TBK1

Chr 12ADAR

TANK binding kinase 1

Also known as: AIARV, FTDALS4, IIAE8, NAK, T2K

NCBI Gene: 29110 ENSG00000183735 UniProt: Q9UHD2 OMIM: 604834

TBK1 encodes a kinase that phosphorylates IκB proteins to activate NF-κB signaling and mediates antiviral innate immunity responses. Mutations cause autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis 4, autosomal recessive autoinflammation with arthritis and vasculitis, and susceptibility to herpes-specific acute encephalopathy. The pathogenic mechanism involves disrupted NF-κB activation and impaired antiviral immunity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The NF-kappa-B (NFKB) complex of proteins is inhibited by I-kappa-B (IKB) proteins, which inactivate NFKB by trapping it in the cytoplasm. Phosphorylation of serine residues on the IKB proteins by IKB kinases marks them for destruction via the ubiquitination pathway, thereby allowing activation and nuclear translocation of the NFKB complex. The protein encoded by this gene is similar to IKB kinases and can mediate NFKB activation in response to certain growth factors. The protein is also an important kinase for antiviral innate immunity response. [provided by RefSeq, Sep 2021]

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.423 OMIM phenotypes

Clinical Summary— TBK1

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Gene-Disease Validity (ClinGen)

frontotemporal dementia and/or amyotrophic lateral sclerosis 4 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.42LOEUF

pLI 0.075

Z-score 4.55

OE 0.25 (0.16–0.42)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.93Z-score

OE missense 0.72 (0.65–0.79)

267 obs / 372.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.16–0.42)

0≤0.351.4

Missense OE?0.72 (0.65–0.79)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 11 / 43.3Missense obs/exp: 267 / 372.0Syn Z: -0.06

This gene — mechanism propensity

0.5869th %ile

GOF

0.6345th %ile

LOF

0.4038th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

LOF1 literature citation · LOEUF 0.42

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNIn vitro functional expression assays showed that the G159A mutation had a dominant-negative effect, whereas the D50A mutation resulted in haploinsufficiency.1

GOFGain-of-function of TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE.2

LOFHaploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References