🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal dominant inheritance HP:0000006

Reported patients are HETEROZYGOUS for rare missense variants in a POL III subunit, which is why the condition is recorded as autosomal dominant. Two caveats belong with that label. Penetrance is plainly incomplete — most people carrying a rare POL III variant never develop severe VZV disease, and the disease requires the virus as well as the genotype. And one of the four children in the founding series was DIGENIC, carrying variants in both POLR3A and POLR3C, so a single heterozygous allele is not in every case the whole genetic explanation.

Autosomal dominant inheritance

Show evidence (4 references)

PMID:28783042 SUPPORT Human Clinical

"unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients)"

Establishes heterozygous inheritance and documents the digenic genotype in two of the four founding patients.

PMID:28783042 SUPPORT Human Clinical

"This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children"

The authors' own framing of the genotypes as monogenic or digenic, which is the basis for the digenic caveat in this block.

PMID:30211253 SUPPORT Human Clinical

"The mutation was inherited from the father"

Documents vertical transmission of the POLR3F allele, establishing germline origin.

+ 1 more reference

?

Discussions and Knowledge Gaps

3

Are severe PRIMARY VZV disease in POL III-deficient children and adult VZV REACTIVATION vasculitis one disease entity or two, and does MONDO:0030813 cover both?

KNOWLEDGE GAP OPEN imd101_nosology_primary_versus_reactivation

Attached to

pathophysiology#Failure to Restrict VZV Replication

OMIM's summary of IMD101 is written entirely around adult reactivation — reactivation in adulthood after primary childhood infection, presenting as CNS vasculitis — and MedGen anchors the entity on POLR3F. But the founding literature is paediatric and primary-infection, in POLR3A and POLR3C, and the review literature treats all four subunits as one susceptibility. The neuronal model complicates rather than settles this: its authors conclude that POL III matters to VZV immunity MAINLY UPON REACTIVATION, which if correct would make the paediatric primary-infection cases the harder ones to explain by this mechanism, not the easier. This entry curates both arms off a shared upstream chain and flags the question rather than choosing an answer, because the choice determines whether the paediatric POLR3A/POLR3C cases belong under this MONDO concept at all.

Proposed experiments

Stage-resolved comparison of POL III dependence in primary versus reactivating VZV infection

exp_imd101_lifecycle_stage_comparison

In matched neuronal and non-neuronal human cells carrying POLR3A, POLR3C, POLR3E and POLR3F patient alleles, quantify interferon induction and viral control separately during de novo infection and during reactivation from a quiescent state, to test whether the subunits differ in which life-cycle stage they gate — which would be the mechanistic basis for splitting or lumping the two clinical presentations.

Show evidence (2 references)

PMID:41739639 SUPPORT In Vitro

"POL III) plays a role in immunity to VZV mainly upon reactivation in humans"

The claim that POL III acts mainly at reactivation, which is what puts the paediatric primary-infection arm in question.

PMID:28783042 SUPPORT Human Clinical

"4 cases of acute severe VZV infection affecting the central nervous system or the lungs"

The paediatric primary-infection cases that the reactivation-centred framing has to accommodate.

Every model of this disease is a model of the wrong compartment. Does evidence from circulating leukocytes and a neuroblastoma line license claims about cerebral arteries and sensory ganglia, which is where the disease actually happens?

HUMAN MODEL MISMATCH OPEN imd101_no_model_of_the_affected_tissue

Attached to

pathophysiology#VZV Vasculopathy of Cerebral Arteries

The functional evidence in this entry comes from two sources, and neither is the affected tissue. Patient peripheral blood mononuclear cells give the cleanest genotype-phenotype link - impaired interferon and cytokine responses to the POL III agonist, intact responses to a ligand that bypasses POL III, increased viral transcript - but they are circulating mixed cells, not neurons, ganglia, or cerebral arterial endothelium. The SH-SY5Y model reaches the neuronal compartment and the reactivation step, but it is a neuroblastoma line carrying an engineered heterozygous knockout rather than the patients' R50W missense allele, so it tests gene dosage rather than the human variant. No animal model of this disorder exists, and no histopathological confirmation of the CNS vasculitis was obtainable in either reported patient. The vasculopathy node is therefore supported by clinical, CSF and imaging evidence in humans and by mechanistic evidence in the wrong cell types, with nothing bridging the two.

Proposed experiments

Patient-derived iPSC neurons and brain microvascular endothelial cells carrying R50W

exp_imd101_patient_ipsc_neurovascular_model

Differentiate iPSCs from an R50W carrier, and isogenic corrected controls, into sensory-type neurons and brain microvascular endothelial cells; assay VZV infection, latency establishment, reactivation, interferon induction and endothelial activation in each. This would test the disease mechanism in the two cell types the disease actually damages, with the patient's own allele rather than a knockout.

Show evidence (2 references)

PMID:30211253 SUPPORT Human Clinical

"histopathologic evidence of vasculitis in the CNS could not be provided in the 2 cases described here"

Establishes that the tissue diagnosis was never obtained, which is one half of the gap this discussion records.

PMID:41739639 SUPPORT In Vitro

"We generated human SH-SY5Y (POLR3F+/-) knockout cells."

Identifies the only neuronal model as an engineered knockout line rather than a patient-allele or animal model, which is the other half of the gap.

Why do variants in POL III subunits produce either VZV susceptibility or hypomyelinating leukodystrophy, and what determines which, given that both perturb the same nine-subunit enzyme?

KNOWLEDGE GAP OPEN imd101_pol_iii_genotype_phenotype

Attached to

pathophysiology#RNA Polymerase III Subunit Missense Variant

POL III subunit variants cause tissue-specific diseases rather than a general failure of the enzyme's vital functions, and the two disease groups barely overlap clinically: POLR3A appears in both lists, but VZV-susceptible patients do not have leukodystrophy and leukodystrophy patients are not reported to have VZV susceptibility. The review literature states plainly that the exact molecular mechanisms underlying disease pathogenesis remain enigmatic. This matters practically as well as conceptually: it means a variant in POLR3A cannot be interpreted without knowing which disease mechanism it engages, and it is the reason this entry's counseling entry carries that warning.

Proposed experiments

Partitioned assay of housekeeping versus DNA-sensing POL III function across disease alleles

exp_imd101_subunit_allele_function_partition

Assay VZV-susceptibility alleles and leukodystrophy alleles side by side for tRNA/small-RNA transcription on the one hand and cytosolic AT-rich DNA sensing with interferon induction on the other, to test whether the two disease groups separate along the housekeeping/sensing axis rather than by subunit identity.

Show evidence (2 references)

PMID:34395528 SUPPORT Other

"it was discovered in the last decade that various inherited mutations in genes encoding nine distinct subunits of Pol III cause tissue-specific diseases rather than a general failure of all vital functions"

States the puzzle: subunit variants give tissue-specific disease rather than global enzyme failure.

PMID:34395528 SUPPORT Other

"the exact molecular mechanisms underlying disease pathogenesis remain enigmatic"

The authors' own statement that the mechanism partitioning these diseases is unresolved.

⚙

Pathophysiology

7

RNA Polymerase III Subunit Missense Variant

Rare heterozygous missense variants in genes encoding subunits of RNA polymerase III. Four subunits have been implicated in VZV susceptibility: POLR3A and POLR3C in children with severe primary VZV disease, POLR3A and POLR3E in adults with VZV CNS infection after reactivation, and POLR3F — the subunit on which OMIM anchors IMD101 — in monozygotic twins with recurrent VZV CNS vasculitis. The variants are damaging but not null: the functional assays show impaired, not abolished, responses, and POL III's housekeeping transcription of tRNAs and other small RNAs is evidently preserved enough to be compatible with life and with otherwise normal health.

POLR3A hgnc:30074 POLR3C hgnc:30076 POLR3E hgnc:30347 POLR3F hgnc:15763

Genetic context POLR3F hgnc:15763 allele_type: missense variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

The genetic context is written for POLR3F because that is the subunit on which OMIM and MedGen anchor the numbered IMD101 entity; the twins carried the heterozygous R50W substitution. PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION is the honest category: the reported functional consequence is impaired antiviral and inflammatory responses and increased viral replication relative to controls, not abolished POL III function, and the housekeeping transcription these subunits also serve is evidently retained. The same category applies to the POLR3A, POLR3C and POLR3E alleles listed on this node.

`variant_origin: GERMLINE` is set on the strength of the POLR3F pedigree, in which Sanger sequencing placed the c.148C>T variant in both twins and in their father. That pedigree also carries the penetrance evidence: the father was previously admitted with stroke-like signs that the authors say might retrospectively have been VZV CNS vasculitis, but this was never investigated, so he is neither a confirmed affected transmitting parent nor a confirmed unaffected carrier. Origin is not asserted for the POLR3A, POLR3C or POLR3E alleles, whose parental testing is not reported in the cached sources.

RNA polymerase III complex GO:0005666

Downstream

Impaired Cytosolic Sensing of AT-Rich VZV DNA The variants sit in the sensor itself, so the function that fails is recognition of AT-rich cytosolic DNA.

Show evidence (4 references)

PMID:28783042 SUPPORT Human Clinical

"We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy"

Establishes the founding cohort and, in the phrase "otherwise healthy", the pathogen-restricted character of the susceptibility.

PMID:34395528 SUPPORT Other

"Mutations in the POLR3A, POLR3C, POLR3E and POLR3F subunits are associated with susceptibility to varicella zoster virus-induced encephalitis and pneumonitis."

Enumerates the four implicated subunits, which is the basis for modelling them as one allelic series on this node.

PMID:30211253 SUPPORT Human Clinical

"We performed whole-exome sequencing and identified a rare mutation in the POL III subunit POLR3F."

Identifies the POLR3F variant on which OMIM anchors the numbered IMD101 entity.

+ 1 more reference

Impaired Cytosolic Sensing of AT-Rich VZV DNA

RNA polymerase III has a second job beyond housekeeping transcription: in the cytosol it transcribes AT-rich double-stranded DNA into 5'-triphosphate RNA, which is a ligand for RIG-I and thus a trigger for type I interferon. This node is the failure of that recognition step. It is also the best available explanation for the disease's most striking feature — that the susceptibility is confined to one virus. VZV has an AT-rich genome, so it is the pathogen most dependent on this particular sensing route; patients do not have increased susceptibility to other infections.

leukocyte CL:0000738

RNA polymerase III complex GO:0005666

innate immune response GO:0045087 ↓ DECREASED transcription by RNA polymerase III GO:0006383 ↓ DECREASED

Downstream

Deficient Type I Interferon Induction Failure of sensing means the interferon response that sensing normally triggers is not mounted.

Show evidence (4 references)

PMID:30211253 SUPPORT Other

"RNA POL III is a 17-subunit enzyme with dual functions in both promoter-dependent transcription of tRNA and rRNA and innate sensing of AT-rich DNA, converting this into 5"

States the dual role that makes this node possible: the same enzyme does housekeeping transcription and cytosolic AT-rich DNA sensing, converting that DNA into the 5-prime-phosphorylated RNA that RIG-I recognises. Quoted up to the prime symbol, which does not survive as a stable substring.

PMID:30115567 SUPPORT Other

"Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity."

States both halves of this node: POL III acts as a DNA sensor, and defects in it confer SELECTIVE susceptibility to VZV.

PMID:29728610 SUPPORT In Vitro

"impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection"

Names the specific molecular defect — impaired sensing of AT-rich DNA — in adult patients.

+ 1 more reference

Deficient Type I Interferon Induction

Patient leukocytes mount a poor interferon response to synthetic AT-rich DNA, to VZV-derived DNA, and to VZV infection itself. That the defect is demonstrable with a synthetic agonist as well as with the virus is what separates a sensing defect from a downstream failure of viral handling. The causal weight of this node rests on a rescue experiment: transducing patient cells with the relevant wild-type allele restored the phenotype.

leukocyte CL:0000738

positive regulation of type I interferon production GO:0032481 ↓ DECREASED type I interferon production GO:0032606 ↓ DECREASED

Experimental models

Patient peripheral blood mononuclear cells with wild-type allele rescue PRIMARY CELL CULTURE Direct measurement in patient cells of the interferon and cytokine defect, with genetic rescue.

Downstream

Failure to Restrict VZV Replication Without an adequate interferon response the cell does not establish the antiviral state that limits VZV replication.

Show evidence (5 references)

PMID:28783042 SUPPORT In Vitro

"Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication."

Shows the interferon defect on live VZV infection, not only on synthetic agonist, together with the loss of viral control.

PMID:28783042 SUPPORT In Vitro

"These phenotypes were rescued by transduction with relevant WT alleles."

The rescue experiment that establishes the variants as causal for the interferon phenotype rather than merely associated with it.

PMID:29728610 SUPPORT In Vitro

"we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls"

Replicates the cytokine and viral-replication phenotype in an independent adult cohort with POLR3A and POLR3E variants.

+ 2 more references

Failure to Restrict VZV Replication

Patient cells permit more VZV replication than control cells. This is the convergence point of the disease: whatever the subunit and whichever phase of the viral life cycle, the cell fails to hold the virus down, and everything downstream is a consequence of uncontrolled VZV in a particular tissue.

defense response to virus GO:0051607 ↓ DECREASED

Downstream

VZV Reactivation from Latency Loss of cell-intrinsic restraint in neurons permits reactivation from latency, which is the arm that produces the adult presentation on which the numbered OMIM entity is defined. The direct evidence is a neuronal cell model rather than patient tissue.

Severe Primary VZV Disease of the CNS and Lungs In children meeting the virus for the first time, the same failure of restraint permits severe primary disease rather than uncomplicated varicella.

Show evidence (2 references)

PMID:30211253 SUPPORT In Vitro

"patient PBMCs exhibited impaired antiviral and inflammatory responses to the POL III agonist poly(dA:dT) and increased viral replication compared with controls"

Measures increased viral replication in patient cells relative to controls.

PMID:30211253 SUPPORT In Vitro

"a significantly increased amount of the viral immediate-early gene ORF63 mRNA was detected in P1 cells relative to controls, demonstrating increased viral replication, i.e., reduced viral control in patient cells"

Quantifies the loss of viral control as increased viral immediate-early transcript in patient cells, which is the measurement this node names.

VZV Reactivation from Latency

VZV establishes latency in sensory ganglia after primary infection and reactivates from there. In POL III deficiency the reactivation arm is what produces the defining adult phenotype, and a neuronal knockout model shows both higher viral gene expression and more spontaneous reactivation in POLR3F-heterozygous cells. Note the model's own framing: it supports POL III mattering to VZV immunity MAINLY UPON REACTIVATION, which is a claim about where in the viral life cycle the sensor is rate-limiting and should not be flattened into "POL III controls VZV".

neuron CL:0000540

Experimental models

POLR3F+/- SH-SY5Y human neuronal cell model CELL LINE POLR3F-heterozygous neuronal cells show higher viral gene expression and more spontaneous VZV reactivation than wild type, which the authors describe as reflecting the patient phenotype.

Downstream

VZV Vasculopathy of Cerebral Arteries Reactivated VZV productively infects cerebral arteries, which is the lesion behind the stroke-like presentation.

Show evidence (1 reference)

PMID:41739639 SUPPORT In Vitro

"This work identifies a novel role for POLR3F as a sentinel for VZV reactivation in neuronal cells and lends further support to the hypothesis that polymerase III (POL III) plays a role in immunity to VZV mainly upon reactivation in humans and that POL III defects predispose to VZV central..."

States the reactivation-specific role and the resulting predisposition to CNS infection, with the authors' own hedge on where in the life cycle POL III acts.

VZV Vasculopathy of Cerebral Arteries

Productive VZV infection of cerebral arteries produces a vasculitis affecting large vessels, small vessels, or both. The consequence is ischemic injury, which is why an immunodeficiency presents to a stroke service. Cerebrospinal fluid in the reported twins showed pleocytosis with intrathecal VZV antibody production, and brain MRI showed ischemic lesions.

artery UBERON:0001637 brain UBERON:0000955

Downstream

Cerebral vasculitis The arterial inflammation is itself the curated phenotype.

Ischemic stroke Vasculitic occlusion of cerebral arteries produces ischemic lesions and the stroke-like episodes that bring these patients to attention.

Headache Headache was a recurrent presenting symptom of the vasculitic episodes.

Vertigo Dizziness accompanied the recurrent episodes in the reported twins.

CSF pleocytosis Inflammation of the cerebral vasculature and meninges produces a cerebrospinal fluid pleocytosis with intrathecal VZV antibody.

Show evidence (2 references)

PMID:30211253 SUPPORT Human Clinical

"The clinical presentation and findings included recurrent episodes of headache, dizziness, and neurologic deficits, CSF with pleocytosis and intrathecal VZV antibody production, and MRI of the brain showing ischemic lesions."

Enumerates the clinical, CSF and imaging findings that define this node.

PMID:30211253 SUPPORT Other

"may also present in a more atypical stroke-like manner, in which case, the immunopathogenesis appears to be vasculitis"

States that the stroke-like presentation of VZV CNS disease is vasculitic in mechanism.

Severe Primary VZV Disease of the CNS and Lungs

The paediatric arm: otherwise healthy children who, on first meeting VZV, develop CNS disease or pneumonitis instead of uncomplicated varicella. This is a rare outcome at population level — CNS infection and pneumonia complicate roughly 0.02% and 0.25% of childhood primary infections — which is what made a monogenic explanation worth looking for. This node is retained even though the OMIM definition of IMD101 is written around adult reactivation; see the nosology discussion.

central nervous system UBERON:0001017

Downstream

Infectious encephalitis CNS involvement in severe primary VZV disease manifests as cerebellitis, encephalitis or stroke.

Show evidence (2 references)

PMID:28783042 SUPPORT Human Clinical

"Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people"

States the contrast between typical varicella and the rare severe outcome this node represents.

PMID:28783042 SUPPORT Other

"and pneumonia during primary infection in children are about 0.02% and 0.25%, respectively"

Gives the population frequencies of the two severe outcomes of primary childhood VZV infection - CNS infection and pneumonia, about 0.02% and 0.25% - which is the rarity that motivated looking for a monogenic explanation. The quote starts mid-sentence because the preceding words ("The frequencies of VZV CNS infec-tion") are hyphenated across a line break in the cached typeset text.

⬡

Pathograph

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

●

Phenotypes

11

Cardiovascular 1

Ischemic stroke HP:0002140

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"MRI of the brain showing ischemic lesions"

Documents ischemic brain lesions in the reported patients.

Ear 1

Vertigo HP:0002321

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"recurrent episodes of headache, dizziness, and neurologic deficits"

Documents dizziness; PARTIAL because the reported symptom is dizziness rather than vertigo specifically.

Eye 1

Diplopia HP:0000651

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"she was readmitted with right-sided hemiparesis, and -paresthesias double vision and impaired balance"

Documents double vision and impaired balance in the same episode. The stray hyphen before "paresthesias" is an artefact of the cached text and is quoted as it appears.

Immune 3

Myelitis HP:0012486

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"MRI of the total medulla and brain demonstrated myelitis at the level of C6 and Th2"

Documents spinal cord involvement on imaging.

Infectious encephalitis HP:0002383

Show evidence (1 reference)

PMID:34395528 SUPPORT Other

"susceptibility to varicella zoster virus-induced encephalitis and pneumonitis"

Names encephalitis as a manifestation of POL III subunit deficiency.

Pneumonitis Pneumonia HP:0002090

Show evidence (1 reference)

PMID:34395528 SUPPORT Other

"varicella zoster virus-induced encephalitis and pneumonitis"

Names pneumonitis as a manifestation. Marked PARTIAL because the bound HPO term is Pneumonia, which is broader than the viral pneumonitis meant here.

Nervous System 3

Headache HP:0002315

Temporal: RECURRENT

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"recurrent episodes of headache, dizziness, and neurologic deficits"

Documents recurrent headache.

Hemiparesis HP:0001269

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"The first episode occurred at age 25 years when she experienced an episode of left-sided hemiparesis and headache."

Documents hemiparesis as the presenting deficit and gives the age at onset.

Paresthesia HP:0003401

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"another episode of right-sided paresthesias involving upper and lower extremities and the face"

Documents the distribution of the sensory disturbance in the second twin.

Other 2

Cerebral vasculitis HP:0005318

Temporal: RECURRENT

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"who both experienced severe recurrent CNS vasculitis caused by VZV reactivation"

Documents recurrent CNS vasculitis in both twins.

CSF pleocytosis HP:0012229

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"CSF with pleocytosis and intrathecal VZV antibody production"

Documents the CSF findings.

🧬

Genetic Associations

1

RNA polymerase III subunit variants (Causative)

Gene: POLR3F hgnc:15763 relationship_type: CAUSATIVE

Show evidence (4 references)

PMID:34395528 SUPPORT Other

"Mutations in the POLR3A, POLR3C, POLR3E and POLR3F subunits are associated with susceptibility to varicella zoster virus-induced encephalitis and pneumonitis."

Enumerates the four subunits implicated in VZV susceptibility.

PMID:30211253 SUPPORT Human Clinical

"with the POLR3F variant c.148C>T present in P1, P2, and the father"

Sanger segregation placing the variant in both affected twins and in their father, which is the basis for germline origin and for the caveat about incomplete penetrance in the inheritance block.

PMID:34395528 SUPPORT Other

"an ever-increasing number of distinct mutations in the POLR3A, POLR3B, POLR1C and POLR3K subunits cause a spectrum of neurodegenerative diseases, which includes most notably hypomyelinating leukodystrophy"

Documents the allelic-series problem: the same genes carry variants causing a mechanistically unrelated neurodegenerative disease.

+ 1 more reference

Variants (1)

POLR3F p.Arg50Trp (R50W) Pathogenic

The OMIM-anchoring allele: a rare heterozygous missense change in the N-terminal region of POLR3F, in the winged-helix region of the POLR3F / POLR3C / POLR3G subcomplex required for POL III transcription initiation. Predicted damaging by PolyPhen-2 and SIFT with a CADD score of 25.8, against a mutation significance cutoff of 13.0 for this gene, and POLR3F itself appears to be under purifying selection. Critically, the mutant protein's expression and solubility are normal, so the allele impairs what the subunit DOES rather than how much of it there is.

Show evidence (2 references)

PMID:30211253 SUPPORT Human Clinical

"The mutation, R50W POLR3F, is rare and predicted to be damaging by bioinformatics software, such as PolyPhen-2 and SIFT and with a high combined annotation dependent depletion (CADD) score of 25.8, which is well above the mutation significance cutoff score of 13.0 for this gene."

Names the allele and gives the in-silico support and the gene-specific significance threshold it exceeds.

PMID:30211253 SUPPORT In Vitro

"causes an amino acid shift from the positively charged arginine (R) to a bulky aromatic tryptophan (W) in the N-terminal region of the POLR3F subunit, which together with POLR3C and POLR3G constitutes a POLR3 subcomplex essential for POLR3 promoter transcription initiation"

Gives the physicochemical nature of the substitution and its structural context in the transcription-initiation subcomplex.

💊

Medical Actions

3

Acyclovir

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: aciclovir CHEBI:2453

Antiviral therapy is the mainstay, and OMIM's own summary of IMD101 states that treatment with acyclovir is effective. Two qualifiers belong with that word. Even with acyclovir, the incidence and severity of sequelae after severe VZV infection are considerable, so effective is not curative, and nothing available treats the underlying sensing defect. And in the reported twins the benefit was not durable: both had a good clinical response during episodes but relapsed with new symptoms AND new MRI lesions when acyclovir was discontinued. In a host whose cell-intrinsic control of VZV is permanently impaired, that is what one would expect, and it is the argument for continued rather than episodic antiviral therapy - though no trial has tested a suppression strategy in this disorder.

Mechanism Target:

INHIBITS Failure to Restrict VZV Replication — Acyclovir suppresses viral replication pharmacologically, substituting for the cell-intrinsic restraint that the sensing defect removes. It does not repair the sensor, which is why the mechanism node it acts on is the replication node and not an upstream one.

Show evidence (1 reference)

PMID:28783042 SUPPORT Other

"Antiviral therapy with acyclovir is used for treatment of VZV encephalitis"

Establishes acyclovir as the treatment for the VZV manifestations this disorder produces. The quote stops before "pneumonitis" because the cached typeset text hyphenates that word across a line break.

Show evidence (2 references)

PMID:28783042 SUPPORT Other

"However, despite treatment with acyclovir, the incidence and severity of sequelae following severe VZV infection are considerable"

The qualifier that belongs with calling acyclovir effective: sequelae after severe VZV infection remain considerable despite it.

PMID:30211253 SUPPORT Human Clinical

"both patients described in the present study have a good clinical response to acyclovir and corticosteroid treatment during clinical episodes but experience recurrence of symptoms and new MRI lesions during discontinuation of acyclovir"

The single most clinically actionable observation in this disorder: the response to acyclovir is good but not durable, and stopping it produced both symptomatic recurrence and new imaging lesions in both twins. This is the argument for continued rather than episodic antiviral therapy.

Corticosteroids During Acute Vasculitic Episodes

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Agent: prednisolone CHEBI:8378

Corticosteroids were given alongside acyclovir during acute episodes in the reported twins, on the reasoning that the presentation is an inflammatory vasculitis and not simply viral replication. The index patient received prednisolone 50 mg daily for 10 days with acyclovir 10 mg/kg three times daily for 14 days, and the authors report good clinical response to the combination. Two cautions belong with this. The contribution of the steroid cannot be separated from that of the antiviral in a two-patient series. And immunosuppression in a patient who already fails to control VZV is not a neutral act - it is given here for the vasculitic component, under antiviral cover, not as monotherapy.

Mechanism Target:

MODULATES VZV Vasculopathy of Cerebral Arteries — Corticosteroids act on the inflammatory arterial lesion rather than on the virus or on the sensing defect, which is why the mechanism target is the vasculopathy node and why the treatment is given under antiviral cover.

Show evidence (1 reference)

PMID:30211253 SUPPORT INDIRECT Human Clinical

"The patient was treated with acyclovir 10 mg/kg tds for 14 days together with corticosteroids (prednisolone 50 mg once daily for 10 days) because the clinical presentation was interpreted as CNS vasculitis."

Documents the regimen and, crucially, the stated reason for adding the steroid - the vasculitic interpretation of the presentation. Marked INDIRECT because this is a treatment decision in a two-patient series, not evidence of steroid efficacy.

Show evidence (1 reference)

PMID:30211253 SUPPORT Human Clinical

"good clinical response to acyclovir and corticosteroid treatment during clinical episodes"

Reports the response to the combination. PARTIAL because the steroid's individual contribution is not separable from the antiviral's.

Genetic Testing and Counseling

Category: Counseling / Informational Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Whole-exome or targeted POL III sequencing is how every reported case was identified, and it is worth considering in an otherwise healthy person with severe or recurrent VZV CNS disease. Counseling has to convey two things that make this condition unusual: penetrance is plainly incomplete and the phenotype requires the virus as well as the genotype, so a carrier relative is not a patient-in-waiting; and a variant in one of these genes may belong to a different disease entirely, since POLR3A and several other POL III subunits also carry variants causing hypomyelinating leukodystrophy.

Show evidence (2 references)

PMID:29728610 SUPPORT Human Clinical

"By whole exome sequencing we identified mutations in POL III genes in two of eight patients."

Demonstrates the diagnostic yield of exome sequencing in adults presenting with VZV CNS infection, which is the basis for testing in that setting.

PMID:34395528 SUPPORT Other

"an ever-increasing number of distinct mutations in the POLR3A, POLR3B, POLR1C and POLR3K subunits cause a spectrum of neurodegenerative diseases"

Supports the counseling point that a POL III variant may belong to a different disease entity than this one.

🔬

Diagnosis

4

Cerebrospinal Fluid Intrathecal Anti-VZV IgG Index

The diagnostic point that most often goes wrong in practice. In VZV CNS vasculitis, CSF PCR for VZV DNA is frequently NEGATIVE - in a case series of 14 adults with cerebral vasculitis it was positive in only four - and both reported twins had negative CSF PCR. What establishes the diagnosis is a positive intrathecal anti-VZV IgG index together with compatible neurological symptoms and imaging. Treating a negative PCR as excluding VZV is therefore the way this diagnosis is missed.

lumbar puncture NCIT:C15327

Show evidence (2 references)

PMID:30211253 SUPPORT Human Clinical

"it was reported that positive intrathecal anti-VZV IgG combined with relevant neurologic symptoms and imaging was a definite marker of this disease rather than VZV DNA detection by PCR because the latter was positive in only 4 of the patients"

States that the intrathecal antibody index, not PCR, is the definite diagnostic marker, and gives the PCR yield that justifies it.

PMID:30211253 SUPPORT Human Clinical

"the absence of detectable VZV by PCR in CSF is not surprising and is consistent with VZV CNS meningoencephalitis, including vasculitis"

Makes explicit that a negative CSF PCR does not argue against the diagnosis.

Brain and Spinal Magnetic Resonance Imaging

Imaging demonstrates the ischemic consequences: infarcts, lacunar infarction, paraventricular and juxtacortical white-matter lesions, and in one twin spinal cord lesions. MR angiography is suggestive rather than conclusive, and histopathological confirmation of CNS vasculitis was not obtainable in either reported patient - so the diagnosis rests on the combination of imaging, intrathecal antibody and clinical course rather than on any single test.

magnetic resonance imaging NCIT:C16809

Show evidence (2 references)

PMID:30211253 SUPPORT Human Clinical

"signs of paraventricular parietal cerebral ischemic lesions on the left side with several small juxtacortical lesions bilaterally"

Documents the imaging findings that support the diagnosis.

PMID:30211253 SUPPORT Human Clinical

"this diagnosis is rather difficult to make with certainty, and even MR angiography is only suggestive and not a conclusive evidence of this diagnosis"

The authors' own statement of the diagnostic uncertainty, which is why this entry does not present imaging as confirmatory.

Immunological Evaluation (to Exclude Broader Immunodeficiency)

Routine immunological workup is NORMAL in this condition, and that negative result is diagnostically informative rather than merely reassuring: it is what distinguishes a pathogen-restricted innate sensing defect from the combined and phagocyte immunodeficiencies that also predispose to disseminated VZV. In the reported twins, immunoglobulins, lymphocyte distribution and lymphocyte proliferation were all normal and HIV testing was negative.

laboratory procedure NCIT:C25294

Show evidence (2 references)

PMID:30211253 SUPPORT Human Clinical

"A routine clinical immunologic evaluation was normal, including normal immunoglobulins, lymphocyte distribution and proliferation within the normal range, and a negative HIV test."

Documents the normal immunological evaluation that frames this as a pathogen-restricted rather than general immunodeficiency.

PMID:30211253 SUPPORT Human Clinical

"they did not report any increased susceptibility to other viral, bacterial, or fungal infections, neither in the past nor at present"

Documents the absence of broader infectious susceptibility, the clinical counterpart of the normal immunological workup.

Exome Sequencing

Whole-exome sequencing identified the causal variant in every reported case, and is the only way this diagnosis is made. It is worth considering in an otherwise immunologically normal person with severe or recurrent VZV CNS disease - a setting in which a genetic cause is not routinely sought.

genetic testing NCIT:C15709

Show evidence (2 references)

PMID:29728610 SUPPORT Human Clinical

"By whole exome sequencing we identified mutations in POL III genes in two of eight patients."

Gives the diagnostic yield of exome sequencing in a consecutive adult VZV CNS infection cohort.

PMID:30211253 SUPPORT Human Clinical

"Because of this unusual presentation in both monozygotic twin sisters, we suspected a genetic etiology of the recurrent VZV CNS vasculitis."

States the clinical trigger for genetic investigation - an unusual, recurrent VZV CNS presentation - which is the setting this entry recommends.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Published cases number in the single figures: four children in the founding series (POLR3A and/or POLR3C), two of eight sequenced adults with VZV CNS infection (POLR3A, POLR3E), and one monozygotic twin pair (POLR3F). No population prevalence estimate exists, and none is straightforward to derive, because the phenotype requires both a rare genotype and exposure to a near-universal virus, with plainly incomplete penetrance. For context on the denominator, VZV CNS infection and pneumonia complicate roughly 0.02% and 0.25% of childhood primary infections respectively — most of which are not POL III deficient.

Show evidence (1 reference)

PMID:29728610 SUPPORT Human Clinical

"By whole exome sequencing we identified mutations in POL III genes in two of eight patients."

Gives the yield in a consecutive adult VZV CNS infection cohort, which is the only denominator-bearing figure available.

🦠

Infectious Agent

1

Varicella zoster virus

VZV is the alphaherpesvirus that causes varicella on primary infection and zoster on reactivation from latency in sensory ganglia. Its relevance here is not merely that it is the offending pathogen but that its genome is AT-rich, which is what makes it a substrate for POL III sensing and is the leading explanation for why this immunodeficiency is VZV-restricted rather than pan-viral.

Human alphaherpesvirus 3 NCBITaxon:10335

Show evidence (2 references)

PMID:28783042 SUPPORT Other

"the causative agent of varicella (chickenpox) during primary infection and zoster (shingles) during reactivation from latency in sensory ganglia"

Identifies the agent and both phases of its life cycle. The sentence's opening clause is not quoted because the cached typeset text hyphenates "alphaherpesvirus" across a line break.

PMID:30211253 SUPPORT Other

"Varicella-zoster virus (VZV) is a human pathogenic alpha-herpesvirus causing chickenpox in children during primary infection and herpes zoster in elderly or immunocompromised individuals on reactivation from latency."

States the two phases of the VZV life cycle, both of which this disorder can fail to control.

🧫

Experimental Models

2

POLR3F+/- SH-SY5Y human neuronal cell model CELL_LINE

Human SH-SY5Y neuroblastoma cells engineered to POLR3F heterozygous knockout, used both as differentiated neurons in acute VZV infection and in a quiescent infection model that permits spontaneous reactivation to be quantified. This is the only model that addresses the reactivation arm directly.

Pathograph links

VZV Reactivation from Latency recapitulates fidelity: moderate POLR3F-heterozygous neuronal cells show higher viral gene expression and more spontaneous VZV reactivation than wild type, which the authors describe as reflecting the patient phenotype.

Limitations: SH-SY5Y is a neuroblastoma line rather than a sensory ganglion neuron, and the quiescent-infection system is a surrogate for latency rather than latency itself. The genotype is an engineered heterozygous knockout, not the patients' R50W missense allele, so the model tests gene dosage rather than the specific human variant. Effects were noted in early-passage cells.

Readouts

VZV gene expression by RT-qPCR

Direction: INCREASED

Interpretation: Higher viral gene expression in POLR3F+/- neuronal cells is the acute infection readout of impaired restraint.

Show evidence (1 reference)

PMID:41739639 SUPPORT In Vitro

"resulted in higher viral gene expression and more VZV reactivation in the POLR3F neuronal heterozygous (POLR3F+/-) knockout cells"

Reports the direction of both measurements in the model.

Spontaneous reactivation from quiescent infection

Direction: INCREASED

Interpretation: Increased spontaneous reactivation is the readout that makes this model informative for the reactivation node specifically.

Show evidence (1 reference)

PMID:41739639 SUPPORT In Vitro

"We also established a quiescent infection model and quantified spontaneous reactivation by detection of viral proteins fused to fluorophores."

Describes the assay behind the reactivation readout.

Show evidence (1 reference)

PMID:41739639 SUPPORT In Vitro

"This work identifies a novel role for POLR3F as a sentinel for VZV reactivation in neuronal cells"

The authors' statement of what the model establishes, which is what makes it informative for this node.

Patient peripheral blood mononuclear cells with wild-type allele rescue PRIMARY_CELL_CULTURE

Primary patient leukocytes stimulated with the POL III agonist poly(dA:dT), with VZV-derived DNA, or infected with VZV, and compared against healthy controls. In the founding study the defective phenotypes were rescued by transduction with the relevant wild-type allele, which is what converts an association into a causal claim.

Pathograph links

Deficient Type I Interferon Induction measures fidelity: high Direct measurement in patient cells of the interferon and cytokine defect, with genetic rescue.

Limitations: Peripheral blood mononuclear cells are not the cell type in which the disease manifests — the lesion presents in cerebral arteries and neurons — so the assay establishes the cell-intrinsic defect rather than its tissue consequence. Rescue was reported for the founding POLR3A/POLR3C patients; no equivalent rescue is reported for the POLR3F twins.

Readouts

Interferon induction by synthetic and VZV-derived DNA

Direction: DECREASED

Interpretation: Poor interferon induction to both agonists is the defining laboratory phenotype of the disorder.

Show evidence (1 reference)

PMID:28783042 SUPPORT In Vitro

"Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA."

Reports the direction and the stimuli.

Interferon phenotype after wild-type allele transduction

Direction: RESTORED

Interpretation: Restoration on transduction with the wild-type allele is the causal test.

Show evidence (1 reference)

PMID:28783042 SUPPORT In Vitro

"These phenotypes were rescued by transduction with relevant WT alleles."

Reports the rescue result.

Show evidence (1 reference)

PMID:28783042 SUPPORT In Vitro

"confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity"

The authors frame the patient-cell work as evidence for an essential role of a DNA sensor in human immunity, which is what this model measures.

{ }

Source YAML

click to show

name: Immunodeficiency 101 (Varicella Zoster Virus-Specific)
creation_date: "2026-08-25T00:00:00Z"
category: Mendelian
synonyms:
- IMD101
- RNA polymerase III deficiency with varicella zoster virus susceptibility
- POL III deficiency, VZV-specific
description: >-
  Immunodeficiency-101 is a monogenic susceptibility to severe varicella zoster
  virus (VZV) disease, and it is unusual among the inborn errors of immunity in
  being genuinely pathogen-specific: affected individuals are not broadly
  infection-prone, they fail at one virus. The defect lies in RNA polymerase III,
  which besides its housekeeping job of transcribing tRNAs and other small
  untranslated RNAs also acts as a CYTOSOLIC SENSOR OF AT-RICH
  DOUBLE-STRANDED DNA. Sensing DNA is what makes it immunologically relevant:
  POL III transcribes AT-rich cytosolic DNA into 5'-triphosphate RNA that
  triggers RIG-I-dependent type I interferon induction. Rare heterozygous
  missense variants in POL III subunits impair that sensing, interferon
  induction to synthetic AT-rich DNA and to VZV-derived DNA falls, and patient
  cells lose control of VZV replication. Clinically this presents at two points
  in the viral life cycle: severe primary VZV disease of the CNS or lungs in
  otherwise healthy children, and — the presentation on which the numbered OMIM
  entity is defined — VZV reactivation in adulthood producing recurrent CNS
  vasculitis with stroke-like episodes, headache, hemiparesis, impaired balance
  and ischemic lesions on brain imaging. Acyclovir is effective, but sequelae
  after severe VZV disease remain considerable despite it.


  Identifier note, and a MONDO gap worth recording: MONDO:0030813 carries NO
  causal-gene relationship at all, while OMIM #619872 and MedGen both anchor
  IMD101 on POLR3F at 20p11.23 — the subunit mutated in the monozygotic twins
  with recurrent VZV CNS vasculitis. This entry therefore takes its gene anchor
  from OMIM/MedGen rather than from MONDO, and models the wider POL III allelic
  series (POLR3A, POLR3C, POLR3E, POLR3F) as one mechanism, because the reported
  variants across those four subunits produce the same sensing defect and the
  same VZV-restricted susceptibility. Whether the paediatric primary-infection
  cases and the adult reactivation cases are one MONDO concept or two is an open
  nosological question and is recorded as such rather than silently decided.
disease_term:
  preferred_term: immunodeficiency 101 (varicella zoster virus-specific)
  term:
    id: MONDO:0030813
    label: immunodeficiency 101 (varicella zoster virus-specific)
parents:
- Primary Immunodeficiency
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
    notes: >-
      Placed with the immune disorders because the entity is an inborn error of
      innate antiviral immunity; the presenting illness is neurological, but the
      lesion is immunological and the susceptibility is what defines the disease.
infectious_agent:
- name: Varicella zoster virus
  infectious_agent_term:
    preferred_term: Human alphaherpesvirus 3
    term:
      id: NCBITaxon:10335
      label: Human alphaherpesvirus 3
  description: >-
    VZV is the alphaherpesvirus that causes varicella on primary infection and
    zoster on reactivation from latency in sensory ganglia. Its relevance here is
    not merely that it is the offending pathogen but that its genome is AT-rich,
    which is what makes it a substrate for POL III sensing and is the leading
    explanation for why this immunodeficiency is VZV-restricted rather than
    pan-viral.
  evidence:
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the causative agent of varicella (chickenpox) during primary infection and zoster (shingles) during reactivation from latency in sensory ganglia"
    explanation: >-
      Identifies the agent and both phases of its life cycle. The sentence's
      opening clause is not quoted because the cached typeset text hyphenates
      "alphaherpesvirus" across a line break.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Varicella-zoster virus (VZV) is a human pathogenic alpha-herpesvirus causing chickenpox in children during primary infection and herpes zoster in elderly or immunocompromised individuals on reactivation from latency."
    explanation: >-
      States the two phases of the VZV life cycle, both of which this disorder
      can fail to control.
inheritance:
- name: Autosomal dominant inheritance
  description: >-
    Reported patients are HETEROZYGOUS for rare missense variants in a POL III
    subunit, which is why the condition is recorded as autosomal dominant. Two
    caveats belong with that label. Penetrance is plainly incomplete — most
    people carrying a rare POL III variant never develop severe VZV disease, and
    the disease requires the virus as well as the genotype. And one of the four
    children in the founding series was DIGENIC, carrying variants in both
    POLR3A and POLR3C, so a single heterozygous allele is not in every case the
    whole genetic explanation.
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "unrelated, otherwise healthy children who are heterozygous for rare missense mutations in POLR3A (one patient), POLR3C (one patient), or both (two patients)"
    explanation: >-
      Establishes heterozygous inheritance and documents the digenic genotype in
      two of the four founding patients.
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This work demonstrates that monogenic or digenic POLR3A and POLR3C deficiencies confer increased susceptibility to severe VZV disease in otherwise healthy children"
    explanation: >-
      The authors' own framing of the genotypes as monogenic or digenic, which is
      the basis for the digenic caveat in this block.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation was inherited from the father"
    explanation: >-
      Documents vertical transmission of the POLR3F allele, establishing germline
      origin.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who was previously admitted to hospital with clinical signs and symptoms of stroke, which retrospectively might have been linked to VZV CNS vasculitis; however, this was not examined at the time"
    explanation: >-
      The transmitting father's status is genuinely undetermined - possibly
      affected, never investigated - which is why this entry describes penetrance
      as incomplete rather than asserting an unaffected carrier parent. Marked
      PARTIAL because the authors themselves only say it "might" have been.
pathophysiology:
- name: RNA Polymerase III Subunit Missense Variant
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Rare heterozygous missense variants in genes encoding subunits of RNA
    polymerase III. Four subunits have been implicated in VZV susceptibility:
    POLR3A and POLR3C in children with severe primary VZV disease, POLR3A and
    POLR3E in adults with VZV CNS infection after reactivation, and POLR3F —
    the subunit on which OMIM anchors IMD101 — in monozygotic twins with
    recurrent VZV CNS vasculitis. The variants are damaging but not null: the
    functional assays show impaired, not abolished, responses, and POL III's
    housekeeping transcription of tRNAs and other small RNAs is evidently
    preserved enough to be compatible with life and with otherwise normal health.
  genes:
  - preferred_term: POLR3A
    term:
      id: hgnc:30074
      label: POLR3A
  - preferred_term: POLR3C
    term:
      id: hgnc:30076
      label: POLR3C
  - preferred_term: POLR3E
    term:
      id: hgnc:30347
      label: POLR3E
  - preferred_term: POLR3F
    term:
      id: hgnc:15763
      label: POLR3F
  genetic_context:
    gene:
      preferred_term: POLR3F
      term:
        id: hgnc:15763
        label: POLR3F
    allele_type: missense
    zygosity: HETEROZYGOUS
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      The genetic context is written for POLR3F because that is the subunit on
      which OMIM and MedGen anchor the numbered IMD101 entity; the twins carried
      the heterozygous R50W substitution. PARTIAL_LOSS_OF_FUNCTION rather than
      LOSS_OF_FUNCTION is the honest category: the reported functional
      consequence is impaired antiviral and inflammatory responses and increased
      viral replication relative to controls, not abolished POL III function,
      and the housekeeping transcription these subunits also serve is evidently
      retained. The same category applies to the POLR3A, POLR3C and POLR3E
      alleles listed on this node.
    variant_origin: GERMLINE
    notes: >-
      `variant_origin: GERMLINE` is set on the strength of the POLR3F pedigree,
      in which Sanger sequencing placed the c.148C>T variant in both twins and in
      their father. That pedigree also carries the penetrance evidence: the
      father was previously admitted with stroke-like signs that the authors say
      might retrospectively have been VZV CNS vasculitis, but this was never
      investigated, so he is neither a confirmed affected transmitting parent nor
      a confirmed unaffected carrier. Origin is not asserted for the POLR3A,
      POLR3C or POLR3E alleles, whose parental testing is not reported in the
      cached sources.
  protein_complexes:
  - preferred_term: RNA polymerase III complex
    term:
      id: GO:0005666
      label: RNA polymerase III complex
  evidence:
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report 4 cases of acute severe VZV infection affecting the central nervous system or the lungs in unrelated, otherwise healthy"
    explanation: >-
      Establishes the founding cohort and, in the phrase "otherwise healthy", the
      pathogen-restricted character of the susceptibility.
  - reference: PMID:34395528
    reference_title: "RNA Polymerase III Subunit Mutations in Genetic Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in the POLR3A, POLR3C, POLR3E and POLR3F subunits are associated with susceptibility to varicella zoster virus-induced encephalitis and pneumonitis."
    explanation: >-
      Enumerates the four implicated subunits, which is the basis for modelling
      them as one allelic series on this node.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We performed whole-exome sequencing and identified a rare mutation in the POL III subunit POLR3F."
    explanation: >-
      Identifies the POLR3F variant on which OMIM anchors the numbered IMD101
      entity.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "expression and solubility of the mutant POLR3F protein were unaltered compared with wild type, suggesting that the R50W mutation affects protein function, such as ligand recognition or enzymatic conversion of the adenosine-thymidine-rich DNA ligand into 5' triphosphorylated RNA, rather than expression of the POLR3F protein"
    explanation: >-
      Establishes that the disease allele impairs FUNCTION rather than protein
      abundance, which is the basis for typing it as a partial loss of function
      of the sensing activity rather than a loss of the subunit.
  downstream:
  - target: Impaired Cytosolic Sensing of AT-Rich VZV DNA
    causal_link_type: DIRECT
    description: >-
      The variants sit in the sensor itself, so the function that fails is
      recognition of AT-rich cytosolic DNA.
    evidence:
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The identified R50W POLR3F mutation is predicted by bioinformatics to be damaging, and when tested in functional assays, patient PBMCs exhibited impaired antiviral and inflammatory responses to the POL III agonist poly(dA:dT) and increased viral replication compared with controls."
      explanation: >-
        Links the variant directly to impaired responses to the AT-rich POL III
        agonist poly(dA:dT), which is the sensing step.
- name: Impaired Cytosolic Sensing of AT-Rich VZV DNA
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    RNA polymerase III has a second job beyond housekeeping transcription: in the
    cytosol it transcribes AT-rich double-stranded DNA into 5'-triphosphate RNA,
    which is a ligand for RIG-I and thus a trigger for type I interferon. This
    node is the failure of that recognition step. It is also the best available
    explanation for the disease's most striking feature — that the
    susceptibility is confined to one virus. VZV has an AT-rich genome, so it is
    the pathogen most dependent on this particular sensing route; patients do not
    have increased susceptibility to other infections.
  biological_processes:
  - preferred_term: innate immune response
    term:
      id: GO:0045087
      label: innate immune response
    modifier: DECREASED
  - preferred_term: transcription by RNA polymerase III
    term:
      id: GO:0006383
      label: transcription by RNA polymerase III
    modifier: DECREASED
  protein_complexes:
  - preferred_term: RNA polymerase III complex
    term:
      id: GO:0005666
      label: RNA polymerase III complex
  cell_types:
  - preferred_term: leukocyte
    term:
      id: CL:0000738
      label: leukocyte
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "RNA POL III is a 17-subunit enzyme with dual functions in both promoter-dependent transcription of tRNA and rRNA and innate sensing of AT-rich DNA, converting this into 5"
    explanation: >-
      States the dual role that makes this node possible: the same enzyme does
      housekeeping transcription and cytosolic AT-rich DNA sensing, converting
      that DNA into the 5-prime-phosphorylated RNA that RIG-I recognises. Quoted
      up to the prime symbol, which does not survive as a stable substring.
  - reference: PMID:30115567
    reference_title: "RNA Polymerase III as a Gatekeeper to Prevent Severe VZV Infections."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Recent studies have demonstrated that defects in the DNA sensor RNA polymerase III (POL III) confer selective increased susceptibility to VZV infection, thus providing fundamental new insight into VZV immunity."
    explanation: >-
      States both halves of this node: POL III acts as a DNA sensor, and defects
      in it confer SELECTIVE susceptibility to VZV.
  - reference: PMID:29728610
    reference_title: "Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "impaired immunological sensing of AT-rich DNA in adult patients with VZV CNS infection"
    explanation: >-
      Names the specific molecular defect — impaired sensing of AT-rich DNA — in
      adult patients.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the novel association between defects in sensing of AT-rich DNA present in the VZV genome and increased susceptibility to severe manifestations of VZV infection in the CNS in humans"
    explanation: >-
      Connects the AT-rich content of the VZV genome specifically to the sensing
      defect, which is the basis for the pathogen-restriction claim in this node.
  downstream:
  - target: Deficient Type I Interferon Induction
    causal_link_type: DIRECT
    description: >-
      Failure of sensing means the interferon response that sensing normally
      triggers is not mounted.
    evidence:
    - reference: PMID:28783042
      reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA."
      explanation: >-
        Directly measures the interferon consequence of the sensing defect, in
        response both to synthetic DNA and to VZV-derived DNA.
- name: Deficient Type I Interferon Induction
  biological_scale: CELLULAR
  role: amplifier
  description: >-
    Patient leukocytes mount a poor interferon response to synthetic AT-rich DNA,
    to VZV-derived DNA, and to VZV infection itself. That the defect is
    demonstrable with a synthetic agonist as well as with the virus is what
    separates a sensing defect from a downstream failure of viral handling. The
    causal weight of this node rests on a rescue experiment: transducing patient
    cells with the relevant wild-type allele restored the phenotype.
  biological_processes:
  - preferred_term: positive regulation of type I interferon production
    term:
      id: GO:0032481
      label: positive regulation of type I interferon production
    modifier: DECREASED
  - preferred_term: type I interferon production
    term:
      id: GO:0032606
      label: type I interferon production
    modifier: DECREASED
  cell_types:
  - preferred_term: leukocyte
    term:
      id: CL:0000738
      label: leukocyte
  evidence:
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Moreover, leukocytes from 3 of the patients displayed defective IFN production upon VZV infection and reduced control of VZV replication."
    explanation: >-
      Shows the interferon defect on live VZV infection, not only on synthetic
      agonist, together with the loss of viral control.
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These phenotypes were rescued by transduction with relevant WT alleles."
    explanation: >-
      The rescue experiment that establishes the variants as causal for the
      interferon phenotype rather than merely associated with it.
  - reference: PMID:29728610
    reference_title: "Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found impaired expression of antiviral and inflammatory cytokines in response to the POL III agonist Poly(dA:dT) as well as increased viral replication in patient cells compared to controls"
    explanation: >-
      Replicates the cytokine and viral-replication phenotype in an independent
      adult cohort with POLR3A and POLR3E variants.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By contrast, responses to transfected Poly(I:C) were normal as expected because this ligand activates the cytosolic RNA receptor Retinoic acid-inducible-I (RIG-I) directly downstream of POL III"
    explanation: >-
      The internal control that localizes the lesion. Poly(I:C) bypasses POL III
      and engages RIG-I directly, and the response to it is intact, so the defect
      is in the sensor rather than anywhere in the pathway below it. This is what
      makes the interferon deficit specific to the DNA-sensing route.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PBMCs from P1 showed significantly impaired IFN"
    explanation: >-
      Reports the impaired interferon response to the POL III agonist in patient
      cells. Quoted short because the cached text uses a Greek beta immediately
      after, which does not survive as a stable substring.
  downstream:
  - target: Failure to Restrict VZV Replication
    causal_link_type: DIRECT
    description: >-
      Without an adequate interferon response the cell does not establish the
      antiviral state that limits VZV replication.
    evidence:
    - reference: PMID:28783042
      reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "defective IFN production upon VZV infection and reduced control of VZV replication"
      explanation: >-
        Couples the interferon defect to loss of control of viral replication in
        the same cells.
- name: Failure to Restrict VZV Replication
  biological_scale: CELLULAR
  role: effector
  description: >-
    Patient cells permit more VZV replication than control cells. This is the
    convergence point of the disease: whatever the subunit and whichever phase of
    the viral life cycle, the cell fails to hold the virus down, and everything
    downstream is a consequence of uncontrolled VZV in a particular tissue.
  biological_processes:
  - preferred_term: defense response to virus
    term:
      id: GO:0051607
      label: defense response to virus
    modifier: DECREASED
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "patient PBMCs exhibited impaired antiviral and inflammatory responses to the POL III agonist poly(dA:dT) and increased viral replication compared with controls"
    explanation: >-
      Measures increased viral replication in patient cells relative to controls.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a significantly increased amount of the viral immediate-early gene ORF63 mRNA was detected in P1 cells relative to controls, demonstrating increased viral replication, i.e., reduced viral control in patient cells"
    explanation: >-
      Quantifies the loss of viral control as increased viral immediate-early
      transcript in patient cells, which is the measurement this node names.
  downstream:
  - target: VZV Reactivation from Latency
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Loss of cell-intrinsic restraint in neurons permits reactivation from
      latency, which is the arm that produces the adult presentation on which the
      numbered OMIM entity is defined. The direct evidence is a neuronal cell
      model rather than patient tissue.
    evidence:
    - reference: PMID:41739639
      reference_title: "RNA Polymerase III Suppresses Varicella Zoster Virus in Human Neurons."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Varicella zoster virus infection of undifferentiated as well as terminally differentiated early passage SH-SY5Y cells resulted in higher viral gene expression and more VZV reactivation in the POLR3F neuronal heterozygous (POLR3F+/-) knockout cells, reflecting the patient phenotype, compared with wild-type cells."
      explanation: >-
        Directly demonstrates increased reactivation in POLR3F-heterozygous
        neuronal cells, which is the mechanistic basis for this edge.
  - target: Severe Primary VZV Disease of the CNS and Lungs
    causal_link_type: DIRECT
    description: >-
      In children meeting the virus for the first time, the same failure of
      restraint permits severe primary disease rather than uncomplicated
      varicella.
    evidence:
    - reference: PMID:28783042
      reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "4 cases of acute severe VZV infection affecting the central nervous system or the lungs"
      explanation: >-
        Documents the paediatric primary-infection presentation of the same
        mechanism.
- name: VZV Reactivation from Latency
  biological_scale: TISSUE
  role: effector
  description: >-
    VZV establishes latency in sensory ganglia after primary infection and
    reactivates from there. In POL III deficiency the reactivation arm is what
    produces the defining adult phenotype, and a neuronal knockout model shows
    both higher viral gene expression and more spontaneous reactivation in
    POLR3F-heterozygous cells. Note the model's own framing: it supports POL III
    mattering to VZV immunity MAINLY UPON REACTIVATION, which is a claim about
    where in the viral life cycle the sensor is rate-limiting and should not be
    flattened into "POL III controls VZV".
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:41739639
    reference_title: "RNA Polymerase III Suppresses Varicella Zoster Virus in Human Neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This work identifies a novel role for POLR3F as a sentinel for VZV reactivation in neuronal cells and lends further support to the hypothesis that polymerase III (POL III) plays a role in immunity to VZV mainly upon reactivation in humans and that POL III defects predispose to VZV central nervous system infection."
    explanation: >-
      States the reactivation-specific role and the resulting predisposition to
      CNS infection, with the authors' own hedge on where in the life cycle POL
      III acts.
  downstream:
  - target: VZV Vasculopathy of Cerebral Arteries
    causal_link_type: DIRECT
    description: >-
      Reactivated VZV productively infects cerebral arteries, which is the lesion
      behind the stroke-like presentation.
    evidence:
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "we describe a pair of monozygotic female twins, who both experienced severe recurrent CNS vasculitis caused by VZV reactivation"
      explanation: >-
        Attributes recurrent CNS vasculitis directly to VZV reactivation in the
        POLR3F patients.
- name: VZV Vasculopathy of Cerebral Arteries
  biological_scale: TISSUE
  role: consequence
  description: >-
    Productive VZV infection of cerebral arteries produces a vasculitis affecting
    large vessels, small vessels, or both. The consequence is ischemic injury,
    which is why an immunodeficiency presents to a stroke service. Cerebrospinal
    fluid in the reported twins showed pleocytosis with intrathecal VZV antibody
    production, and brain MRI showed ischemic lesions.
  locations:
  - preferred_term: artery
    term:
      id: UBERON:0001637
      label: artery
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical presentation and findings included recurrent episodes of headache, dizziness, and neurologic deficits, CSF with pleocytosis and intrathecal VZV antibody production, and MRI of the brain showing ischemic lesions."
    explanation: >-
      Enumerates the clinical, CSF and imaging findings that define this node.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "may also present in a more atypical stroke-like manner, in which case, the immunopathogenesis appears to be vasculitis"
    explanation: >-
      States that the stroke-like presentation of VZV CNS disease is
      vasculitic in mechanism.
  downstream:
  - target: Cerebral vasculitis
    causal_link_type: DIRECT
    description: >-
      The arterial inflammation is itself the curated phenotype.
    evidence:
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "severe recurrent CNS vasculitis caused by VZV reactivation"
      explanation: >-
        Documents the vasculitis phenotype in the reported patients.
  - target: Ischemic stroke
    causal_link_type: DIRECT
    description: >-
      Vasculitic occlusion of cerebral arteries produces ischemic lesions and the
      stroke-like episodes that bring these patients to attention.
    evidence:
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "MRI of the brain showing ischemic lesions"
      explanation: >-
        Documents the ischemic lesions produced by the vasculopathy.
  - target: Headache
    causal_link_type: DIRECT
    description: >-
      Headache was a recurrent presenting symptom of the vasculitic episodes.
    evidence:
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "recurrent episodes of headache, dizziness, and neurologic deficits"
      explanation: >-
        Documents headache among the recurrent episode features.
  - target: Vertigo
    causal_link_type: DIRECT
    description: >-
      Dizziness accompanied the recurrent episodes in the reported twins.
    evidence:
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "recurrent episodes of headache, dizziness, and neurologic deficits"
      explanation: >-
        Documents dizziness. Marked PARTIAL because the source says "dizziness",
        which is not necessarily vertigo in the strict vestibular sense; the HPO
        term is the closest available.
  - target: CSF pleocytosis
    causal_link_type: DIRECT
    description: >-
      Inflammation of the cerebral vasculature and meninges produces a
      cerebrospinal fluid pleocytosis with intrathecal VZV antibody.
    evidence:
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "CSF with pleocytosis and intrathecal VZV antibody production"
      explanation: >-
        Documents the CSF findings.
- name: Severe Primary VZV Disease of the CNS and Lungs
  biological_scale: ORGANISM
  role: consequence
  description: >-
    The paediatric arm: otherwise healthy children who, on first meeting VZV,
    develop CNS disease or pneumonitis instead of uncomplicated varicella. This
    is a rare outcome at population level — CNS infection and pneumonia
    complicate roughly 0.02% and 0.25% of childhood primary infections — which is
    what made a monogenic explanation worth looking for. This node is retained
    even though the OMIM definition of IMD101 is written around adult
    reactivation; see the nosology discussion.
  locations:
  - preferred_term: central nervous system
    term:
      id: UBERON:0001017
      label: central nervous system
  evidence:
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Varicella zoster virus (VZV) typically causes chickenpox upon primary infection. In rare cases, VZV can give rise to life-threatening disease in otherwise healthy people"
    explanation: >-
      States the contrast between typical varicella and the rare severe outcome
      this node represents.
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "and pneumonia during primary infection in children are about 0.02% and 0.25%, respectively"
    explanation: >-
      Gives the population frequencies of the two severe outcomes of primary
      childhood VZV infection - CNS infection and pneumonia, about 0.02% and
      0.25% - which is the rarity that motivated looking for a monogenic
      explanation. The quote starts mid-sentence because the preceding words
      ("The frequencies of VZV CNS infec-tion") are hyphenated across a line
      break in the cached typeset text.
  downstream:
  - target: Infectious encephalitis
    causal_link_type: DIRECT
    description: >-
      CNS involvement in severe primary VZV disease manifests as cerebellitis,
      encephalitis or stroke.
    evidence:
    - reference: PMID:28783042
      reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "pneumonitis and CNS disease, manifesting as cerebellitis, encephalitis, or stroke"
      explanation: >-
        Names the CNS and pulmonary manifestations of severe VZV disease. The
        quote starts at "pneumonitis" because the preceding word ("includ-ing")
        is hyphenated across a line break in the cached typeset text.
phenotypes:
- category: Neurological
  name: Cerebral vasculitis
  description: >-
    Inflammation of cerebral arteries caused by productive VZV infection
    following reactivation. In the reported POLR3F twins it was recurrent.
  phenotype_term:
    preferred_term: Cerebral vasculitis
    term:
      id: HP:0005318
      label: Cerebral vasculitis
    temporality: RECURRENT
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who both experienced severe recurrent CNS vasculitis caused by VZV reactivation"
    explanation: >-
      Documents recurrent CNS vasculitis in both twins.
- category: Neurological
  name: Ischemic stroke
  description: >-
    Stroke-like episodes with ischemic lesions on brain MRI, the presentation
    that typically brings an adult with this condition to medical attention.
  phenotype_term:
    preferred_term: Ischemic stroke
    term:
      id: HP:0002140
      label: Ischemic stroke
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI of the brain showing ischemic lesions"
    explanation: >-
      Documents ischemic brain lesions in the reported patients.
- category: Neurological
  name: Headache
  description: Recurrent headache accompanying the vasculitic episodes.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
    temporality: RECURRENT
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent episodes of headache, dizziness, and neurologic deficits"
    explanation: >-
      Documents recurrent headache.
- category: Neurological
  name: Vertigo
  description: >-
    Dizziness during the recurrent episodes. Curated against the closest HPO
    term; the source says "dizziness", which is not necessarily vestibular
    vertigo.
  phenotype_term:
    preferred_term: Vertigo
    term:
      id: HP:0002321
      label: Vertigo
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "recurrent episodes of headache, dizziness, and neurologic deficits"
    explanation: >-
      Documents dizziness; PARTIAL because the reported symptom is dizziness
      rather than vertigo specifically.
- category: Neurological
  name: Hemiparesis
  description: >-
    Unilateral weakness during vasculitic episodes; the first episode in the
    index twin was left-sided hemiparesis with headache at age 25, and a later
    episode was right-sided.
  phenotype_term:
    preferred_term: Hemiparesis
    term:
      id: HP:0001269
      label: Hemiparesis
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first episode occurred at age 25 years when she experienced an episode of left-sided hemiparesis and headache."
    explanation: >-
      Documents hemiparesis as the presenting deficit and gives the age at onset.
- category: Neurological
  name: Paresthesia
  description: >-
    Sensory disturbance of the limbs and face during episodes, in both twins.
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "another episode of right-sided paresthesias involving upper and lower extremities and the face"
    explanation: >-
      Documents the distribution of the sensory disturbance in the second twin.
- category: Neurological
  name: Diplopia
  description: >-
    Double vision accompanying an episode of hemiparesis and impaired balance.
  phenotype_term:
    preferred_term: Diplopia
    term:
      id: HP:0000651
      label: Diplopia
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she was readmitted with right-sided hemiparesis, and -paresthesias double vision and impaired balance"
    explanation: >-
      Documents double vision and impaired balance in the same episode. The
      stray hyphen before "paresthesias" is an artefact of the cached text and is
      quoted as it appears.
- category: Neurological
  name: Myelitis
  description: >-
    Spinal cord involvement was demonstrated in the second twin, with lesions at
    C6 and Th2 on MRI - evidence that the vasculopathy is not confined to the
    brain.
  phenotype_term:
    preferred_term: Myelitis
    term:
      id: HP:0012486
      label: Myelitis
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MRI of the total medulla and brain demonstrated myelitis at the level of C6 and Th2"
    explanation: >-
      Documents spinal cord involvement on imaging.
- category: Laboratory
  name: CSF pleocytosis
  description: >-
    Cerebrospinal fluid pleocytosis with intrathecal VZV antibody production,
    which is what establishes the infection as intrathecal rather than incidental.
  phenotype_term:
    preferred_term: CSF pleocytosis
    term:
      id: HP:0012229
      label: CSF pleocytosis
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CSF with pleocytosis and intrathecal VZV antibody production"
    explanation: >-
      Documents the CSF findings.
- category: Neurological
  name: Infectious encephalitis
  description: >-
    VZV encephalitis, part of the CNS disease spectrum in both the paediatric
    primary-infection and the adult reactivation presentations.
  phenotype_term:
    preferred_term: Infectious encephalitis
    term:
      id: HP:0002383
      label: Infectious encephalitis
  evidence:
  - reference: PMID:34395528
    reference_title: "RNA Polymerase III Subunit Mutations in Genetic Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "susceptibility to varicella zoster virus-induced encephalitis and pneumonitis"
    explanation: >-
      Names encephalitis as a manifestation of POL III subunit deficiency.
- category: Respiratory
  name: Pneumonitis
  description: >-
    VZV pneumonitis, the non-CNS manifestation of severe primary infection in the
    paediatric arm.
  phenotype_term:
    preferred_term: Pneumonia
    term:
      id: HP:0002090
      label: Pneumonia
  evidence:
  - reference: PMID:34395528
    reference_title: "RNA Polymerase III Subunit Mutations in Genetic Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "varicella zoster virus-induced encephalitis and pneumonitis"
    explanation: >-
      Names pneumonitis as a manifestation. Marked PARTIAL because the bound HPO
      term is Pneumonia, which is broader than the viral pneumonitis meant here.
diagnosis:
- name: Cerebrospinal Fluid Intrathecal Anti-VZV IgG Index
  description: >-
    The diagnostic point that most often goes wrong in practice. In VZV CNS
    vasculitis, CSF PCR for VZV DNA is frequently NEGATIVE - in a case series of
    14 adults with cerebral vasculitis it was positive in only four - and both
    reported twins had negative CSF PCR. What establishes the diagnosis is a
    positive intrathecal anti-VZV IgG index together with compatible neurological
    symptoms and imaging. Treating a negative PCR as excluding VZV is therefore
    the way this diagnosis is missed.
  diagnosis_term:
    preferred_term: lumbar puncture
    term:
      id: NCIT:C15327
      label: Lumbar Puncture
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "it was reported that positive intrathecal anti-VZV IgG combined with relevant neurologic symptoms and imaging was a definite marker of this disease rather than VZV DNA detection by PCR because the latter was positive in only 4 of the patients"
    explanation: >-
      States that the intrathecal antibody index, not PCR, is the definite
      diagnostic marker, and gives the PCR yield that justifies it.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the absence of detectable VZV by PCR in CSF is not surprising and is consistent with VZV CNS meningoencephalitis, including vasculitis"
    explanation: >-
      Makes explicit that a negative CSF PCR does not argue against the
      diagnosis.
- name: Brain and Spinal Magnetic Resonance Imaging
  description: >-
    Imaging demonstrates the ischemic consequences: infarcts, lacunar infarction,
    paraventricular and juxtacortical white-matter lesions, and in one twin
    spinal cord lesions. MR angiography is suggestive rather than conclusive, and
    histopathological confirmation of CNS vasculitis was not obtainable in either
    reported patient - so the diagnosis rests on the combination of imaging,
    intrathecal antibody and clinical course rather than on any single test.
  diagnosis_term:
    preferred_term: magnetic resonance imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "signs of paraventricular parietal cerebral ischemic lesions on the left side with several small juxtacortical lesions bilaterally"
    explanation: >-
      Documents the imaging findings that support the diagnosis.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "this diagnosis is rather difficult to make with certainty, and even MR angiography is only suggestive and not a conclusive evidence of this diagnosis"
    explanation: >-
      The authors' own statement of the diagnostic uncertainty, which is why this
      entry does not present imaging as confirmatory.
- name: Immunological Evaluation (to Exclude Broader Immunodeficiency)
  description: >-
    Routine immunological workup is NORMAL in this condition, and that negative
    result is diagnostically informative rather than merely reassuring: it is
    what distinguishes a pathogen-restricted innate sensing defect from the
    combined and phagocyte immunodeficiencies that also predispose to
    disseminated VZV. In the reported twins, immunoglobulins, lymphocyte
    distribution and lymphocyte proliferation were all normal and HIV testing was
    negative.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A routine clinical immunologic evaluation was normal, including normal immunoglobulins, lymphocyte distribution and proliferation within the normal range, and a negative HIV test."
    explanation: >-
      Documents the normal immunological evaluation that frames this as a
      pathogen-restricted rather than general immunodeficiency.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "they did not report any increased susceptibility to other viral, bacterial, or fungal infections, neither in the past nor at present"
    explanation: >-
      Documents the absence of broader infectious susceptibility, the clinical
      counterpart of the normal immunological workup.
- name: Exome Sequencing
  description: >-
    Whole-exome sequencing identified the causal variant in every reported case,
    and is the only way this diagnosis is made. It is worth considering in an
    otherwise immunologically normal person with severe or recurrent VZV CNS
    disease - a setting in which a genetic cause is not routinely sought.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29728610
    reference_title: "Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By whole exome sequencing we identified mutations in POL III genes in two of eight patients."
    explanation: >-
      Gives the diagnostic yield of exome sequencing in a consecutive adult VZV
      CNS infection cohort.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because of this unusual presentation in both monozygotic twin sisters, we suspected a genetic etiology of the recurrent VZV CNS vasculitis."
    explanation: >-
      States the clinical trigger for genetic investigation - an unusual,
      recurrent VZV CNS presentation - which is the setting this entry recommends.
genetic:
- name: RNA polymerase III subunit variants
  gene_term:
    preferred_term: POLR3F
    term:
      id: hgnc:15763
      label: POLR3F
  association: Causative
  relationship_type: CAUSATIVE
  notes: >-
    OMIM #619872 and MedGen anchor IMD101 on POLR3F (20p11.23). The wider
    VZV-susceptibility allelic series spans four POL III subunits — POLR3A and
    POLR3C (severe primary VZV disease in children), POLR3A and POLR3E (adult
    VZV CNS infection after reactivation), POLR3F (recurrent adult CNS
    vasculitis, the OMIM anchor). Note that MONDO:0030813 records no causal-gene
    relationship of its own, so the gene anchor here comes from OMIM/MedGen; that
    gap is worth reporting upstream. Note also that other variants in some of the
    same genes cause an entirely different disease: POLR3A, POLR3B, POLR1C and
    POLR3K variants cause hypomyelinating leukodystrophy, with no reported VZV
    susceptibility. Any variant interpretation in these genes therefore has to
    ask which disease the allele belongs to, not merely whether the gene is
    disease-associated.
  variants:
  - name: POLR3F p.Arg50Trp (R50W)
    description: >-
      The OMIM-anchoring allele: a rare heterozygous missense change in the
      N-terminal region of POLR3F, in the winged-helix region of the POLR3F /
      POLR3C / POLR3G subcomplex required for POL III transcription initiation.
      Predicted damaging by PolyPhen-2 and SIFT with a CADD score of 25.8,
      against a mutation significance cutoff of 13.0 for this gene, and POLR3F
      itself appears to be under purifying selection. Critically, the mutant
      protein's expression and solubility are normal, so the allele impairs what
      the subunit DOES rather than how much of it there is.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The mutation, R50W POLR3F, is rare and predicted to be damaging by bioinformatics software, such as PolyPhen-2 and SIFT and with a high combined annotation dependent depletion (CADD) score of 25.8, which is well above the mutation significance cutoff score of 13.0 for this gene."
      explanation: >-
        Names the allele and gives the in-silico support and the gene-specific
        significance threshold it exceeds.
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "causes an amino acid shift from the positively charged arginine (R) to a bulky aromatic tryptophan (W) in the N-terminal region of the POLR3F subunit, which together with POLR3C and POLR3G constitutes a POLR3 subcomplex essential for POLR3 promoter transcription initiation"
      explanation: >-
        Gives the physicochemical nature of the substitution and its structural
        context in the transcription-initiation subcomplex.
  evidence:
  - reference: PMID:34395528
    reference_title: "RNA Polymerase III Subunit Mutations in Genetic Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Mutations in the POLR3A, POLR3C, POLR3E and POLR3F subunits are associated with susceptibility to varicella zoster virus-induced encephalitis and pneumonitis."
    explanation: >-
      Enumerates the four subunits implicated in VZV susceptibility.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with the POLR3F variant c.148C>T present in P1, P2, and the father"
    explanation: >-
      Sanger segregation placing the variant in both affected twins and in their
      father, which is the basis for germline origin and for the caveat about
      incomplete penetrance in the inheritance block.
  - reference: PMID:34395528
    reference_title: "RNA Polymerase III Subunit Mutations in Genetic Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "an ever-increasing number of distinct mutations in the POLR3A, POLR3B, POLR1C and POLR3K subunits cause a spectrum of neurodegenerative diseases, which includes most notably hypomyelinating leukodystrophy"
    explanation: >-
      Documents the allelic-series problem: the same genes carry variants causing
      a mechanistically unrelated neurodegenerative disease.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified a rare mutation in the POL III subunit POLR3F"
    explanation: >-
      Identifies the POLR3F variant underlying the OMIM-anchored presentation.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Published cases number in the single figures: four children in the founding
    series (POLR3A and/or POLR3C), two of eight sequenced adults with VZV CNS
    infection (POLR3A, POLR3E), and one monozygotic twin pair (POLR3F). No
    population prevalence estimate exists, and none is straightforward to derive,
    because the phenotype requires both a rare genotype and exposure to a
    near-universal virus, with plainly incomplete penetrance. For context on the
    denominator, VZV CNS infection and pneumonia complicate roughly 0.02% and
    0.25% of childhood primary infections respectively — most of which are not
    POL III deficient.
  evidence:
  - reference: PMID:29728610
    reference_title: "Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By whole exome sequencing we identified mutations in POL III genes in two of eight patients."
    explanation: >-
      Gives the yield in a consecutive adult VZV CNS infection cohort, which is
      the only denominator-bearing figure available.
experimental_models:
- name: POLR3F+/- SH-SY5Y human neuronal cell model
  experimental_model_type: CELL_LINE
  description: >-
    Human SH-SY5Y neuroblastoma cells engineered to POLR3F heterozygous knockout,
    used both as differentiated neurons in acute VZV infection and in a quiescent
    infection model that permits spontaneous reactivation to be quantified. This
    is the only model that addresses the reactivation arm directly.
  modeled_mechanisms:
  - target: VZV Reactivation from Latency
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      POLR3F-heterozygous neuronal cells show higher viral gene expression and
      more spontaneous VZV reactivation than wild type, which the authors
      describe as reflecting the patient phenotype.
    limitations: >-
      SH-SY5Y is a neuroblastoma line rather than a sensory ganglion neuron, and
      the quiescent-infection system is a surrogate for latency rather than
      latency itself. The genotype is an engineered heterozygous knockout, not
      the patients' R50W missense allele, so the model tests gene dosage rather
      than the specific human variant. Effects were noted in early-passage cells.
    readouts:
    - name: VZV gene expression by RT-qPCR
      target: VZV Reactivation from Latency
      direction: INCREASED
      interpretation: >-
        Higher viral gene expression in POLR3F+/- neuronal cells is the acute
        infection readout of impaired restraint.
      evidence:
      - reference: PMID:41739639
        reference_title: "RNA Polymerase III Suppresses Varicella Zoster Virus in Human Neurons."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "resulted in higher viral gene expression and more VZV reactivation in the POLR3F neuronal heterozygous (POLR3F+/-) knockout cells"
        explanation: >-
          Reports the direction of both measurements in the model.
    - name: Spontaneous reactivation from quiescent infection
      target: VZV Reactivation from Latency
      direction: INCREASED
      interpretation: >-
        Increased spontaneous reactivation is the readout that makes this model
        informative for the reactivation node specifically.
      evidence:
      - reference: PMID:41739639
        reference_title: "RNA Polymerase III Suppresses Varicella Zoster Virus in Human Neurons."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "We also established a quiescent infection model and quantified spontaneous reactivation by detection of viral proteins fused to fluorophores."
        explanation: >-
          Describes the assay behind the reactivation readout.
    evidence:
    - reference: PMID:41739639
      reference_title: "RNA Polymerase III Suppresses Varicella Zoster Virus in Human Neurons."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This work identifies a novel role for POLR3F as a sentinel for VZV reactivation in neuronal cells"
      explanation: >-
        The authors' statement of what the model establishes, which is what makes
        it informative for this node.
- name: Patient peripheral blood mononuclear cells with wild-type allele rescue
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary patient leukocytes stimulated with the POL III agonist poly(dA:dT),
    with VZV-derived DNA, or infected with VZV, and compared against healthy
    controls. In the founding study the defective phenotypes were rescued by
    transduction with the relevant wild-type allele, which is what converts an
    association into a causal claim.
  modeled_mechanisms:
  - target: Deficient Type I Interferon Induction
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      Direct measurement in patient cells of the interferon and cytokine defect,
      with genetic rescue.
    limitations: >-
      Peripheral blood mononuclear cells are not the cell type in which the
      disease manifests — the lesion presents in cerebral arteries and neurons —
      so the assay establishes the cell-intrinsic defect rather than its tissue
      consequence. Rescue was reported for the founding POLR3A/POLR3C patients;
      no equivalent rescue is reported for the POLR3F twins.
    readouts:
    - name: Interferon induction by synthetic and VZV-derived DNA
      target: Deficient Type I Interferon Induction
      direction: DECREASED
      interpretation: >-
        Poor interferon induction to both agonists is the defining laboratory
        phenotype of the disorder.
      evidence:
      - reference: PMID:28783042
        reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Leukocytes from all 4 patients tested exhibited poor IFN induction in response to synthetic or VZV-derived DNA."
        explanation: >-
          Reports the direction and the stimuli.
    - name: Interferon phenotype after wild-type allele transduction
      target: Deficient Type I Interferon Induction
      direction: RESTORED
      interpretation: >-
        Restoration on transduction with the wild-type allele is the causal test.
      evidence:
      - reference: PMID:28783042
        reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "These phenotypes were rescued by transduction with relevant WT alleles."
        explanation: >-
          Reports the rescue result.
    evidence:
    - reference: PMID:28783042
      reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "confer increased susceptibility to severe VZV disease in otherwise healthy children, providing evidence for an essential role of a DNA sensor in human immunity"
      explanation: >-
        The authors frame the patient-cell work as evidence for an essential role
        of a DNA sensor in human immunity, which is what this model measures.
treatments:
- name: Acyclovir
  description: >-
    Antiviral therapy is the mainstay, and OMIM's own summary of IMD101 states
    that treatment with acyclovir is effective. Two qualifiers belong with that
    word. Even with acyclovir, the incidence and severity of sequelae after
    severe VZV infection are considerable, so effective is not curative, and
    nothing available treats the underlying sensing defect. And in the reported
    twins the benefit was not durable: both had a good clinical response during
    episodes but relapsed with new symptoms AND new MRI lesions when acyclovir
    was discontinued. In a host whose cell-intrinsic control of VZV is
    permanently impaired, that is what one would expect, and it is the argument
    for continued rather than episodic antiviral therapy - though no trial has
    tested a suppression strategy in this disorder.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: aciclovir
      term:
        id: CHEBI:2453
        label: acyclovir
  target_mechanisms:
  - target: Failure to Restrict VZV Replication
    treatment_effect: INHIBITS
    description: >-
      Acyclovir suppresses viral replication pharmacologically, substituting for
      the cell-intrinsic restraint that the sensing defect removes. It does not
      repair the sensor, which is why the mechanism node it acts on is the
      replication node and not an upstream one.
    evidence:
    - reference: PMID:28783042
      reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Antiviral therapy with acyclovir is used for treatment of VZV encephalitis"
      explanation: >-
        Establishes acyclovir as the treatment for the VZV manifestations this
        disorder produces. The quote stops before "pneumonitis" because the
        cached typeset text hyphenates that word across a line break.
  evidence:
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, despite treatment with acyclovir, the incidence and severity of sequelae following severe VZV infection are considerable"
    explanation: >-
      The qualifier that belongs with calling acyclovir effective: sequelae after
      severe VZV infection remain considerable despite it.
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both patients described in the present study have a good clinical response to acyclovir and corticosteroid treatment during clinical episodes but experience recurrence of symptoms and new MRI lesions during discontinuation of acyclovir"
    explanation: >-
      The single most clinically actionable observation in this disorder: the
      response to acyclovir is good but not durable, and stopping it produced
      both symptomatic recurrence and new imaging lesions in both twins. This is
      the argument for continued rather than episodic antiviral therapy.
- name: Corticosteroids During Acute Vasculitic Episodes
  description: >-
    Corticosteroids were given alongside acyclovir during acute episodes in the
    reported twins, on the reasoning that the presentation is an inflammatory
    vasculitis and not simply viral replication. The index patient received
    prednisolone 50 mg daily for 10 days with acyclovir 10 mg/kg three times
    daily for 14 days, and the authors report good clinical response to the
    combination. Two cautions belong with this. The contribution of the steroid
    cannot be separated from that of the antiviral in a two-patient series. And
    immunosuppression in a patient who already fails to control VZV is not a
    neutral act - it is given here for the vasculitic component, under antiviral
    cover, not as monotherapy.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: prednisolone
      term:
        id: CHEBI:8378
        label: prednisolone
  target_mechanisms:
  - target: VZV Vasculopathy of Cerebral Arteries
    treatment_effect: MODULATES
    description: >-
      Corticosteroids act on the inflammatory arterial lesion rather than on the
      virus or on the sensing defect, which is why the mechanism target is the
      vasculopathy node and why the treatment is given under antiviral cover.
    evidence:
    - reference: PMID:30211253
      reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: "The patient was treated with acyclovir 10 mg/kg tds for 14 days together with corticosteroids (prednisolone 50 mg once daily for 10 days) because the clinical presentation was interpreted as CNS vasculitis."
      explanation: >-
        Documents the regimen and, crucially, the stated reason for adding the
        steroid - the vasculitic interpretation of the presentation. Marked
        INDIRECT because this is a treatment decision in a two-patient series, not
        evidence of steroid efficacy.
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "good clinical response to acyclovir and corticosteroid treatment during clinical episodes"
    explanation: >-
      Reports the response to the combination. PARTIAL because the steroid's
      individual contribution is not separable from the antiviral's.
- name: Genetic Testing and Counseling
  description: >-
    Whole-exome or targeted POL III sequencing is how every reported case was
    identified, and it is worth considering in an otherwise healthy person with
    severe or recurrent VZV CNS disease. Counseling has to convey two things that
    make this condition unusual: penetrance is plainly incomplete and the
    phenotype requires the virus as well as the genotype, so a carrier relative
    is not a patient-in-waiting; and a variant in one of these genes may belong
    to a different disease entirely, since POLR3A and several other POL III
    subunits also carry variants causing hypomyelinating leukodystrophy.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29728610
    reference_title: "Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By whole exome sequencing we identified mutations in POL III genes in two of eight patients."
    explanation: >-
      Demonstrates the diagnostic yield of exome sequencing in adults presenting
      with VZV CNS infection, which is the basis for testing in that setting.
  - reference: PMID:34395528
    reference_title: "RNA Polymerase III Subunit Mutations in Genetic Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "an ever-increasing number of distinct mutations in the POLR3A, POLR3B, POLR1C and POLR3K subunits cause a spectrum of neurodegenerative diseases"
    explanation: >-
      Supports the counseling point that a POL III variant may belong to a
      different disease entity than this one.
discussions:
- discussion_id: imd101_nosology_primary_versus_reactivation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Are severe PRIMARY VZV disease in POL III-deficient children and adult VZV
    REACTIVATION vasculitis one disease entity or two, and does MONDO:0030813
    cover both?
  attaches_to:
  - "pathophysiology#Failure to Restrict VZV Replication"
  rationale: >-
    OMIM's summary of IMD101 is written entirely around adult reactivation —
    reactivation in adulthood after primary childhood infection, presenting as
    CNS vasculitis — and MedGen anchors the entity on POLR3F. But the founding
    literature is paediatric and primary-infection, in POLR3A and POLR3C, and the
    review literature treats all four subunits as one susceptibility. The
    neuronal model complicates rather than settles this: its authors conclude
    that POL III matters to VZV immunity MAINLY UPON REACTIVATION, which if
    correct would make the paediatric primary-infection cases the harder ones to
    explain by this mechanism, not the easier. This entry curates both arms off a
    shared upstream chain and flags the question rather than choosing an answer,
    because the choice determines whether the paediatric POLR3A/POLR3C cases
    belong under this MONDO concept at all.
  proposed_experiments:
  - experiment_id: exp_imd101_lifecycle_stage_comparison
    name: Stage-resolved comparison of POL III dependence in primary versus reactivating VZV infection
    description: >-
      In matched neuronal and non-neuronal human cells carrying POLR3A, POLR3C,
      POLR3E and POLR3F patient alleles, quantify interferon induction and viral
      control separately during de novo infection and during reactivation from a
      quiescent state, to test whether the subunits differ in which life-cycle
      stage they gate — which would be the mechanistic basis for splitting or
      lumping the two clinical presentations.
  evidence:
  - reference: PMID:41739639
    reference_title: "RNA Polymerase III Suppresses Varicella Zoster Virus in Human Neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "POL III) plays a role in immunity to VZV mainly upon reactivation in humans"
    explanation: >-
      The claim that POL III acts mainly at reactivation, which is what puts the
      paediatric primary-infection arm in question.
  - reference: PMID:28783042
    reference_title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "4 cases of acute severe VZV infection affecting the central nervous system or the lungs"
    explanation: >-
      The paediatric primary-infection cases that the reactivation-centred
      framing has to accommodate.
- discussion_id: imd101_no_model_of_the_affected_tissue
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Every model of this disease is a model of the wrong compartment. Does
    evidence from circulating leukocytes and a neuroblastoma line license claims
    about cerebral arteries and sensory ganglia, which is where the disease
    actually happens?
  attaches_to:
  - "pathophysiology#VZV Vasculopathy of Cerebral Arteries"
  rationale: >-
    The functional evidence in this entry comes from two sources, and neither is
    the affected tissue. Patient peripheral blood mononuclear cells give the
    cleanest genotype-phenotype link - impaired interferon and cytokine responses
    to the POL III agonist, intact responses to a ligand that bypasses POL III,
    increased viral transcript - but they are circulating mixed cells, not
    neurons, ganglia, or cerebral arterial endothelium. The SH-SY5Y model reaches
    the neuronal compartment and the reactivation step, but it is a
    neuroblastoma line carrying an engineered heterozygous knockout rather than
    the patients' R50W missense allele, so it tests gene dosage rather than the
    human variant. No animal model of this disorder exists, and no
    histopathological confirmation of the CNS vasculitis was obtainable in either
    reported patient. The vasculopathy node is therefore supported by clinical,
    CSF and imaging evidence in humans and by mechanistic evidence in the wrong
    cell types, with nothing bridging the two.
  proposed_experiments:
  - experiment_id: exp_imd101_patient_ipsc_neurovascular_model
    name: Patient-derived iPSC neurons and brain microvascular endothelial cells carrying R50W
    description: >-
      Differentiate iPSCs from an R50W carrier, and isogenic corrected controls,
      into sensory-type neurons and brain microvascular endothelial cells; assay
      VZV infection, latency establishment, reactivation, interferon induction
      and endothelial activation in each. This would test the disease mechanism
      in the two cell types the disease actually damages, with the patient's own
      allele rather than a knockout.
  evidence:
  - reference: PMID:30211253
    reference_title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "histopathologic evidence of vasculitis in the CNS could not be provided in the 2 cases described here"
    explanation: >-
      Establishes that the tissue diagnosis was never obtained, which is one half
      of the gap this discussion records.
  - reference: PMID:41739639
    reference_title: "RNA Polymerase III Suppresses Varicella Zoster Virus in Human Neurons."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We generated human SH-SY5Y (POLR3F+/-) knockout cells."
    explanation: >-
      Identifies the only neuronal model as an engineered knockout line rather
      than a patient-allele or animal model, which is the other half of the gap.
- discussion_id: imd101_pol_iii_genotype_phenotype
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why do variants in POL III subunits produce either VZV susceptibility or
    hypomyelinating leukodystrophy, and what determines which, given that both
    perturb the same nine-subunit enzyme?
  attaches_to:
  - "pathophysiology#RNA Polymerase III Subunit Missense Variant"
  rationale: >-
    POL III subunit variants cause tissue-specific diseases rather than a general
    failure of the enzyme's vital functions, and the two disease groups barely
    overlap clinically: POLR3A appears in both lists, but VZV-susceptible
    patients do not have leukodystrophy and leukodystrophy patients are not
    reported to have VZV susceptibility. The review literature states plainly
    that the exact molecular mechanisms underlying disease pathogenesis remain
    enigmatic. This matters practically as well as conceptually: it means a
    variant in POLR3A cannot be interpreted without knowing which disease
    mechanism it engages, and it is the reason this entry's counseling entry
    carries that warning.
  proposed_experiments:
  - experiment_id: exp_imd101_subunit_allele_function_partition
    name: Partitioned assay of housekeeping versus DNA-sensing POL III function across disease alleles
    description: >-
      Assay VZV-susceptibility alleles and leukodystrophy alleles side by side
      for tRNA/small-RNA transcription on the one hand and cytosolic AT-rich DNA
      sensing with interferon induction on the other, to test whether the two
      disease groups separate along the housekeeping/sensing axis rather than by
      subunit identity.
  evidence:
  - reference: PMID:34395528
    reference_title: "RNA Polymerase III Subunit Mutations in Genetic Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "it was discovered in the last decade that various inherited mutations in genes encoding nine distinct subunits of Pol III cause tissue-specific diseases rather than a general failure of all vital functions"
    explanation: >-
      States the puzzle: subunit variants give tissue-specific disease rather
      than global enzyme failure.
  - reference: PMID:34395528
    reference_title: "RNA Polymerase III Subunit Mutations in Genetic Diseases."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "the exact molecular mechanisms underlying disease pathogenesis remain enigmatic"
    explanation: >-
      The authors' own statement that the mechanism partitioning these diseases
      is unresolved.
notes: >-
  Identifier and gene anchor. MONDO:0030813 carries no causal-gene relationship;
  OMIM #619872 and MedGen (CUI C5676983) both associate IMD101 with POLR3F at
  20p11.23. The gene anchor in this entry therefore comes from OMIM/MedGen. That
  MONDO gap is worth reporting upstream and is not a curation choice made here.


  Scope. The entry models the POL III VZV-susceptibility mechanism as one chain
  across POLR3A, POLR3C, POLR3E and POLR3F, because the reported variants in all
  four produce the same sensing defect and the same pathogen-restricted
  susceptibility. Whether the paediatric primary-infection arm and the adult
  reactivation arm are one MONDO concept is recorded as an open question in the
  discussions rather than decided silently.


  Evidence mechanics. The PMID:28783042 cache is `full_text_xml` of a typeset
  PDF, so words are hyphenated across line breaks ("alphaherpes-virus",
  "pneu-monitis", "infec-tion"). Snippet matching normalizes ordinary line breaks
  but not those intra-word hyphens, so every quote from that source is bounded to
  stop short of a hyphenated word rather than reproduce the break. Where that
  clipped the opening clause of a sentence, the clipped part is stated in the
  surrounding description and the reason is given in the evidence explanation.


  No `datasets:` block. No disease-specific omics accession was identified; the
  published work is targeted functional immunology rather than deposited
  datasets, and searching the POL III gene names alone would surface
  leukodystrophy and cancer datasets, which is the Named Entity Confusion hazard
  the dataset SOP warns about.


  No ORPHA evidence asserted. `just refresh-orphadata` is currently failing on a
  manifest checksum mismatch and no cached ORPHA record for this concept was
  available.
references:
- reference: PMID:28783042
  title: "Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections."
  findings: []
- reference: PMID:30211253
  title: "Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins."
  findings: []
- reference: PMID:29728610
  title: "Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection."
  findings: []
- reference: PMID:41739639
  title: "RNA Polymerase III Suppresses Varicella Zoster Virus in Human Neurons."
  findings: []
- reference: PMID:34395528
  title: "RNA Polymerase III Subunit Mutations in Genetic Diseases."
  findings: []
- reference: PMID:30115567
  title: "RNA Polymerase III as a Gatekeeper to Prevent Severe VZV Infections."
  findings: []

📚

References & Deep Research

References

6

PMID:28783042

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections.

No top-level findings curated for this source.

PMID:30211253

Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins.

No top-level findings curated for this source.

PMID:29728610

Mutations in RNA Polymerase III genes and defective DNA sensing in adults with varicella-zoster virus CNS infection.

No top-level findings curated for this source.

PMID:41739639

RNA Polymerase III Suppresses Varicella Zoster Virus in Human Neurons.

No top-level findings curated for this source.

PMID:34395528

RNA Polymerase III Subunit Mutations in Genetic Diseases.

No top-level findings curated for this source.

PMID:30115567

RNA Polymerase III as a Gatekeeper to Prevent Severe VZV Infections.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Immunodeficiency 101 (Varicella-Zoster Virus–Specific): Disease Characteristics Report

Edison Scientific Literature 31 citations 2026-08-25T20:07:36.201321

Immunodeficiency 101 (Varicella-Zoster Virus–Specific): Disease Characteristics Report

Executive summary and evidence limitations

Immunodeficiency 101, varicella-zoster virus–specific is best mapped to an ultra-rare, Mendelian, selective susceptibility to severe varicella-zoster virus (VZV) disease caused by a monoallelic POLR3F defect. The defining report described two monozygotic adult female twins with recurrent VZV-associated central nervous system (CNS) vasculitis and a heterozygous POLR3F c.25C>T (p.Arg50Trp; R50W) variant. Patient peripheral-blood mononuclear cells (PBMCs) had deficient responses to AT-rich DNA and increased VZV replication, connecting the genotype to impaired RNA polymerase III (Pol III) antiviral sensing. This is distinct from the broader group of Pol III–related VZV susceptibilities caused by POLR3A, POLR3C, or POLR3E variants. (cartertimofte2018varicellazosterviruscns pages 6-8, cartertimofte2018varicellazosterviruscns pages 4-5, ansari2021primaryandacquired pages 5-6)

The evidence base is exceptionally small: two molecularly confirmed POLR3F-affected individuals from one family. Consequently, phenotype frequencies, penetrance, prevalence, survival, treatment-response rates, sex ratio, and genotype–phenotype correlations cannot be estimated reliably. No clearly documented additional POLR3F-specific cases were found in the retrieved 2023–2024 literature. Most disease-specific evidence is therefore human case-level evidence supplemented by ex vivo PBMC studies and broader VZV/Pol III reviews.

Topic	Key finding	Evidence type	Key publication / DOI
Disease identity	Best-mapped entity is a Mendelian, selective susceptibility to severe VZV disease caused by monoallelic POLR3F deficiency; reported presentation is recurrent VZV CNS vasculitis/meningoencephalitis rather than broad combined immunodeficiency. No confirmed MONDO/OMIM identifier was established from retrieved sources. (cartertimofte2018varicellazosterviruscns pages 6-8, cartertimofte2018varicellazosterviruscns pages 4-5)	Human case report + review	Carter-Timofte et al., 2018, Neurol Neuroimmunol Neuroinflamm; DOI: https://doi.org/10.1212/NXI.0000000000000500
Causal gene / variant	Causal gene: POLR3F (RNA polymerase III subunit F). Reported disease-associated variant: c.25C>T, p.Arg50Trp (R50W), heterozygous; predicted damaging with CADD 25.8; biochemical work suggested preserved expression/solubility, implying functional rather than stability defect. (cartertimofte2018varicellazosterviruscns pages 4-5)	Human genetics + ex vivo functional follow-up	Carter-Timofte et al., 2018; DOI: https://doi.org/10.1212/NXI.0000000000000500
Inheritance	Evidence supports autosomal dominant / monoallelic susceptibility with likely incomplete penetrance: the variant was present in both affected monozygotic twins and inherited from the father, who reportedly had a prior stroke possibly related to VZV vasculitis. (cartertimofte2018varicellazosterviruscns pages 4-5, cartertimofte2018rnapolymeraseiii pages 6-8)	Family segregation + expert review	Carter-Timofte et al., 2018; DOI: https://doi.org/10.1212/NXI.0000000000000500; Carter-Timofte et al., 2018 review; DOI: https://doi.org/10.1016/j.molmed.2018.07.009
Reported patients	Confirmed POLR3F-specific cases in retrieved evidence: 2 monozygotic adult female twins, both age 37 in review summaries, with recurrent VZV CNS vasculitis due to reactivation. No additional clearly documented POLR3F cases were identified in retrieved 2023–2024 literature. (cartertimofte2018varicellazosterviruscns pages 6-8, cartertimofte2018rnapolymeraseiii pages 6-8)	Human case report + review synthesis	Carter-Timofte et al., 2018; DOI: https://doi.org/10.1212/NXI.0000000000000500
Core phenotype	Recurrent stroke-like CNS disease with headache, dizziness, hemiparesis/sensory deficits, CSF pleocytosis and intrathecal anti-VZV antibody production, and brain MRI ischemic lesions; one summary also notes myelitis and parietal/juxtacortical lesions. Patients reportedly had normal childhood varicella and no unusual susceptibility to other infections. (cartertimofte2018varicellazosterviruscns pages 6-8, cartertimofte2018varicellazosterviruscns pages 3-4, cartertimofte2018varicellazosterviruscns pages 4-5)	Human clinical phenotype	Carter-Timofte et al., 2018; DOI: https://doi.org/10.1212/NXI.0000000000000500
Diagnostic findings	Supportive findings included CSF pleocytosis, intrathecal VZV IgG production, VZV CNS vasculitis-compatible MRI ischemic lesions, and normal routine immune workup (normal immunoglobulins, lymphocyte distribution/proliferation, HIV negative). Broader VZV vasculopathy literature emphasizes that CSF anti-VZV IgG is often more sensitive than PCR and that negative PCR does not exclude disease. (cartertimofte2018varicellazosterviruscns pages 6-8, cartertimofte2018varicellazosterviruscns pages 3-4, cartertimofte2018varicellazosterviruscns pages 4-5)	Human case report + disease review	Carter-Timofte et al., 2018; DOI: https://doi.org/10.1212/NXI.0000000000000500; Nagel & Bubak, 2018; DOI: https://doi.org/10.1093/infdis/jiy425
Functional mechanism	POLR3F deficiency impairs POL III sensing of AT-rich DNA and downstream RIG-I/MAVS/type I and III IFN responses. Patient PBMCs showed reduced antiviral/inflammatory responses to poly(dA:dT) and increased VZV replication/gene expression versus controls. Reviews place POLR3F with POLR3A/C/E as Pol III subunits involved in human VZV susceptibility. (cartertimofte2018varicellazosterviruscns pages 6-8, ansari2021primaryandacquired pages 5-6, lata2021rnapolymeraseiii pages 21-22, cartertimofte2018rnapolymeraseiii pages 4-6, cartertimofte2018rnapolymeraseiii pages 6-8)	Human ex vivo immunology + mechanistic reviews	Carter-Timofte et al., 2018; DOI: https://doi.org/10.1212/NXI.0000000000000500; Lata et al., 2021; DOI: https://doi.org/10.3389/fmolb.2021.696438
Acute treatment	In the reported family/case summaries, acute episodes were treated with intravenous acyclovir 10 mg/kg three times daily for 14 days plus prednisolone 50 mg daily for 10 days. Broader VZV vasculopathy reviews support IV acyclovir as standard acute therapy, with corticosteroids used as adjuncts in selected cases. (cartertimofte2018varicellazosterviruscns pages 3-4, ansari2021primaryandacquired pages 5-6)	Human case report + clinical review	Carter-Timofte et al., 2018; DOI: https://doi.org/10.1212/NXI.0000000000000500; Nagel & Bubak, 2018; DOI: https://doi.org/10.1093/infdis/jiy425
Prophylaxis	Both twins reportedly received acyclovir prophylaxis; one twin had symptom recurrence/new white matter lesions after stopping prophylaxis. Expert review further suggested that individuals with POL III defects may benefit from childhood varicella vaccination, adult zoster vaccination, and acyclovir prophylaxis after severe/recurrent VZV, but these are opinion-based rather than trial-proven for POLR3F disease. (cartertimofte2018varicellazosterviruscns pages 6-8, cartertimofte2018rnapolymeraseiii pages 10-11)	Human case follow-up + expert opinion	Carter-Timofte et al., 2018; DOI: https://doi.org/10.1212/NXI.0000000000000500; Carter-Timofte et al., 2018 review; DOI: https://doi.org/10.1016/j.molmed.2018.07.009
Epidemiology	Unknown disease prevalence/incidence. Retrieved evidence supports only a single affected family (2 confirmed twins). By contrast, the wider Pol III/VZV susceptibility literature includes additional non-POLR3F patients with POLR3A/C/E variants. Thus, POLR3F-related disease appears ultra-rare. (cartertimofte2018rnapolymeraseiii pages 6-8, lata2021rnapolymeraseiii pages 21-22, cartertimofte2018varicellazosterviruscns pages 4-5)	Case-based evidence + review synthesis	Carter-Timofte et al., 2018; DOI: https://doi.org/10.1212/NXI.0000000000000500; Lata et al., 2021; DOI: https://doi.org/10.3389/fmolb.2021.696438
Major evidence gaps	No disease-specific prevalence estimates, natural-history cohort, penetrance study, controlled treatment trial, validated biomarker panel, or disease-specific animal model were identified. It remains unclear which cell types are decisive in vivo, whether POL III acts mainly in cytosolic DNA sensing versus nuclear RNA5SP14-related signaling, and how POLR3F defects influence latency/reactivation control. (cartertimofte2018rnapolymeraseiii pages 10-11, kennedy2021recentissuesin pages 8-9, cartertimofte2018varicellazosterviruscns pages 4-5)	Knowledge-gap synthesis from reviews + case report	Carter-Timofte et al., 2018 review; DOI: https://doi.org/10.1016/j.molmed.2018.07.009; Kennedy et al., 2021; DOI: https://doi.org/10.3390/v13102018

Table: This table summarizes the highest-confidence evidence for Immunodeficiency 101 (VZV-specific), best mapped here to POLR3F-related selective susceptibility to severe VZV CNS disease. It highlights what is known from primary human cases and reviews, while clearly marking major unresolved gaps.

1. Disease information

Definition

This condition is an inborn error of intrinsic/innate antiviral immunity in which defective POLR3F-containing RNA polymerase III compromises recognition of the AT-rich VZV genome. Clinically, the reported phenotype is recurrent VZV reactivation in the CNS, causing meningoencephalitis/vasculitis, ischemic lesions, and stroke-like neurologic episodes despite an otherwise normal routine immune evaluation. The patients did not exhibit broad susceptibility to bacterial, fungal, or unrelated viral infections. (cartertimofte2018varicellazosterviruscns pages 1-2, cartertimofte2018varicellazosterviruscns pages 4-5)

Names and identifiers

Preferred label: Immunodeficiency 101, varicella-zoster virus–specific.
Useful synonyms: POLR3F-related VZV susceptibility; POLR3F deficiency; RNA polymerase III deficiency due to POLR3F; selective susceptibility to severe VZV infection; VZV CNS vasculitis associated with POLR3F mutation.
Gene: POLR3F, encoding RNA polymerase III subunit F/RPC6.
MONDO, OMIM phenotype, Orphanet: a stable disease-level identifier could not be verified from the retrieved full-text sources; it should therefore not be inferred from the numbered disease label alone.
ICD-10/ICD-11: no disease-specific code was identified. Component manifestations may be coded as hereditary immunodeficiency, viral encephalitis/meningitis, cerebral vasculitis, or VZV infection, depending on the coding system and confirmed presentation.
MeSH: relevant concepts include Immunologic Deficiency Syndromes, Herpesvirus 3, Human, Encephalitis, Viral, and Central Nervous System Vasculitis.

The source is aggregated disease-level interpretation derived primarily from two individual patients, not an EHR cohort or population registry.

Foundational evidence

Carter-Timofte et al., “Varicella-zoster virus CNS vasculitis and RNA polymerase III gene mutation in identical twins,” Neurology: Neuroimmunology & Neuroinflammation, volume 5, published November 2018, DOI: 10.1212/NXI.0000000000000500. PMID was not available in the retrieved text and is not supplied here to avoid an unverified identifier. (cartertimofte2018varicellazosterviruscns pages 6-8)

A direct abstract statement is: “The identified R50W POLR3F mutation is predicted by bioinformatics to be damaging, and when tested in functional assays, patient PBMCs exhibited impaired antiviral and inflammatory responses to the POL III agonist poly(dA:dT) and increased viral replication compared with controls.” (cartertimofte2018varicellazosterviruscns pages 1-2)

2. Etiology, risk factors, and protective factors

Causal factors

The proximal inherited cause is the heterozygous POLR3F p.Arg50Trp variant. The necessary infectious trigger is exposure to and subsequent latency/reactivation of VZV, a human alphaherpesvirus. Both twins reportedly had ordinary childhood varicella; their severe phenotype emerged later during viral reactivation rather than during primary infection. (cartertimofte2018varicellazosterviruscns pages 3-4, cartertimofte2018varicellazosterviruscns pages 4-5)

Genetic risk

The reported variant was inherited from the father, who had a previous stroke that the authors considered possibly compatible with VZV CNS vasculitis. This segregation supports autosomal-dominant susceptibility but does not establish complete penetrance. The variant had a reported CADD score of 25.8, above the cited significance threshold of 13, and was predicted damaging. Its expression and solubility were not materially altered, favoring impaired molecular function rather than protein instability. (cartertimofte2018varicellazosterviruscns pages 4-5)

Other genes—POLR3A, POLR3C, and POLR3E—cause related Pol III–dependent VZV susceptibility, but they should not be recorded as causal genes for the narrowly defined POLR3F-specific entity. Across the wider syndrome, VZV-associated Pol III variants map mainly near DNA-binding/initiation or catalytic regions, unlike many biallelic variants causing POLR3-related hypomyelinating leukodystrophy. (lata2021rnapolymeraseiii pages 21-22, cartertimofte2018rnapolymeraseiii pages 6-8)

Environmental and acquired modifiers

VZV infection is indispensable. General factors that impair VZV control—aging, HIV, hematologic disease, transplantation, immunosuppressive drugs, and T/NK-cell deficiencies—can independently increase severe VZV risk, but none was demonstrated as causal in the twins. Their immunoglobulins, lymphocyte distribution/proliferation, and HIV testing were normal. (kennedy2021recentissuesin pages 8-9, cartertimofte2018varicellazosterviruscns pages 4-5)

No disease-specific evidence supports smoking, diet, alcohol, exercise, occupational exposure, toxins, radiation, sex, or ancestry as modifiers.

Protective factors and gene–environment interaction

Antiviral prophylaxis appeared protective in the reported family: both twins received acyclovir prophylaxis, and one developed recurrent symptoms and new white-matter lesions after discontinuation. Expert review—not controlled trial evidence—suggests varicella vaccination in childhood, recombinant zoster vaccination in adulthood, and antiviral prophylaxis after severe or recurrent CNS disease. (cartertimofte2018varicellazosterviruscns pages 6-8, cartertimofte2018rnapolymeraseiii pages 10-11)

The causal interaction is: monoallelic POLR3F dysfunction + latent/reactivating VZV → inadequate AT-rich DNA sensing → deficient interferon response → excessive viral replication → CNS arterial infection/inflammation and ischemia. Ordinary VZV exposure is therefore usually benign in the population but becomes pathogenic in the genetically susceptible host. (cartertimofte2018rnapolymeraseiii pages 6-8, ansari2021primaryandacquired pages 5-6)

3. Phenotypes

Because only two twins are confirmed, “2/2” means occurrence in the index family, not a generalizable population frequency.

Phenotype	Type and characteristics	Suggested HPO term
Recurrent CNS vasculitis	Clinical diagnosis/sign; adult onset, severe, episodic/relapsing; reported in 2/2	Cerebral vasculitis; Recurrent meningitis
Headache and dizziness	Symptoms during attacks; recurrent and variable	Headache (HP:0002315); Vertigo (HP:0002321)
Focal neurologic deficits	Hemiparesis, sensory deficits/paresthesias and stroke-like attacks	Hemiparesis (HP:0001269); Paresthesia (HP:0003401)
Cerebral ischemic lesions	MRI abnormality; recurrent/new lesions possible	Cerebral ischemia (HP:0002637); Abnormal brain MRI
Myelitis	MRI/clinical manifestation described in one twin, spanning approximately C6–T2	Myelitis (HP:0012198)
CSF pleocytosis	Laboratory abnormality during CNS attacks	CSF pleocytosis (HP:0012227)
Intrathecal anti-VZV IgG production	Disease-supporting laboratory biomarker	No highly specific HPO term; use abnormal CSF immunoglobulin/positive pathogen-specific intrathecal antibody
Selective severe VZV susceptibility	Immunologic phenotype without broad recurrent infection	Recurrent viral infections (HP:0004429), qualified as VZV-specific

The reported clinical picture included headache, dizziness, neurologic deficits, CSF pleocytosis with intrathecal VZV antibody production, and ischemic brain lesions. One summary reports paraventricular parietal and bilateral juxtacortical lesions and cervical–upper thoracic myelitis. (cartertimofte2018varicellazosterviruscns pages 1-2, cartertimofte2018varicellazosterviruscns pages 3-4)

Quality-of-life instruments were not administered. Nevertheless, recurrent stroke-like events, hospitalization, neurologic impairment, repeated lumbar puncture/imaging, and chronic antiviral use imply potentially major functional and psychosocial burden. Quantified EQ-5D, SF-36, PROMIS, educational, employment, and caregiver outcomes are unavailable.

4. Genetic and molecular information

Causal gene and variant

Gene: POLR3F.
Protein: RNA polymerase III subunit F/RPC6, part of the Pol III initiation-associated peripheral subcomplex.
Reported variant: c.25C>T, p.Arg50Trp (R50W), heterozygous and germline.
Variant class: missense, monoallelic.
Functional interpretation: loss/hypomorphic impairment of antiviral DNA sensing is supported; a dominant-negative mechanism was not established.
Computational evidence: CADD 25.8 and damaging predictions.
Protein studies: mutant abundance/solubility was reportedly preserved, suggesting altered ligand recognition, initiation, or enzyme activity rather than degradation. (cartertimofte2018varicellazosterviruscns pages 4-5)

The primary paper called the variant novel. A precise modern gnomAD allele count, rsID, ClinVar accession, ACMG/AMP classification, HGNC ID, and transcript version were not established by the retrieved evidence. It should not automatically be labeled “pathogenic” in a clinical database without checking current ClinVar/ClinGen submissions and transcript-specific HGVS normalization. The case data provide strong phenotype, segregation, computational, and functional support but remain limited to one family.

Broader allelic and mechanistic context

Heterozygous VZV-susceptibility variants reported in the larger Pol III group include POLR3A M307V, R437Q, R582C and Q707R; POLR3C L11F, R84Q and R438G; POLR3E T275M; and POLR3F R50W. POLR3F R50W was associated specifically with adult reactivation and CNS vasculitis, whereas POLR3A/C variants also caused childhood encephalitis, cerebellitis, or pneumonitis during primary infection. (cartertimofte2018rnapolymeraseiii pages 6-8)

No validated POLR3F modifier gene, protective allele, founder mutation, germline mosaicism, anticipation, somatic mutation, copy-number abnormality, translocation, inversion, or aneuploidy has been reported for this phenotype. No disease-specific methylation, histone, chromatin, or imprinting abnormality is known.

5. Environmental and infectious information

The direct non-genetic agent is varicella-zoster virus (human alphaherpesvirus 3; NCBI Taxonomy identification should be attached at the pathogen record level). Primary infection produces varicella; lifelong latency is established in sensory, cranial, and autonomic ganglionic neurons; reactivation can produce zoster or neurologic disease. The POLR3F cases represent neurologic reactivation, potentially without reliance on a contemporaneous typical rash. (kennedy2021recentissuesin pages 8-9, cartertimofte2018rnapolymeraseiii pages 1-2)

No toxin, pollutant, radiation, dietary, occupational, smoking, alcohol, or exercise association is known. Immunosuppression and aging are important general VZV modifiers but were not defining features of these patients.

6. Mechanism and pathophysiology

Causal chain

Trigger: latent VZV reactivates and viral AT-rich DNA becomes available to intracellular sensing.
Upstream lesion: POLR3F p.Arg50Trp impairs the cytoplasmic antiviral function of the 17-subunit RNA polymerase III complex.
Normal pathway: Pol III transcribes AT-rich DNA into 5′-triphosphorylated RNA, which activates RIG-I, then MAVS, IRF/NF-κB signaling, and type I/III interferon production.
Patient-cell defect: poly(dA:dT)-induced antiviral and inflammatory responses, including IFN-β and TNF-α, are reduced; VZV gene expression/replication rises.
Tissue consequence: inadequate viral restriction permits infection and inflammation involving CNS tissue and cerebral arterial walls.
Clinical consequence: vasculopathy, vessel narrowing/ischemia, headache, sensory or motor deficits, and recurrent stroke-like episodes. (cartertimofte2018rnapolymeraseiii pages 4-6, cartertimofte2018rnapolymeraseiii pages 6-8, ansari2021primaryandacquired pages 5-6)

Nuclear Pol III normally transcribes tRNAs, 5S rRNA, U6 snRNA, and other small RNAs. In VZV-susceptibility patients, housekeeping transcription such as 5S rRNA production was preserved, helping explain the narrow infectious phenotype and distinguishing it from biallelic POLR3-related leukodystrophy. (lata2021rnapolymeraseiii pages 21-22, cartertimofte2018rnapolymeraseiii pages 4-6)

Cells, tissues, and ontology suggestions

Experimentally studied: PBMCs, including mixed lymphoid and myeloid populations. Biologically plausible but not directly proven in the twins: monocytes/macrophages, cerebral endothelial or vascular smooth-muscle cells, neurons, microglia, astrocytes, and dermal fibroblasts. Reviews explicitly identify the decisive in-vivo cell type and the site at which Pol III controls latency/reactivation as unresolved. (kennedy2021recentissuesin pages 8-9, cartertimofte2018rnapolymeraseiii pages 10-11)

Suggested GO biological processes include:

cytoplasmic pattern-recognition receptor signaling pathway in response to virus;
defense response to virus (GO:0051607);
type I interferon production (GO:0032606);
response to type I interferon (GO:0034340);
RNA polymerase III transcription;
negative regulation of viral genome replication;
RIG-I signaling pathway;
inflammatory response and regulation of cytokine production.

Suggested cellular components include cytosol (GO:0005829), nucleus (GO:0005634), RNA polymerase III complex, and mitochondrial outer membrane/MAVS signaling platform. Suggested CL mappings include peripheral-blood mononuclear cell, monocyte (CL:0000576), T cell (CL:0000084), B cell (CL:0000236), natural killer cell (CL:0000623), neuron (CL:0000540), microglial cell (CL:0000129), astrocyte (CL:0000127), and vascular endothelial cell. These are knowledge-base mappings, not all directly demonstrated disease cell types.

Molecular profiling and advanced technologies

Disease-specific bulk or single-cell transcriptomics, spatial transcriptomics, proteomics, metabolomics, lipidomics, epigenomics, and multi-omics datasets were not found. The available molecular profile consists principally of targeted cytokine measurements and VZV gene-expression/replication assays in patient PBMCs. No disease-specific CRISPR screen or patient-derived iPSC/organoid model was identified.

Recent structural work on human Pol III supports the broader interpretation that viral-sensing variants are situated near DNA-interacting regions, whereas neurodevelopmental variants tend to affect enzyme stability or biogenesis. This provides structural plausibility but is not a POLR3F-p.Arg50Trp clinical validation by itself. (lata2021rnapolymeraseiii pages 21-22, lata2021rnapolymeraseiii pages 10-11)

7. Anatomical structures affected

Primary system: nervous system.
Organs: brain and spinal cord; meninges may be involved through meningoencephalitic disease.
Vascular structures: intracranial/cerebral arteries affected by VZV vasculopathy.
Sites reported: parietal periventricular/paraventricular and juxtacortical cerebral white matter; cervical-to-upper-thoracic spinal cord, approximately C6–T2, in one patient.
Secondary structures in VZV biology: dorsal-root, cranial, and autonomic ganglia harbor latent virus.
Lateralization: neurologic deficits can be unilateral, but imaging lesions may be bilateral or multifocal. (kennedy2021recentissuesin pages 8-9, cartertimofte2018varicellazosterviruscns pages 3-4)

Suggested UBERON mappings include brain (UBERON:0000955), spinal cord (UBERON:0002240), central nervous system (UBERON:0001017), cerebral artery, cerebral white matter, meninges, dorsal-root ganglion, and blood-vessel wall. At the subcellular level, both cytosolic immune sensing and nuclear housekeeping Pol III functions are relevant.

8. Temporal development

The twins had uncomplicated primary varicella in childhood and developed recurrent CNS disease in adulthood. Review summaries describe both as 37-year-old women; patient-level summaries indicate initial presentations at approximately 25 and 35 years, reflecting differing episode histories or ages at first documented presentation. The disorder should therefore be modeled as genetic from conception but clinically latent until VZV reactivation, with variable adult onset. (cartertimofte2018rnapolymeraseiii pages 6-8, cartertimofte2018varicellazosterviruscns pages 3-4)

The clinical course is acute-to-subacute during each neurologic attack but lifelong and relapsing at the susceptibility level. Remission can follow antiviral treatment, while stopping prophylaxis may permit recurrence. No formal disease stages, median recurrence interval, critical developmental window, or long-term natural-history curve has been established. (cartertimofte2018varicellazosterviruscns pages 6-8)

9. Inheritance and population

Inheritance

The best-supported model is autosomal dominant/monoallelic susceptibility with incomplete or context-dependent penetrance. Both monozygotic twins inherited the allele from their father; his possible VZV-related stroke suggests expression but is not a molecularly confirmed third case. Because VZV exposure/reactivation and additional immune factors are required, penetrance is likely infection- and age-dependent. (cartertimofte2018varicellazosterviruscns pages 4-5)

There is no evidence for anticipation, a founder effect, consanguinity dependence, or a sex-limited phenotype. The occurrence in female twins cannot establish a female predominance.

Epidemiology

Confirmed disease-specific patients: 2.
Families: 1.
Prevalence/incidence: unknown; no registry or population estimate.
Carrier frequency: unknown.
Geographic/ancestral distribution: insufficiently reported.
Sex ratio: indeterminate.

The condition is appropriately classified as ultra-rare, but a numerical prevalence per 100,000 cannot be justified.

10. Diagnostics

Clinical recognition

Consider the disorder in an otherwise healthy person with recurrent or unusually severe VZV meningoencephalitis, CNS vasculopathy, myelitis, ischemic stroke, pneumonitis, or disseminated disease—particularly with normal routine immune testing or a family history of similar neurologic events. Recurrent VZV CNS disease is a stronger warning sign than uncomplicated zoster.

Acute VZV/CNS evaluation

Recommended evaluation is phenotype-driven and includes:

Brain MRI with diffusion-weighted and vascular imaging; spinal MRI if myelopathy is present.
Lumbar puncture with cell count, protein/glucose, VZV PCR, and paired serum/CSF anti-VZV IgG to demonstrate intrathecal synthesis.
Recognition that negative CSF VZV PCR does not exclude vasculopathy; intrathecal anti-VZV IgG may remain positive and can be more sensitive in protracted disease. The affected twin had pleocytosis and intrathecal VZV IgG despite negative PCR. (cartertimofte2018varicellazosterviruscns pages 3-4)
Baseline immune assessment: complete blood count/differential, quantitative immunoglobulins, lymphocyte subsets and proliferation, HIV testing, and evaluation for acquired immunosuppression. These tests were normal in the reported patients. (cartertimofte2018varicellazosterviruscns pages 4-5)

Genetic testing

Preferred approach: an inborn-error-of-immunity or severe viral-infection panel containing POLR3F, POLR3A, POLR3C, POLR3E, and relevant differential genes; alternatively WES/WGS.
Confirmation: Sanger or orthogonal confirmation, parental testing, segregation analysis, transcript-specific HGVS normalization, and current ClinVar/gnomAD review.
Functional support: PBMC stimulation with poly(dA:dT), measurement of IFN-β/type I or III IFN and inflammatory cytokines, and VZV replication/gene-expression assays. These remain specialized research tests rather than standardized clinical diagnostics. (cartertimofte2018varicellazosterviruscns pages 6-8, ansari2021primaryandacquired pages 5-6)
CMA, karyotype, FISH, mitochondrial testing, and repeat-expansion testing: low expected yield for an isolated missense disorder unless another phenotype suggests a structural or mitochondrial diagnosis.
RNA sequencing: not validated diagnostically for p.Arg50Trp; it may help evaluate splice or expression variants in unsolved cases.

Differential diagnosis

Important alternatives include acquired immunosuppression/HIV; hematologic malignancy or transplantation; anti-type-I-IFN autoantibodies; broad T/NK-cell defects such as GATA2, DOCK2, DOCK8, STK4, MAGT1, CXCR4, STAT1/STAT3/STAT5B-associated disorders; TLR3-pathway defects; other Pol III subunit defects; antiphospholipid or primary autoimmune vasculitis; atherosclerotic/dissection-related stroke; multiple sclerosis and other inflammatory myelitis; HSV encephalitis; and non-VZV infectious vasculopathies. Broader immunodeficiencies usually produce additional infections or characteristic immunologic abnormalities, whereas POLR3F disease was narrowly VZV-specific. (kennedy2021recentissuesin pages 8-9, ansari2021primaryandacquired pages 21-22, ansari2021primaryandacquired pages 24-25, ansari2021primaryandacquired pages 22-23)

No newborn or population screening is indicated. Once a familial pathogenic/likely pathogenic variant is established, cascade testing is reasonable with careful counseling about uncertain penetrance.

11. Outcome and prognosis

Disease-specific survival, mortality, life expectancy, and five- or ten-year outcomes are unknown. Both reported patients survived recurrent attacks and received prophylaxis, but ischemic lesions and recurring neurologic deficits indicate a risk of cumulative disability. One twin developed renewed symptoms and new white-matter lesions after stopping prophylaxis. (cartertimofte2018varicellazosterviruscns pages 6-8)

Prognosis probably depends on rapid antiviral treatment, recurrence prevention, lesion burden and location, presence of large-vessel vasculopathy or myelitis, and residual motor/cognitive deficits. These are clinically plausible factors rather than validated POLR3F prognostic models. No prognostic biomarker beyond virologic activity, CSF inflammation, and imaging has been validated.

12. Treatment

Acute disease

In the reported family, treatment included intravenous acyclovir 10 mg/kg every eight hours for 14 days and prednisolone 50 mg/day for 10 days. This targets viral replication and presumed arterial inflammation, respectively. (cartertimofte2018varicellazosterviruscns pages 3-4)

Suggested NCIt mappings include Acyclovir (NCIt drug concept), antiviral therapy, corticosteroid therapy, and supportive care. Renal function and hydration should be monitored during intravenous acyclovir; dose adjustment is required for kidney impairment. Steroids should not replace antiviral therapy and should be individualized because disease-specific controlled evidence is absent.

Long-term strategy

Both twins received suppressive acyclovir. Expert review recommends considering acyclovir prophylaxis after severe or recurrent CNS disease and age-appropriate varicella/zoster immunization in Pol III defects. The recurrence observed after prophylaxis discontinuation supports continued suppression in this family, but optimal drug, dose, and duration are unknown. (cartertimofte2018varicellazosterviruscns pages 6-8, cartertimofte2018rnapolymeraseiii pages 10-11)

Experimental and precision therapies

No POLR3F-specific interventional trial, gene therapy, gene editing, RNA therapy, hematopoietic stem-cell transplantation protocol, or adoptive VZV-specific T-cell trial was identified. Interferon therapy has been proposed more broadly for selected IFN-pathway defects, and IFN-α/IFN-γ inhibit VZV in vitro, but this is not established treatment for POLR3F deficiency. (ansari2021primaryandacquired pages 10-11)

A rational current algorithm is: suspected VZV CNS disease → collect CSF and imaging promptly without delaying IV acyclovir → consider adjunct corticosteroid for vasculopathy → confirm intrathecal VZV immunity/PCR → investigate immune and genetic causes → institute individualized long-term antiviral suppression and rehabilitation.

13. Prevention

Primary prevention

Preventing primary VZV infection through routine varicella vaccination is biologically attractive, but the safety and efficacy of live-attenuated varicella vaccine in a known POLR3F carrier have not been studied. Decisions should be made with clinical immunology and infectious-disease specialists after assessing immune competence. Expert review also advocates adult zoster vaccination, especially a non-live recombinant subunit vaccine, although direct POLR3F data are unavailable. (cartertimofte2018rnapolymeraseiii pages 10-11)

Secondary and tertiary prevention

Educate carriers to seek urgent care for headache, focal deficits, altered consciousness, myelopathic symptoms, or zoster-associated neurologic symptoms.
Use rapid CSF/imaging evaluation and early antiviral treatment.
Consider long-term acyclovir/valacyclovir suppression after recurrent CNS disease.
Monitor renal toxicity and antiviral adherence.
Use physical, occupational, speech, visual, or neuropsychological rehabilitation according to residual deficits.
Offer cascade genetic testing and counseling to adult relatives once variant pathogenicity is clinically accepted.

Prenatal or preimplantation testing is technically possible for a known familial variant, but uncertain penetrance and a potentially preventable/treatable infectious phenotype require nuanced counseling. No population carrier-screening program is justified.

14. Other species and natural disease

VZV is highly human-restricted; no naturally occurring veterinary counterpart of human POLR3F-specific VZV immunodeficiency was identified. Therefore, breed ontology entries, veterinary prevalence, zoonotic transmission, and natural cross-species disease are not applicable.

Simian varicella virus in rhesus macaques resembles human primary and reactivated VZV disease and has demonstrated an important role for CD4 T-cell immunity, but it is an analog infection rather than a natural POLR3F-deficiency model. Small-animal VZV inoculation can establish ganglionic infection without faithfully reproducing human rash or the full neurologic syndrome. Human tissue xenografts in SCID mice and simian varicella models are useful for VZV neurotropism, latency, and immunity research. These systems do not yet recapitulate the human POLR3F p.Arg50Trp genotype. (cartertimofte2018rnapolymeraseiii pages 10-11)

POLR3F and the Pol III machinery are evolutionarily conserved, but specific ortholog identifiers and a naturally occurring orthologous animal syndrome were not established by the retrieved evidence.

15. Model organisms and experimental models

Available models

Patient PBMCs: the most disease-specific model; they reproduce deficient poly(dA:dT)-induced cytokine responses and increased VZV replication. Strength: direct human genotype–phenotype relevance. Limitation: mixed circulating cells do not reproduce neurons, ganglia, cerebral arteries, or tissue-resident immunity. (cartertimofte2018varicellazosterviruscns pages 6-8, ansari2021primaryandacquired pages 5-6)
Recombinant/expression assays: mutant POLR3F expression and solubility can be compared with wild type. Strength: tests protein stability; limitation: does not capture the intact tissue response. (cartertimofte2018varicellazosterviruscns pages 4-5)
SCID-human xenografts: human skin or neural tissue implanted in immunodeficient mice supports VZV pathogenesis studies. Strength: human-tissue tropism; limitation: lacks an intact human immune system and has not been engineered for p.Arg50Trp.
Rhesus macaque/simian varicella virus: reproduces key features of primary infection, latency, and reactivation. Strength: intact primate immunity; limitation: different virus and no reported POLR3F disease genotype.
Standard small animals: limited because human VZV is species-restricted and generally fails to reproduce the complete human phenotype.

Needed next-generation models

Priority models include CRISPR knock-in of POLR3F p.Arg50Trp in human iPSCs differentiated into neurons, microglia, astrocytes, and cerebral endothelial cells; vascular organoids combining these cell types; isogenic rescue lines; and a conditional knock-in mammalian model challenged with an appropriate alphaherpesvirus. Single-cell transcriptomics and spatial profiling across infected neurovascular units could determine which cells fail to mount Pol III–RIG-I–MAVS interferon responses.

Recent developments, expert assessment, and knowledge gaps

Research in 2023 broadened host-genetic investigation of severe alphaherpesvirus disease: WES of 17 patients with HSV- or VZV-induced acute retinal necrosis identified 50 potentially disease-associated variants in 16/17, concentrated in innate/adaptive immunity, autophagy, and apoptosis pathways. This does not establish new POLR3F cases, but it supports systematic genomic evaluation of unusually severe, tissue-restricted VZV disease. The study was published October 2023, DOI: 10.3389/fnmol.2023.1253040.

The most defensible current expert interpretation is that Pol III has a nonredundant role in human VZV defense, but several central questions remain unresolved: the decisive in-vivo cell type; whether cytosolic viral-DNA transcription or nuclear RNA-derived signaling predominates; how POLR3F controls neuronal latency and reactivation; whether p.Arg50Trp is fully penetrant; and which prophylactic regimen is optimal. Reviews explicitly note that POLR3-mutant patients have a narrow VZV phenotype and propose vaccination and antiviral prophylaxis, while acknowledging the absence of disease-specific trials. (cartertimofte2018rnapolymeraseiii pages 10-11)

Accordingly, the knowledge-base entry should mark the gene–disease relationship as supported by one segregating family plus functional human-cell evidence, not as a mature disorder with established epidemiology or consensus guidelines. Variant classification, MONDO/OMIM identifiers, transcript HGVS, and current population frequency should be rechecked directly in ClinVar, ClinGen, OMIM, HGNC, and gnomAD before production release.

References

(cartertimofte2018varicellazosterviruscns pages 6-8): Madalina E. Carter-Timofte, Anders F. Hansen, Maibritt Mardahl, Sébastien Fribourg, Franck Rapaport, Shen-Ying Zhang, Jean-Laurent Casanova, Søren R. Paludan, Mette Christiansen, Carsten S. Larsen, and Trine H. Mogensen. Varicella-zoster virus cns vasculitis and rna polymerase iii gene mutation in identical twins. Neurology Neuroimmunology & Neuroinflammation, Nov 2018. URL: https://doi.org/10.1212/nxi.0000000000000500, doi:10.1212/nxi.0000000000000500. This article has 66 citations.
(cartertimofte2018varicellazosterviruscns pages 4-5): Madalina E. Carter-Timofte, Anders F. Hansen, Maibritt Mardahl, Sébastien Fribourg, Franck Rapaport, Shen-Ying Zhang, Jean-Laurent Casanova, Søren R. Paludan, Mette Christiansen, Carsten S. Larsen, and Trine H. Mogensen. Varicella-zoster virus cns vasculitis and rna polymerase iii gene mutation in identical twins. Neurology Neuroimmunology & Neuroinflammation, Nov 2018. URL: https://doi.org/10.1212/nxi.0000000000000500, doi:10.1212/nxi.0000000000000500. This article has 66 citations.
(ansari2021primaryandacquired pages 5-6): Rahila Ansari, Lindsey B Rosen, Andrea Lisco, Don Gilden, Steven M Holland, Christa S Zerbe, Robert A Bonomo, and Jeffrey I Cohen. Primary and acquired immunodeficiencies associated with severe varicella-zoster infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 73:e2705-e2712, Aug 2021. URL: https://doi.org/10.1093/cid/ciaa1274, doi:10.1093/cid/ciaa1274. This article has 59 citations.
(cartertimofte2018rnapolymeraseiii pages 6-8): Madalina E. Carter-Timofte, Søren R. Paludan, and Trine H. Mogensen. Rna polymerase iii as a gatekeeper to prevent severe vzv infections. Trends in molecular medicine, 24 10:904-915, Oct 2018. URL: https://doi.org/10.1016/j.molmed.2018.07.009, doi:10.1016/j.molmed.2018.07.009. This article has 52 citations and is from a domain leading peer-reviewed journal.
(cartertimofte2018varicellazosterviruscns pages 3-4): Madalina E. Carter-Timofte, Anders F. Hansen, Maibritt Mardahl, Sébastien Fribourg, Franck Rapaport, Shen-Ying Zhang, Jean-Laurent Casanova, Søren R. Paludan, Mette Christiansen, Carsten S. Larsen, and Trine H. Mogensen. Varicella-zoster virus cns vasculitis and rna polymerase iii gene mutation in identical twins. Neurology Neuroimmunology & Neuroinflammation, Nov 2018. URL: https://doi.org/10.1212/nxi.0000000000000500, doi:10.1212/nxi.0000000000000500. This article has 66 citations.
(lata2021rnapolymeraseiii pages 21-22): Elisabeth Lata, Karine Choquet, Francis Sagliocco, Bernard Brais, Geneviève Bernard, and Martin Teichmann. Rna polymerase iii subunit mutations in genetic diseases. Frontiers in Molecular Biosciences, Jul 2021. URL: https://doi.org/10.3389/fmolb.2021.696438, doi:10.3389/fmolb.2021.696438. This article has 86 citations.
(cartertimofte2018rnapolymeraseiii pages 4-6): Madalina E. Carter-Timofte, Søren R. Paludan, and Trine H. Mogensen. Rna polymerase iii as a gatekeeper to prevent severe vzv infections. Trends in molecular medicine, 24 10:904-915, Oct 2018. URL: https://doi.org/10.1016/j.molmed.2018.07.009, doi:10.1016/j.molmed.2018.07.009. This article has 52 citations and is from a domain leading peer-reviewed journal.
(cartertimofte2018rnapolymeraseiii pages 10-11): Madalina E. Carter-Timofte, Søren R. Paludan, and Trine H. Mogensen. Rna polymerase iii as a gatekeeper to prevent severe vzv infections. Trends in molecular medicine, 24 10:904-915, Oct 2018. URL: https://doi.org/10.1016/j.molmed.2018.07.009, doi:10.1016/j.molmed.2018.07.009. This article has 52 citations and is from a domain leading peer-reviewed journal.
(kennedy2021recentissuesin pages 8-9): Peter Kennedy, Trine Mogensen, and Randall Cohrs. Recent issues in varicella-zoster virus latency. Viruses, 13:2018, Oct 2021. URL: https://doi.org/10.3390/v13102018, doi:10.3390/v13102018. This article has 83 citations.
(cartertimofte2018varicellazosterviruscns pages 1-2): Madalina E. Carter-Timofte, Anders F. Hansen, Maibritt Mardahl, Sébastien Fribourg, Franck Rapaport, Shen-Ying Zhang, Jean-Laurent Casanova, Søren R. Paludan, Mette Christiansen, Carsten S. Larsen, and Trine H. Mogensen. Varicella-zoster virus cns vasculitis and rna polymerase iii gene mutation in identical twins. Neurology Neuroimmunology & Neuroinflammation, Nov 2018. URL: https://doi.org/10.1212/nxi.0000000000000500, doi:10.1212/nxi.0000000000000500. This article has 66 citations.
(cartertimofte2018rnapolymeraseiii pages 1-2): Madalina E. Carter-Timofte, Søren R. Paludan, and Trine H. Mogensen. Rna polymerase iii as a gatekeeper to prevent severe vzv infections. Trends in molecular medicine, 24 10:904-915, Oct 2018. URL: https://doi.org/10.1016/j.molmed.2018.07.009, doi:10.1016/j.molmed.2018.07.009. This article has 52 citations and is from a domain leading peer-reviewed journal.
(lata2021rnapolymeraseiii pages 10-11): Elisabeth Lata, Karine Choquet, Francis Sagliocco, Bernard Brais, Geneviève Bernard, and Martin Teichmann. Rna polymerase iii subunit mutations in genetic diseases. Frontiers in Molecular Biosciences, Jul 2021. URL: https://doi.org/10.3389/fmolb.2021.696438, doi:10.3389/fmolb.2021.696438. This article has 86 citations.
(ansari2021primaryandacquired pages 21-22): Rahila Ansari, Lindsey B Rosen, Andrea Lisco, Don Gilden, Steven M Holland, Christa S Zerbe, Robert A Bonomo, and Jeffrey I Cohen. Primary and acquired immunodeficiencies associated with severe varicella-zoster infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 73:e2705-e2712, Aug 2021. URL: https://doi.org/10.1093/cid/ciaa1274, doi:10.1093/cid/ciaa1274. This article has 59 citations.
(ansari2021primaryandacquired pages 24-25): Rahila Ansari, Lindsey B Rosen, Andrea Lisco, Don Gilden, Steven M Holland, Christa S Zerbe, Robert A Bonomo, and Jeffrey I Cohen. Primary and acquired immunodeficiencies associated with severe varicella-zoster infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 73:e2705-e2712, Aug 2021. URL: https://doi.org/10.1093/cid/ciaa1274, doi:10.1093/cid/ciaa1274. This article has 59 citations.
(ansari2021primaryandacquired pages 22-23): Rahila Ansari, Lindsey B Rosen, Andrea Lisco, Don Gilden, Steven M Holland, Christa S Zerbe, Robert A Bonomo, and Jeffrey I Cohen. Primary and acquired immunodeficiencies associated with severe varicella-zoster infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 73:e2705-e2712, Aug 2021. URL: https://doi.org/10.1093/cid/ciaa1274, doi:10.1093/cid/ciaa1274. This article has 59 citations.
(ansari2021primaryandacquired pages 10-11): Rahila Ansari, Lindsey B Rosen, Andrea Lisco, Don Gilden, Steven M Holland, Christa S Zerbe, Robert A Bonomo, and Jeffrey I Cohen. Primary and acquired immunodeficiencies associated with severe varicella-zoster infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 73:e2705-e2712, Aug 2021. URL: https://doi.org/10.1093/cid/ciaa1274, doi:10.1093/cid/ciaa1274. This article has 59 citations.

Artifacts

Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	8
Resolved	8
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	8
On topic	3
Off topic	0

All extracted references resolved successfully.

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Infectious Agent

Experimental Models

Source YAML

References & Deep Research

References

Deep Research

Immunodeficiency 101 (Varicella-Zoster Virus–Specific): Disease Characteristics Report

Executive summary and evidence limitations

1. Disease information

Definition

Names and identifiers

Foundational evidence

2. Etiology, risk factors, and protective factors

Causal factors

Genetic risk

Environmental and acquired modifiers

Protective factors and gene–environment interaction

3. Phenotypes

4. Genetic and molecular information

Causal gene and variant

Broader allelic and mechanistic context

5. Environmental and infectious information

6. Mechanism and pathophysiology

Causal chain

Cells, tissues, and ontology suggestions

Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

Inheritance

Epidemiology

10. Diagnostics

Clinical recognition

Acute VZV/CNS evaluation

Genetic testing

Differential diagnosis

11. Outcome and prognosis

12. Treatment

Acute disease

Long-term strategy

Experimental and precision therapies

13. Prevention

Primary prevention

Secondary and tertiary prevention

14. Other species and natural disease

15. Model organisms and experimental models

Available models

Needed next-generation models

Recent developments, expert assessment, and knowledge gaps

Artifacts

Reference Validation