, autosomal-recessive inborn error of immunity caused by biallelic loss-of-function or severely hypomorphic mutations in RNF31, the gene encoding HOIP (HOIL-1-interacting protein), the catalytic RING-IBR-RING (RBR) E3 ubiquitin-ligase subunit of the Linear Ubiquitin chain Assembly Complex (LUBAC). LUBAC (HOIP + HOIL-1/RBCK1 + SHARPIN) is the sole cellular machinery that builds Met1-linked ("linear") polyubiquitin chains. Because HOIP is the enzymatic engine of the complex, its loss collapses LUBAC and abolishes linear ubiquitination. This single molecular lesion produces a strikingly paradoxical, bifurcated clinical picture: combined immunodeficiency on one hand and multiorgan autoinflammation on the other, accompanied by subclinical amylopectinosis (polyglucosan storage) and systemic/intestinal lymphangiectasia (Boisson et al. 2015, PMID: 26008899).

The mechanistic unifying concept is that LUBAC acts as a survival brake and a signaling amplifier. Loss of linear ubiquitination simultaneously (A) impairs canonical NF-κB activation — producing immunodeficiency, defective germinal-center B-cell development, and impaired antiviral (TLR3) immunity — and (B) de-represses TNFR1-, TLR3-, and inflammasome-driven programmed cell death executed through RIPK1/RIPK3/MLKL (necroptosis), caspase-8 (apoptosis), and caspase-1 (pyroptosis). The resulting cell death (particularly of endothelium and epithelium) and the release of damage- and cytokine-driven inflammation constitute the autoinflammatory arm of disease. This model is directly supported by human cellular studies, biochemical reconstitution, and multiple mouse models in which removal of TNFR1 rescues embryonic lethality and inflammation.

Because TNF-superfamily signaling drives the lethal cell-death branch, anti-TNF therapy is the mechanism-aligned treatment; in a patient with the sister disorder SHARPIN deficiency (same LUBAC-deficiency group), anti-TNF produced complete clinical and transcriptomic resolution of autoinflammation (Oda et al. 2024, PMID: 38609546). However, no treatment is curative: hematopoietic stem cell transplantation could correct the hematopoietic immunodeficiency but would not restore LUBAC function in non-hematopoietic cells (endothelium, fibroblasts, muscle) that drive lymphangiectasia and amylopectinosis. The disease is exceedingly rare — only a handful of patients have been reported worldwide since 2015 — and prevention is limited to genetic counseling.

1. Disease Information

Overview. HOIP deficiency is a Mendelian, autosomal-recessive systemic disorder combining features of primary immunodeficiency and autoinflammation, first defined in humans in 2015. It is the "index" LUBAC-deficiency disorder involving the catalytic subunit of LUBAC. The cardinal presentation is multiorgan autoinflammation, combined immunodeficiency, subclinical amylopectinosis, and systemic lymphangiectasia (Boisson et al. 2015, PMID: 26008899).

Key identifiers.

Resource	Identifier
MONDO	MONDO:0957981
Disease (OMIM phenotype)	Immunodeficiency-115 with autoinflammation (IMD115)
Gene symbol	RNF31 (aliases: HOIP, IMD115, ZIBRA, Paul)
NCBI Gene ID	55072
HGNC	HGNC:16031
Gene OMIM	612487
Ensembl	ENSG00000092098
UniProt	Q96EP0 (RNF31_HUMAN, 1072 aa)
Cytogenetic locus	14q12

(Identifier set from MyGene.info; see Finding F004.)

Synonyms / alternative names. HOIP deficiency; LUBAC deficiency (HOIP subtype); RNF31 deficiency; Immunodeficiency 115 with autoinflammation (IMD115). LUBAC deficiency as a category encompasses HOIP, HOIL-1/RBCK1, and SHARPIN deficiencies.

Nature of information. Evidence is derived from individual patients (a very small number of case reports and their in-depth cellular immunology) supplemented by mechanistic model-organism and in-vitro work — not from aggregated disease-level or EHR datasets, given the disorder's rarity.

2. Etiology

Primary cause (genetic). HOIP deficiency is caused by biallelic (homozygous) loss-of-function or severely hypomorphic mutations in RNF31. Two molecular classes are documented:

A PUB-domain missense allele, L72P, in the first reported patient — "at least severely hypomorphic, as it impairs HOIP expression and destabilizes the whole LUBAC complex," abolishing linear ubiquitination (Boisson et al. 2015, PMID: 26008899).
A C-terminal frameshift null allele generating a premature termination codon and "a C-terminal truncated HOIP mutant, that is, the loss of the linear ubiquitin chain-specific catalytic domain" (Wang et al. 2024, PMID: 39009172).

Genetic risk factors. The disease is monogenic; the causal variants themselves are the risk factor. Consanguinity / founder background is the principal predisposing context, as all reported patients are homozygous. RNF31 is relatively loss-of-function-constrained in gnomAD, so biallelic disease is vanishingly rare.

Environmental risk factors. None established as causal. Infections (bacterial, viral) act as triggers/complications because of the immunodeficiency and can precipitate autoinflammatory flares, but are downstream of the genetic lesion.

Protective factors. None identified. No protective alleles or environmental protective factors are described for this monogenic disorder.

Gene-environment interactions. MyD88-dependent innate signaling (downstream of IL-1 and TLR pathways sensing microbial/endogenous ligands) is required for the autoinflammatory phenotype in HOIP deficiency (Wu et al. 2021, PMID: 34253576) — implying that microbial/inflammatory environmental input interacts with the genetic lesion to shape the inflammatory phenotype.

3. Phenotypes

Synthesized from the two index HOIP-deficient patients and the overlapping HOIL-1/RBCK1 disorder (Boisson et al. 2015, PMID: 26008899; Oda et al. 2019, PMID: 30936877; Boisson et al. 2012, PMID: 23104095). Onset is in infancy/early childhood, with a chronic/relapsing course.

Phenotype	Type	HPO term(s)	Onset / severity / frequency
Multiorgan autoinflammation, recurrent fever	Clinical sign / symptom	HP:0001954 (Recurrent fever), HP:0002960 (Autoimmunity/autoinflammation)	Infancy; moderate–severe; core feature
Elevated inflammatory markers (CRP/ESR)	Lab abnormality	HP:0011227 (Elevated CRP)	Present during flares; frequent
Combined immunodeficiency, recurrent/invasive infections	Clinical sign	HP:0005387 (Combined immunodeficiency), HP:0002719 (Recurrent infections)	Infancy; severe; core feature
Impaired antibody responses (defective CD40-driven B-cell activation)	Lab abnormality	HP:0004313 (Decreased circulating antibody level)	Early; variable
Systemic / intestinal lymphangiectasia (± protein-losing enteropathy)	Physical manifestation	HP:0100767 (Lymphangiectasis), HP:0002593 (Intestinal lymphangiectasia)	Early; variable; core feature
Amylopectinosis (polyglucosan storage, often subclinical, muscle)	Pathologic manifestation	related to HP:0003198 (Myopathy)	Subclinical; storage
Hepatosplenomegaly	Clinical sign	HP:0001433 (Hepatosplenomegaly), HP:0001744 (Splenomegaly)	Variable
Failure to thrive / chronic diarrhea	Clinical sign	HP:0001508 (Failure to thrive), HP:0002028 (Chronic diarrhea)	Infancy; variable

Progression: chronic, relapsing autoinflammation punctuated by infection-triggered flares. Quality-of-life impact: substantial — recurrent invasive infections, chronic inflammation, and protein-losing enteropathy impair growth, nutrition, and daily functioning; formal QoL instruments (EQ-5D/SF-36/PROMIS) have not been applied given rarity.

Cellular signature underpinning the paradox: patient fibroblasts show impaired NF-κB activation to IL-1β/TNF, whereas monocytes are hyper-responsive to IL-1β, and B-cell activation/differentiation to CD40 is impaired — "the patient's monocytes respond to IL-1β more vigorously than control monocytes. However, the activation and differentiation of the patient's B cells are impaired in response to CD40 engagement" (PMID: 26008899).

4. Genetic / Molecular Information

Causal gene: RNF31 (HOIP), OMIM 612487, HGNC:16031, NCBI Gene 55072, Ensembl ENSG00000092098, UniProt Q96EP0, locus 14q12. HOIP is the catalytic RBR E3 ligase subunit of LUBAC (HOIP + HOIL-1/RBCK1 + SHARPIN).

Pathogenic variants (documented):

Variant	Type	Domain / consequence	Classification	Reference
L72P	Missense	PUB domain; impairs HOIP expression, destabilizes LUBAC (severely hypomorphic)	Pathogenic	PMID: 26008899
C-terminal frameshift	Frameshift/null	Premature stop; deletes linear-ubiquitin catalytic (RBR-LDD) domain	Pathogenic (LOF)	PMID: 39009172

Functional consequence: loss of function — abolition of Met1/linear ubiquitination and destabilization of the LUBAC holocomplex. Allele frequency: extremely low; RNF31 is LoF-constrained in gnomAD, so carrier frequency is very low. Origin: germline (autosomal recessive); no somatic disease association is described.

Modifier genes / interactors. MyD88 is required for the autoinflammatory phenotype (PMID: 34253576). TNFR1 (TNFRSF1A) is the dominant genetic modifier in models — its removal rescues lethality/inflammation (PMID: 25284787, PMID: 25443632). OTULIN and A20 (TNFAIP3) counter-regulate the same linear-ubiquitin/NF-κB axis. Epigenetic contributions and chromosomal abnormalities are not implicated in this monogenic disorder.

5. Environmental Information

Environmental factors / toxins: none causal.
Lifestyle factors: not applicable (monogenic, pediatric-onset).
Infectious agents: bacteria and viruses act as triggers and complications of the underlying combined immunodeficiency (invasive bacterial infections are prominent in the sister HOIL-1 disorder — "invasive bacterial infections," PMID: 23104095). LUBAC is required for TLR3-dependent immunity to influenza A virus, so viral susceptibility is expected (PMID: 27810922). Microbial/inflammatory input feeding MyD88 signaling drives autoinflammation (PMID: 34253576).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Biallelic RNF31 (HOIP) LOF/hypomorphic mutation → leads to reduced HOIP protein and destabilization/collapse of the LUBAC complex (demonstrated: PMID: 26008899).
LUBAC collapse → results in loss of Met1-linked (linear) polyubiquitination of substrates (NEMO, RIPK1, etc.), because HOIP's RBR + unique LDD extension is the sole activity specifying linear chains (demonstrated: PMID: 22863777).
Loss of linear ubiquitination branches into two signaling outputs plus a storage/vascular arm:

Branch A — Impaired canonical NF-κB signaling (→ immunodeficiency): - 4A. Reduced linear ubiquitination of NEMO → leads to defective canonical NF-κB activation in fibroblasts and lymphocytes (PMID: 26008899; PMID: 39009172). - 5A. Impaired NF-κB → results in defective CD40-driven B-cell activation/differentiation and substantial reduction of germinal-center B-cell development (PMID: 26008899; PMID: 38609546) and impaired TLR3 antiviral immunity (PMID: 27810922) → combined immunodeficiency.

Branch B — De-repression of TNFR1/TLR3/inflammasome cell death (→ autoinflammation): - 4B. Without linear ubiquitin scaffolding, TNFR1 stimulation leads to aberrant cytosolic complex-II formation (PMID: 25284787). - 5B. Complex-II engages RIPK1 → caspase-8/BID (apoptosis) and RIPK3/MLKL (necroptosis) (PMID: 25443632); LUBAC loss also heightens caspase-1 activation and pyroptosis upon inflammasome engagement (PMID: 32122970) and increases a TLR3-induced death-inducing complex (PMID: 27810922). - 6B. Excess programmed death of endothelial and epithelial/keratinocyte cells results in tissue injury, release of inflammatory mediators, and (MyD88-dependent) multiorgan autoinflammation (PMID: 34253576).

Branch C — Storage / vascular pathology (mechanism partly inferred): - 4C. LUBAC-subunit loss is associated with accumulation of amylopectin-like polyglucosan (amylopectinosis), paralleling RBCK1/HOIL-1 polyglucosan body myopathy (PMID: 23995275) — the precise link between linear-ubiquitin loss and polyglucosan storage remains inferred. - 5C. Endothelial dysfunction/death contributes to systemic and intestinal lymphangiectasia (mechanism inferred from the endothelial-survival role of HOIP; PMID: 25284787).

Detail by category

Molecular pathways: TNFR1/TNF-superfamily signaling, canonical NF-κB (IKK/NEMO), TLR3/TRIF, inflammasome/caspase-1, MyD88/IL-1R. LUBAC-generated linear ubiquitin is the upstream node.
Cellular processes: apoptosis, necroptosis, pyroptosis (all de-repressed); inflammation; impaired lymphocyte activation. Upstream: loss of linear ubiquitination. Downstream: RIPK1/RIPK3/MLKL/caspase-8/caspase-1 effectors and cytokine release.
Protein dysfunction: loss of function and complex destabilization; HOIP L72P impairs expression, frameshift deletes the catalytic domain — "both LUBAC catalytic activity and LUBAC specificity for linear ubiquitin chain formation are embedded within the RING-IBR-RING (RBR) ubiquitin ligase subunit HOIP" (PMID: 22863777).
Immune involvement: both immunodeficiency (NF-κB↓, GC B-cell↓, TLR3 antiviral↓) and autoinflammation (death-driven, monocyte IL-1β hyperresponse).
Tissue damage: endothelial and epithelial programmed cell death; polyglucosan storage.
GO / CL suggestions: GO:0071797 (LUBAC complex), GO:0006954 (inflammatory response), GO:0043123 (positive regulation of canonical NF-κB), GO:0097527 (necroptotic signaling), GO:0006915 (apoptotic process), GO:0043069 (negative regulation of programmed cell death), GO:1990592 (protein linear polyubiquitination), GO:0005829 (cytosol). Cell types: CL:0000115 (endothelial cell), CL:0000576 (monocyte), CL:0000236 (B cell), CL:0000312 (keratinocyte), CL:0000057 (fibroblast), CL:0000815 (regulatory T cell).

7. Anatomical Structures Affected

Organ level (primary): skin (UBERON:0002097), lymphatic vessels (UBERON:0001473), liver (UBERON:0002107), spleen (UBERON:0002106), intestine (UBERON:0000160), skeletal muscle (UBERON:0001134), vascular endothelium (UBERON:0001981).
Secondary/system involvement: immune/lymphoreticular system (secondary lymphoid germinal centers), gastrointestinal system (protein-losing enteropathy), cardiovascular/vascular system.
Tissue and cell level: vascular endothelial cells (CL:0000115), keratinocytes (CL:0000312), monocytes (CL:0000576), B cells (CL:0000236), fibroblasts (CL:0000057), regulatory T cells (CL:0000815).
Subcellular (GO-CC): cytosol (GO:0005829), LUBAC complex (GO:0071797).
Localization/lateralization: systemic and typically bilateral/generalized (multiorgan); no consistent lateralization.

8. Temporal Development

Onset: congenital/pediatric — manifests in infancy/early childhood; pattern chronic/insidious with acute infection- or inflammation-triggered flares.
Progression: chronic, relapsing–remitting inflammatory course; lifelong; storage (amylopectinosis) is slowly accumulating and often subclinical.
Disease course: severe multisystem; potentially life-threatening (the complete HOIL-1 counterpart was originally a "fatal human inherited disorder," PMID: 23104095).
Remission patterns: treatment-induced (anti-TNF produced complete remission of autoinflammation in a LUBAC-group patient, PMID: 38609546); no reliable spontaneous remission.
Critical periods: early infancy (infection vulnerability) is the key window for diagnosis and intervention.

9. Inheritance and Population

Epidemiology: exceedingly rare; only a small number of patients reported worldwide since the 2015 first description. No established prevalence/incidence (Orphanet-level "unknown"; ORPHA not firmly assigned).
Inheritance: autosomal recessive — all patients homozygous for biallelic RNF31 LOF/hypomorphic alleles (PMID: 26008899); consistent with consanguineous/founder backgrounds.
Penetrance: complete in reported homozygotes; expressivity severe.
Anticipation / germline mosaicism: not applicable/not reported.
Founder effects / carrier frequency: very low carrier frequency (RNF31 LoF-constrained in gnomAD); biallelic disease vanishingly rare.
Sex ratio: no predilection (AR). Age distribution: pediatric onset.

10. Diagnostics

Recommended approach: molecular genetics plus functional confirmation.

Genetic testing: identification of biallelic RNF31 pathogenic variants by whole-exome (WES) or whole-genome (WGS) sequencing, or via inborn-errors-of-immunity / autoinflammatory gene panels including RNF31/HOIP; confirm with single-gene/Sanger testing and family segregation (AR). CMA/karyotype/FISH/mtDNA/repeat-expansion testing are not indicated as first-line.
Functional confirmation (established in original reports): reduced HOIP expression and destabilized LUBAC on immunoblot; impaired Met1/linear ubiquitination; defective NF-κB activation in patient fibroblasts to IL-1β/TNF with paradoxical monocyte IL-1β hyper-responsiveness; impaired CD40-induced B-cell activation — "Linear ubiquitination and NF-κB activation are impaired in the patient's fibroblasts stimulated by IL-1β or TNF. In contrast, the patient's monocytes respond to IL-1β more vigorously than control monocytes" (PMID: 26008899).
Supportive labs/pathology: elevated CRP/ESR and proinflammatory cytokines; immunologic workup showing combined immunodeficiency (antibody defect); PAS-positive, diastase-resistant polyglucosan/amylopectin inclusions on muscle/tissue biopsy (amylopectinosis); imaging/endoscopy showing lymphangiectasia and protein-losing enteropathy.
Differential diagnosis: HOIL-1/RBCK1 deficiency and SHARPIN deficiency (sister LUBAC disorders), OTULIN deficiency (ORAS/otulipenia), A20 haploinsufficiency (HA20), other combined immunodeficiencies/CVID, and glycogen storage disease type IV / polyglucosan body disorders. OTULIN- and A20-deficient cells show excess Met1/K63 chains and constitutive NF-κB — the mirror image of LUBAC deficiency: "OTULIN or A20-deficient cells have an excess of Met1 or K63 Ub chains on NEMO, RIPK1, and other target substrates, which lead to constitutive activation of the NF-kB pathway" (PMID: 28469620).
Screening: carrier/cascade testing in affected families; prenatal / preimplantation genetic testing available; not a newborn-screening target.

11. Outcome / Prognosis

Severity/mortality: severe, potentially life-threatening multisystem disease; the analogous complete HOIL-1 deficiency was a "fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis" (PMID: 23104095). Morbidity/mortality are driven by recurrent invasive infections and organ-damaging autoinflammation.
Morbidity/function: chronic inflammation, protein-losing enteropathy, growth failure, and infection burden impair function and quality of life.
Complications: invasive bacterial/viral infections, organ inflammation (liver, spleen, gut), lymphangiectasia-related protein loss, storage pathology.
Prognostic factors: variant severity (hypomorphic vs null), infection control, and access to anti-cytokine therapy. Formal survival statistics are not established due to rarity.

12. Treatment

No curative therapy exists. Management combines targeted anti-cytokine therapy, immune support, and supportive care.

Modality	Rationale / evidence	NCIT suggestion
Anti-TNF therapy (etanercept, infliximab, adalimumab)	TNF-superfamily drives the lethal cell-death branch; anti-TNF gave complete clinical and transcriptomic resolution of autoinflammation in a SHARPIN-deficient (LUBAC-group) patient (PMID: 38609546)	NCIT:C2536 (TNF antagonist)
IL-1 blockade (anakinra, canakinumab)	Monocyte IL-1β hyperresponse; inflammasomopathy treatment "often aimed at interleukin-1 (IL-1) blockade" (PMID: 37821203)	NCIT:C2551 (Interleukin-1 Receptor Antagonist)
JAK inhibition (ruxolitinib, baricitinib)	Rational for NF-κB/inflammasome-driven inflammation and interferon signatures (PMID: 37821203)	NCIT:C129824 (JAK inhibitor)
Immunoglobulin replacement + antimicrobial prophylaxis	Corrects/mitigates combined immunodeficiency; avoid live vaccines	NCIT:C29799 (IVIG)
Supportive care for lymphangiectasia/enteropathy (nutrition, albumin)	Manages protein-losing enteropathy	—
HSCT (theoretical)	Could correct hematopoietic immunodeficiency but would NOT correct LUBAC loss in non-hematopoietic cells (endothelium, fibroblasts, muscle) driving lymphangiectasia and amylopectinosis	NCIT:C15431 (Hematopoietic Stem Cell Transplantation)

Pharmacogenomics / personalized medicine: treatment is genotype-driven at the level of pathway (TNF/IL-1/JAK blockade selected by mechanism). Experimental: LUBAC-targeting small molecules (HOIPINs) exist as research tools but are inhibitors, not activators, and are not therapeutic here.

13. Prevention

Primary prevention: not possible (monogenic, germline). Prevention is limited to reproductive/genetic strategies.
Genetic counseling: 25% recurrence risk for carrier couples; cascade carrier testing; options for prenatal diagnosis and preimplantation genetic testing (PGT).
Secondary/tertiary prevention: early diagnosis and initiation of anti-cytokine therapy; antimicrobial prophylaxis and immunoglobulin replacement to prevent infections; avoidance of live vaccines given combined immunodeficiency; nutritional support to prevent complications of enteropathy.
Public health / environmental interventions: not applicable.

14. Other Species / Natural Disease

Taxonomy / orthologs: mouse Rnf31 (Hoip), NCBI Taxon 10090. HOIP/LUBAC is evolutionarily conserved across mammals.
Natural disease in other species: no naturally occurring companion-animal or wildlife HOIP-deficiency disease is documented (OMIA); disease knowledge is from engineered laboratory models. RBCK1/HOIL-1 links to polyglucosan storage provide comparative-pathology parallels (PMID: 23995275).
Evolutionary conservation of mechanism: the TNFR1-driven death sensitivity and NF-κB dependence on linear ubiquitination are conserved between human and mouse (rescue of murine lethality by Tnfr1 ablation mirrors human TNF-driven pathology).
Zoonotic potential: not applicable.

15. Model Organisms

Mouse (Mus musculus, Taxon 10090) is the principal model system.

Model	Phenotype	Key finding	Reference
Constitutive Hoip KO; Tie2-Cre endothelial Hoip deletion	Embryonic lethal ~E10.5 from aberrant TNFR1-mediated endothelial death, defective vascularization	"Ablation of tumor necrosis factor receptor 1 (TNFR1) prevents cell death, vascularization defects, and death at midgestation"	PMID: 25284787
Sharpin-null cpdm mouse (spontaneous)	Chronic proliferative dermatitis, liver inflammation, splenomegaly, loss of Peyer's patches	"TNF-dependent multi-organ inflammation"; RIPK3/MLKL + caspase-8 effectors	PMID: 25443632
cpdm variants (Tlr3 co-ablation)	Dermatitis ameliorated	Excess TLR3-induced cell death contributes to disease	PMID: 27810922
Treg-specific Sharpin ± Hoip disruption	cpdm-like → T-cell-predominant autoimmune lesions	"additional disruption of the Hoip locus... converts cpdm-like dermatitis to T cell-predominant autoimmune lesions"	PMID: 31462647

Model types available: knockout (constitutive and conditional/tissue-specific via Cre), spontaneous mutant (cpdm). Phenotype recapitulation: models faithfully reproduce the TNF-driven cell-death and inflammation arm and its genetic rescue, providing strong mechanistic validation. Limitations: complete Hoip/Hoil-1 knockouts are embryonic lethal — "their genetic ablation is embryonically lethal in mice" (PMID: 32122970) — so viable models rely on Sharpin-null cpdm or conditional deletions; the human hypomorphic (partial-function) state and full multisystem human phenotype (amylopectinosis, lymphangiectasia) are incompletely captured. Resources: MGI, IMPC/IMSR for Rnf31 alleles.

Mechanistic Model / Interpretation

Capstone synthesis (Finding F013). HOIP deficiency is best understood as a LUBAC "survival-brake" disorder. A single molecular lesion — loss of Met1/linear ubiquitination — produces a bifurcated signaling output plus storage/vascular pathology:

   Biallelic RNF31 (HOIP) LOF / hypomorphic mutation
 │
 ▼
     LUBAC complex collapse  (HOIP + HOIL-1 + SHARPIN)
 │
 ▼
   Loss of Met1-linked (linear) polyubiquitination
(NEMO, RIPK1, caspase-1 CARD, ...)
 │
      ┌──────────┴───────────────┬─────────────────────┐
      ▼                          ▼                     ▼
 (A) Impaired canonical     (B) De-repressed         (C) Storage /
     NF-κB signaling            programmed cell           vascular
      │                          death (TNFR1          pathology
      ▼                          complex-II,             │
 - Defective CD40 B-cell         TLR3, inflammasome)    ▼
   activation                    │                   - Amylopectinosis
 - ↓ Germinal-center         RIPK1→caspase-8         (polyglucosan)
   B cells                    (apoptosis)            - Systemic /
 - Impaired TLR3               RIPK3/MLKL              intestinal
   antiviral immunity         (necroptosis)           lymphangiectasia
      │                       caspase-1               (endothelial
      ▼                       (pyroptosis)             death; inferred)
 COMBINED                        │
 IMMUNODEFICIENCY                ▼  (MyD88-dependent)
            MULTIORGAN AUTOINFLAMMATION
                 │
                 ▼
    Anti-TNF / IL-1 / JAK blockade
    resolves the inflammatory branch

The elegance — and the paradox — of the disease is that the same enzymatic defect that weakens activating signaling (NF-κB → immunodeficiency) simultaneously removes a checkpoint that normally restrains death-inducing complexes (→ autoinflammation). The two arms are not contradictory but two faces of one lost function: linear ubiquitin is both a signaling amplifier for NF-κB and a survival scaffold that keeps TNFR1/TLR3/inflammasome signaling from tipping into cell death. This places HOIP deficiency firmly within the ubiquitin/NF-κB-dysregulation class of autoinflammatory diseases, alongside OTULIN deficiency (ORAS) and A20 haploinsufficiency (HA20) — but on the opposite side of the ubiquitin balance: LUBAC deficiency removes linear chains, whereas OTULIN/A20 loss leaves excess chains and constitutive NF-κB. As Boisson et al. concluded, "human HOIP is essential for the assembly and function of LUBAC and for various processes governing inflammation and immunity in both hematopoietic and nonhematopoietic cells" (PMID: 26008899) — explaining why HSCT (a hematopoietic fix) cannot cure the non-hematopoietic (vascular, muscle, epithelial) manifestations.

Evidence Base

PMID	Title (abbrev.)	Role in this report
26008899	Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia	Index case; defines cardinal phenotype, L72P allele, LUBAC destabilization, and the fibroblast-NF-κB↓/monocyte-IL-1β↑ signature
39009172	A novel HOIP frameshift variant alleviates NF-κB signalling and sensitizes cells to TNF-induced death	Second molecular class (frameshift null); confirms NF-κB suppression + TNF-induced death in human cells
30936877	Second Case of HOIP Deficiency…	Expands clinical features; defines LUBAC-regulated inflammatory transcriptome
22863777	E3 ligase HOIP specifies linear ubiquitin chain assembly…	Biochemical basis: HOIP RBR+LDD is the catalytic engine for linear chains
25284787	HOIP deficiency causes embryonic lethality by aberrant TNFR1-mediated endothelial cell death	Mouse model; TNFR1-driven death branch, rescued by TNFR1 ablation
25443632	TNFR1-dependent cell death drives inflammation in Sharpin-deficient mice	cpdm model; RIPK3/MLKL + caspase-8 effectors
27810922	LUBAC deficiency perturbs TLR3 signaling…	TLR3 antiviral gating; TLR3-induced death complex
32122970	Cross-regulation between LUBAC and caspase-1…	Inflammasome/pyroptosis branch; embryonic lethality of KO
34253576	MyD88-Dependent Signaling Is Required for HOIP Deficiency-Induced Autoinflammation	MyD88 as required node for the autoinflammatory arm
31462647	Modulation of autoimmune pathogenesis by T cell-triggered inflammatory cell death	Conditional Hoip mouse; T-cell autoimmune lesions
38609546	Biallelic human SHARPIN loss of function…	Completes LUBAC trio; shared GC-B-cell defect; anti-TNF resolves autoinflammation
28469620	NF-κB Pathway in Autoinflammatory Diseases… Ubiquitin	Nosology: LUBAC vs OTULIN vs A20; shared cellular signature
23104095	Immunodeficiency, autoinflammation and amylopectinosis… HOIL-1 and LUBAC deficiency	Sister disorder; overlapping fatal phenotype
23995275	New insights in muscle glycogenoses	RBCK1/polyglucosan storage link (amylopectinosis)
37821203	Targeted Treatment of Diseases of Immune Dysregulation	IL-1 blockade / JAK inhibition rationale

Evidence source types: human clinical/cellular (26008899, 39009172, 30936877, 38609546, 23104095), biochemical/in-vitro (22863777, 32122970), and model-organism (25284787, 25443632, 27810922, 31462647, 34253576).

Limitations and Knowledge Gaps

Extreme rarity / very small n. Only a handful of HOIP-deficient patients are described; phenotype frequencies, natural history, penetrance nuances, and survival statistics are not robustly quantified. Much of the clinical spectrum is extrapolated from the sister LUBAC disorders (HOIL-1, SHARPIN).
No HOIP-specific treatment trials. The strongest therapeutic evidence (complete anti-TNF remission) comes from a SHARPIN-deficient patient; direct HOIP-deficiency treatment outcomes are anecdotal.
Model limitations. Complete Hoip knockout is embryonic lethal, so viable mechanistic modeling depends on conditional deletions and the Sharpin cpdm mouse; the human hypomorphic state and the full multisystem human phenotype (amylopectinosis, lymphangiectasia) are incompletely recapitulated.
Mechanism of storage and lymphangiectasia is inferred. The causal link from linear-ubiquitin loss to polyglucosan storage and to lymphatic pathology is not fully demonstrated.
No disease-specific population genetics. RNF31 constraint is inferred from gnomAD; no formal carrier-screening or founder studies exist.
Incomplete ontology mapping. ORPHA assignment and some HPO frequency annotations remain incomplete for this newly delineated entity.

Proposed Follow-up Experiments / Actions

Patient registry / natural-history study pooling all reported HOIP (and LUBAC-trio) cases to quantify phenotype frequencies, onset, penetrance, and survival, and to standardize HPO annotation.
Genotype–phenotype correlation: systematically compare hypomorphic missense (L72P-type) vs null (frameshift) alleles for severity, storage burden, and treatment response.
Prospective anti-cytokine therapy evaluation in confirmed HOIP-deficiency patients (anti-TNF first-line; IL-1 and JAK inhibition as alternatives) with transcriptomic monitoring, mirroring the SHARPIN case.
Patient-derived iPSC / organoid and endothelial models to dissect the amylopectinosis and lymphangiectasia mechanisms that mouse models miss, and to test whether death-pathway inhibitors (RIPK1/RIPK3/MLKL/caspase inhibitors) protect endothelium.
HSCT outcome documentation to empirically test the prediction that transplantation corrects immunodeficiency but not the non-hematopoietic (vascular/storage) pathology.
Functional variant curation in ClinVar/ClinGen for RNF31 to support ACMG classification and cascade/prenatal testing.

Report compiled from 13 confirmed findings and 29 reviewed papers across a 5-iteration autonomous investigation. Ontology suggestions (HPO, GO, CL, UBERON, NCIT, MONDO) are provided throughout for knowledge-base ingestion.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0rc3.

Outcome	Count
References checked	15
Resolved	15
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	11
Quoted claims found in source	11
Quoted claims not found in source	0
References weighed for topical relevance	15
On topic	10
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	41
Resolved	40
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	1
Terms whose name was checked	23
Terms named correctly	13
Terms named as a different term	3
Terms whose name is worth a second look	7

Terms the report names something else

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

MONDO:0957981 (2 mentions) - the report calls it "MONDO"; MONDO calls it immunodeficiency 115 with autoinflammation
NCIT:C2551 (1 mention) - the report calls it "Interleukin-1 Receptor Antagonist"; NCIT calls it CP-609,754
NCIT:C29799 (1 mention) - the report calls it "IVIG"; NCIT calls it 3-Nitrobenzo[a]pyrene trans-7,8-Dihydrodiol

Terms whose name is worth a second look

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

HP:0011227 (1 mention) - the report calls it "Elevated CRP"; HP calls it Elevated circulating C-reactive protein concentration, and lists "Elevated CRP" among its other names
GO:0043123 (1 mention) - the report calls it "positive regulation of canonical NF-κB"; GO calls it positive regulation of canonical NF-kappaB signal transduction
GO:0097527 (1 mention) - the report calls it "necroptotic signaling"; GO calls it necroptotic signaling pathway, and lists "necroptosis signaling" among its other names
GO:1990592 (1 mention) - the report calls it "protein linear polyubiquitination"; GO calls it protein K69-linked ufmylation
CL:0000115 (2 mentions) - the report calls it "endothelial cell", "Tissue and cell level: vascular endothelial cells"; CL calls it endothelial cell**
NCIT:C2536 (1 mention) - the report calls it "TNF antagonist"; NCIT calls it Canarypox Antigen, and lists "Canarypox Antigens" among its other names
NCIT:C129824 (1 mention) - the report calls it "JAK inhibitor"; NCIT calls it Antineoplastic Protein Inhibitor, and lists "Anti-cancer Protein Inhibitor" among its other names

Terms named inconsistently

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

CL:0000115 - called "endothelial cell", "Tissue and cell level:** vascular endothelial cells"

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Diagnosis

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References & Deep Research

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Deep Research

HOIP Deficiency (Immunodeficiency-115 with Autoinflammation): A Comprehensive Disease Characteristics Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation)

Detail by category

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Mechanistic Model / Interpretation

Evidence Base

Limitations and Knowledge Gaps

Proposed Follow-up Experiments / Actions

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look

Terms named inconsistently