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TBK1 encodes TANK-binding kinase 1, a serine/threonine kinase involved in innate immunity and neurodegeneration. Heterozygous loss-of-function (LoF) variants in TBK1 have been implicated in frontotemporal dementia with motor neuron disease (FTD-ALS), supporting a pathogenic continuum between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) (PMID:26581300). This summary evaluates the clinical validity of TBK1 in FTD-ALS, genetic evidence from a Belgian cohort, and functional data underpinning haploinsufficiency.
In a sequencing study of 482 FTD/FTD-ALS and 147 ALS patients, 11 unrelated carriers of heterozygous LoF TBK1 mutations were identified, yielding an overall mutation frequency of 1.7% (11/629) in the combined cohort, 4.5% in FTD-ALS (1/22), 1.1% in FTD (5/460), and 3.4% in ALS (5/147) (PMID:26581300). Variants included nonsense, frameshift, and splice-site changes consistent with a haploinsufficiency mechanism. Representative coding variant: c.1305T>A (p.Tyr435Ter).
Autosomal dominant inheritance is established for TBK1 LoF alleles, with segregation demonstrated in the extended Belgian FTD-ALS family DR158, in which the p.Glu643del mutation tracked with disease across six affected relatives (PMID:26581300). Across cohorts, segregation data and absence in controls reinforce pathogenicity. Overall, segregation supports at least 6 affected relatives.
Functional analyses of TBK1 mutation carriers show reduced TBK1 transcript and protein levels in blood and brain, impaired kinase activity, and concordant TDP-43 pathology in neural tissues (PMID:26581300). Loss of TBK1 disrupts autophagy adaptor interactions and IRF3 phosphorylation, linking neuroinflammation and proteinopathy.
Collectively, genetic and experimental findings delineate a mechanism of TBK1 haploinsufficiency leading to neuronal degeneration in FTD-ALS. The spectrum of LoF variants, autosomal dominant inheritance, segregation in families, and consistent functional impairment justify a Strong gene–disease association.
Key Take-home: Heterozygous TBK1 LoF variants confer a strong, autosomal dominant risk for frontotemporal dementia with motor neuron disease via haploinsufficiency, informing genetic diagnosis and therapeutic targeting.
Gene–Disease AssociationStrong1.7% LoF mutation frequency in 629 FTD/ALS cases; 4.5% in FTD-ALS; segregation in family DR158; concordant functional data Genetic EvidenceStrong11 heterozygous LoF variants across FTD, ALS, and FTD-ALS; autosomal dominant inheritance; segregation Functional EvidenceModerateTranscript/protein loss and kinase impairment; TDP-43 pathology concordance |