TY - JOUR
T1 - TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology
T2 - a genetic and histopathological analysis
AU - Van Deerlin, Vivianna M.
AU - Leverenz, James B.
AU - Bekris, Lynn M.
AU - Bird, Thomas D.
AU - Yuan, Wuxing
AU - Elman, Lauren B.
AU - Clay, Dana
AU - Wood, Elisabeth Mc Carty
AU - Chen-Plotkin, Alice S.
AU - Martinez-Lage, Maria
AU - Steinbart, Ellen
AU - McCluskey, Leo
AU - Grossman, Murray
AU - Neumann, Manuela
AU - Wu, I. Lin
AU - Yang, Wei Shiung
AU - Kalb, Robert
AU - Galasko, Douglas R.
AU - Montine, Thomas J.
AU - Trojanowski, John Q.
AU - Lee, Virginia M.Y.
AU - Schellenberg, Gerard D.
AU - Yu, Chang En
N1 - Funding Information:
We thank Hillary Lipe for clinical assistance, and we extend our appreciation to the patients and families who made this research possible. This work was funded by the National Institutes of Health (AG10124, AG17586, AG005136, AG14382), the Department of Veterans Affairs, the Friedrich-Baur Stiftung (0017/2007), the US Public Health Service, the ALS Association, and a fellowship from Fundació ‘la Caixa’, Spain.
PY - 2008/5
Y1 - 2008/5
N2 - Background: TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1). Methods: TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families. Findings: We identified two variants in TARDBP, which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available. Interpretation: The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein-protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U. Funding: National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació 'la Caixa'.
AB - Background: TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1). Methods: TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identified variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families. Findings: We identified two variants in TARDBP, which would encode Gly290Ala and Gly298Ser forms of TDP-43, in two kindreds with familial ALS. The variants seem to be pathogenic because they co-segregated with disease in both families, were absent in controls, and were associated with TDP-43 neuropathology in both members of one of these families for whom CNS tissue was available. Interpretation: The Gly290Ala and Gly298Ser mutations are located in the glycine-rich domain of TDP-43, which regulates gene expression and mediates protein-protein interactions such as those with heterogeneous ribonucleoproteins. Owing to the varied and important cellular functions of TDP-43, these mutations might cause neurodegeneration through both gains and losses of function. The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U. Funding: National Institutes of Health (AG10124, AG17586, AG005136-22, PO1 AG14382), Department of Veterans Affairs, Friedrich-Baur Stiftung (0017/2007), US Public Health Service, ALS Association, and Fundació 'la Caixa'.
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U2 - 10.1016/S1474-4422(08)70071-1
DO - 10.1016/S1474-4422(08)70071-1
M3 - Article
C2 - 18396105
AN - SCOPUS:41949100148
SN - 1474-4422
VL - 7
SP - 409
EP - 416
JO - The Lancet Neurology
JF - The Lancet Neurology
IS - 5
ER -