TBK1 – Amyotrophic Lateral Sclerosis

TANK-binding kinase 1 (TBK1) haploinsufficiency is a well-established cause of autosomal dominant amyotrophic lateral sclerosis (ALS). Initial exome sequencing in 252 familial ALS cases uncovered eight loss-of-function (LoF) TBK1 variants segregating with disease across 13 pedigrees (LOD 4.6), with no enrichment in 1,010 sporadic ALS or 650 controls, establishing a definitive gene-disease link (PMID:25803835).

Subsequent multi-ethnic case series have confirmed TBK1 LoF variants in 0.4–3.6% of ALS patients, including c.1305T>A (p.Tyr435Ter) and c.1330C>T (p.Arg444Ter), with replication in Belgian, Chinese, Australian, Sardinian, Japanese, Taiwanese, and Italian cohorts (PMID:26581300; PMID:26350399; PMID:27156075; PMID:29398122). Segregation of these heterozygous variants with ALS in multiple families and absence from large control datasets support strong genetic evidence.

The inheritance is autosomal dominant with incomplete penetrance. Segregation analyses documented at least 19 additional affected relatives carrying TBK1 variants. Case series encompass over 150 probands with diverse LoF (nonsense, frameshift, splice site) and a minority of likely damaging missense alleles.

Functionally, TBK1 LoF variants lead to reduced transcript via nonsense-mediated decay, diminished protein expression, loss of kinase activity towards substrates IRF3 and optineurin, and impaired autophagy adaptor binding. Cellular models demonstrate altered K63-ubiquitination profiles in patient fibroblasts, consistent with a haploinsufficiency mechanism (PMID:34800171; PMID:27892983).

No convincing reports dispute TBK1’s role in ALS. The weight of genetic and experimental data surpasses ClinGen caps, warranting a definitive classification.

Key Take-home: TBK1 sequencing should be included in genetic panels for ALS, as LoF variants have definitive clinical validity and direct implications for diagnosis, family counseling, and potential therapeutic strategies.

References

• Nature neuroscience • 2015 • Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia PMID:25803835
• Neurobiology of aging • 2015 • Novel TBK1 truncating mutation in a familial amyotrophic lateral sclerosis patient of Chinese origin PMID:26350399
• Neurology • 2015 • Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort PMID:26581300
• Journal of neurology • 2022 • TBK1 haploinsufficiency results in changes in the K63-ubiquitination profiles in brain and fibroblasts from affected and presymptomatic mutation carriers PMID:34800171
• JAMA neurology • 2017 • Association of Mutations in TBK1 With Sporadic and Familial Amyotrophic Lateral Sclerosis and Frontotemporal Dementia PMID:27892983

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