TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis
Journal
The Lancet Neurology
Journal Volume
7
Journal Issue
5
Pages
409-416
Date Issued
2008
Author(s)
Van Deerlin V.M.
Leverenz J.B.
Bekris L.M.
Bird T.D.
Yuan W.
Elman L.B.
Clay D.
Wood E.M.
Chen-Plotkin A.S.
Martinez-Lage M.
Steinbart E.
McCluskey L.
Grossman M.
Neumann M.
Wu I.-L.
Kalb R.
Galasko D.R.
Montine T.J.
Trojanowski J.Q.
Lee V.M.-Y.
Schellenberg G.D.
Yu C.-E.
Abstract
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 Fundaci? 'la Caixa'. ? 2008 Elsevier Ltd. All rights reserved.
Other Subjects
copper zinc superoxide dismutase; DNA binding protein; glycine; ribonucleoprotein; RNA binding protein; serine; TAR DNA binding protein; tdp 43 protein; unclassified drug; adult; aged; amyotrophic lateral sclerosis; article; cell function; controlled study; ethnicity; familial disease; family study; female; frontotemporal dementia; gene expression regulation; gene function; gene location; gene mutation; gene sequence; genetic analysis; genetic association; genetic screening; genetic variability; genotype; histopathology; human; human tissue; major clinical study; male; nerve degeneration; neuropathology; priority journal; protein defect; protein domain; protein protein interaction; single nucleotide polymorphism; Adolescent; Adult; Aged; Aged, 80 and over; Alanine; Amyotrophic Lateral Sclerosis; Brain; Child; Dementia; DNA Mutational Analysis; DNA-Binding Proteins; Family Health; Female; Glycine; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide; Serine; Ubiquitin
Type
journal article