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

(2015) NEUROLOGY. 85(24). p.2116-2125
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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.
Keywords
AMYOTROPHIC-LATERAL-SCLEROSIS, BINDING KINASE 1, LOBAR DEGENERATION, REPEAT EXPANSION, HEXANUCLEOTIDE REPEAT, CRYSTAL-STRUCTURE, SQSTM1, MUTATIONS, C9ORF72, OPTINEURIN, ALS

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Citation

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Chicago
Gijselinck, Ilse, Sara Van Mossevelde, Julie van der Zee, Anne Sieben, Stephanie Philtjens, Bavo Heeman, Sebastiaan Engelborghs, et al. 2015. “Loss of TBK1 Is a Frequent Cause of Frontotemporal Dementia in a Belgian Cohort.” Neurology 85 (24): 2116–2125.
APA
Gijselinck, Ilse, Van Mossevelde, S., van der Zee, J., Sieben, A., Philtjens, S., Heeman, B., Engelborghs, S., et al. (2015). Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. NEUROLOGY, 85(24), 2116–2125.
Vancouver
1.
Gijselinck I, Van Mossevelde S, van der Zee J, Sieben A, Philtjens S, Heeman B, et al. Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort. NEUROLOGY. 2015;85(24):2116–25.
MLA
Gijselinck, Ilse, Sara Van Mossevelde, Julie van der Zee, et al. “Loss of TBK1 Is a Frequent Cause of Frontotemporal Dementia in a Belgian Cohort.” NEUROLOGY 85.24 (2015): 2116–2125. Print.
@article{8547526,
  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.},
  author       = {Gijselinck, Ilse and Van Mossevelde, Sara and van der Zee, Julie and Sieben, Anne and Philtjens, Stephanie and Heeman, Bavo and Engelborghs, Sebastiaan and Vandenbulcke, Mathieu and De Baets, Greet and Baumer, Veerle and Cuijt, Ivy and Van den Broeck, Marleen and Peeters, Karin and Mattheijssens, Maria and Rousseau, Frederic and Vandenberghe, Rik and De Jonghe, Peter and Cras, Patrick and De Deyn, Peter P and Martin, Jean-Jacques and Cruts, Marc and Van Broeckhoven, Christine and BELNEU consortium, the and De Bleecker, Jan and Santens, Patrick and Dermaut, Bart},
  issn         = {0028-3878},
  journal      = {NEUROLOGY},
  language     = {eng},
  number       = {24},
  pages        = {2116--2125},
  title        = {Loss of TBK1 is a frequent cause of frontotemporal dementia in a Belgian cohort},
  url          = {http://dx.doi.org/10.1212/WNL.0000000000002220},
  volume       = {85},
  year         = {2015},
}

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