Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort

Abstract

Objective:To assess the genetic contribution of TBK1, a gene implicated in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and FTD-ALS, in Belgian FTD and ALS patient cohorts containing a significant part of genetically unresolved patients.Methods:We sequenced TBK1 in a hospital-based cohort of 482 unrelated patients with FTD and FTD-ALS and 147 patients with ALS and an extended Belgian FTD-ALS family DR158. We followed up mutation carriers by segregation studies, transcript and protein expression analysis, and immunohistochemistry.Results:We identified 11 patients carrying a loss-of-function (LOF) mutation resulting in an overall mutation frequency of 1.7% (11/629), 1.1% in patients with FTD (5/460), 3.4% in patients with ALS (5/147), and 4.5% in patients with FTD-ALS (1/22). We found 1 LOF mutation, p.Glu643del, in 6 unrelated patients segregating with disease in family DR158. Of 2 mutation carriers, brain and spinal cord was characterized by TDP-43-positive pathology. The LOF mutations including the p.Glu643del mutation led to loss of transcript or protein in blood and brain.Conclusions:TBK1 LOF mutations are the third most frequent cause of clinical FTD in the Belgian clinically based patient cohort, after C9orf72 and GRN, and the second most common cause of clinical ALS after C9orf72. These findings reinforce that FTD and ALS belong to the same disease continuum.

Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation

“…Recently, mutations in TBK1 were found in 4.5% of subjects with concomitant ALS and FTD from Belgium24 and the same frequency was reported in an extended European cohort 18. This frequency reached 10.8% in an independent study performed in French cases 25.…”

Screening of the TBK1 gene in familial and sporadic amyotrophic lateral sclerosis patients of Chinese origin

“…Thus, mutation L62P and I334T may be causative for ALS, and further functional studies are warranted to draw firm conclusions. Previous studies reveal that TBK1 mutations may be associated with ALS, ALS-FTLD and FTD (5,9,10). In our study, neither patient with a TBK1 mutation developed cognitive impairment 48 and 26 months after disease onset, respectively.…”

Human TBK1: A Gatekeeper of Neuroinflammation

“…Research in genetics has experienced an increased pace of discovery owing to the advances in sequencing technologies, which have begun to reveal a number of new genetic etiologies underlying various diseases. The recent discoveries of TBK1 heterozygous mutations in multiple human diseases has demonstrated the non-redundant role of this multifaceted protein in the CNS in particular [6–11] (Figure 1). Here, we review the pleiotropic role of TBK1 in light of new discoveries of human germline TBK1 mutations underlying neuroinflammatory diseases, including herpes simplex encephalitis (HSE), amyotrophic lateral sclerosis (ALS), frontal temporal lobe dementia (FTD) and normal tension glaucoma (NTG).…”