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Neurobiol Aging. 2018 Sep;69:293.e9-293.e11. doi: 10.1016/j.neurobiolaging.2018.05.005. Epub 2018 May 23.

No supportive evidence for TIA1 gene mutations in a European cohort of ALS-FTD spectrum patients.

Author information

1
Neurodegenerative Brain Diseases Group, VIB-UAntwerp Center for Molecular Neurology, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
2
Neurodegenerative Brain Diseases Group, VIB-UAntwerp Center for Molecular Neurology, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital (UZA), Edegem, Belgium.
3
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital (UZA), Edegem, Belgium; Neurogenetics Group, VIB-UAntwerp Center for Molecular Neurology, Antwerp, Belgium.
4
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology and Memory Clinic, Hospital Network Antwerp (ZNA), Middelheim and Hoge Beuken, Antwerp, Belgium.
5
Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium; Department of Old Age Psychiatry and Memory Clinic, University Hospitals Leuven, Leuven, Belgium.
6
Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.
7
Department of Neurology, University Hospitals Leuven, Leuven, Belgium; Department of Neurosciences, Faculty of Medicine, KU Leuven, Leuven, Belgium; Laboratory of Neurobiology, Center for Brain and Disease Research, VIB, Leuven, Belgium.
8
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; Department of Neurology, Antwerp University Hospital (UZA), Edegem, Belgium.
9
Cyclotron Research Centre, University of Liege and Memory Clinic, CHU Liege, Belgium.
10
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany; Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
11
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Germany; Genome Biology of Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
12
Department of Neurology, Neuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Center for Networked Biomedical Research into Rare Diseases (CIBERER).
13
Department of Neurology, Memory Unit, Hospital de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain and Center for Networked Biomedical Research into Neurodegenerative Disorders (CIBERNED).
14
Centre for Neurodegenerative Disorders, Neurology Unit, Department of Clinical and Experimental Sciences, University of Brescia, Italy.
15
Fundació per la Recerca Biomèdica i Social Mútua de Terrassa, Terrassa, Barcelona, Spain; Memory Disorders Unit, Department of Neurology, University Hospital Mutua de Terrassa, Terrassa, Barcelona, Spain.
16
Neurological Tissue Bank of the Biobanc, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
17
Alzheimer's Disease and Other Cognitive Disorders Unit, Neurology Department, Hospital Clínic, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
18
Department of Pathology and Molecular Medicine, Thomayer Hospital, Prague, Czech Republic; Department of Pathology, Third Medical Faculty, Charles University, Prague, Czech Republic.
19
Department of Neuroscience, Psychology, Drug Research and Child Health - University of Florence, Florence, Italy.
20
Department of Neuroscience, Psychology, Drug Research and Child Health - University of Florence, Florence, Italy; IRCCS Don Gnocchi, Florence, Italy.
21
Faculty of Medicine, University of Lisbon, Portugal.
22
NeuroRARE Centre for Rare and Genetic Neurological & Neuromuscular Diseases & Neurogenetics, Athens, Greece.
23
Department of Psychiatry and Psychotherapy, Technische Universität München, München, Germany.
24
Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
25
Neurodegenerative Brain Diseases Group, VIB-UAntwerp Center for Molecular Neurology, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address: christine.vanbroeckhoven@uantwerpen.vib.be.
26
Neurodegenerative Brain Diseases Group, VIB-UAntwerp Center for Molecular Neurology, Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium. Electronic address: julie.vanderzee@uantwerpen.vib.be.

Abstract

We evaluated the genetic contribution of the T cell-restricted intracellular antigen-1 gene (TIA1) in a European cohort of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients. Exonic resequencing of TIA1 in 1120 patients (693 FTD, 341 ALS, 86 FTD-ALS) and 1039 controls identified in total 5 rare heterozygous missense variants, affecting the TIA1 low-complexity domain (LCD). Only 1 missense variant, p.Met290Thr, identified in a familial FTD patient with disease onset at 64 years, was absent from controls yet received a combined annotation-dependent depletion score of 11.42. By contrast, 3 of the 4 variants also detected in unaffected controls, p.Val294Glu, p.Gln318Arg, and p.Ala381Thr, had combined annotation-dependent depletion scores greater than 20. Our findings in a large European patient-control series indicate that variants in TIA1 are not a common cause of ALS and FTD. The observation of recurring TIA1 missense variants in unaffected individuals lead us to conclude that the exact genetic contribution of TIA1 to ALS and FTD pathogenesis remains to be further elucidated.

KEYWORDS:

Amyotrophic lateral sclerosis (ALS); Frontotemporal dementia (FTD); T cell–restricted intracellular antigen-1 gene (TIA1); TAR DNA-Binding protein 43 (TDP-43)

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