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Journal article
Novel Mutations in TARDBP (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis
PLoS genetics, v 4(9), e1000193
19 Sep 2008
PMID: 18802454
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Abstract
The TAR DNA-binding protein 43 (TDP-43) has been identified as the major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U), defining a novel class of neurodegenerative conditions: the TDP-43 proteinopathies. The first pathogenic mutations in the gene encoding TDP-43 (TARDBP) were recently reported in familial and sporadic ALS patients, supporting a direct role for TDP-43 in neurodegeneration. In this study, we report the identification and functional analyses of two novel and one known mutation in TARDBP that we identified as a result of extensive mutation analyses in a cohort of 296 patients with variable neurodegenerative diseases associated with TDP-43 histopathology. Three different heterozygous missense mutations in exon 6 of TARDBP (p.M337V, p.N345K, and p.I383V) were identified in the analysis of 92 familial ALS patients (3.3%), while no mutations were detected in 24 patients with sporadic ALS or 180 patients with other TDP-43–positive neurodegenerative diseases. The presence of p.M337V, p.N345K, and p.I383V was excluded in 825 controls and 652 additional sporadic ALS patients. All three mutations affect highly conserved amino acid residues in the C-terminal part of TDP-43 known to be involved in protein-protein interactions. Biochemical analysis of TDP-43 in ALS patient cell lines revealed a substantial increase in caspase cleaved fragments, including the ∼25 kDa fragment, compared to control cell lines. Our findings support TARDBP mutations as a cause of ALS. Based on the specific C-terminal location of the mutations and the accumulation of a smaller C-terminal fragment, we speculate that TARDBP mutations may cause a toxic gain of function through novel protein interactions or intracellular accumulation of TDP-43 fragments leading to apoptosis. The abnormal accumulation of disease proteins in neuronal cells of the brain is a characteristic feature of many neurodegenerative diseases. Rare mutations in the genes that encode the accumulating proteins have been identified in these disorders and are crucial for the development of cell and animal models used to study neurodegeneration. Recently, the TAR DNA-binding protein 43 (TDP-43) was identified as the disease accumulating protein in patients with frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS). TDP-43 was also found in the brains of 20–30% of patients with Alzheimer's disease (AD). Here, we evaluated whether mutations in TDP-43 cause disease in a cohort of 296 patients presenting with FTLD, ALS or AD. We identified three missense mutations in three out of 92 familial ALS patients (3.3%), and no mutations in AD or FTLD patients. All the identified mutations clustered in exon 6, which codes for a highly conserved region in the C-terminal part of the TDP-43 protein, which is known to be involved in the interaction of TDP-43 with other proteins. We conclude that mutations in TDP-43 are a rare cause of familial ALS, but so far are not found in other neurodegenerative diseases.
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Details
- Title
- Novel Mutations in TARDBP (TDP-43) in Patients with Familial Amyotrophic Lateral Sclerosis
- Creators
- Nicola J. Rutherford - Mayo Clinic in FloridaYong-Jie Zhang - Mayo Clinic in FloridaMatt Baker - Mayo Clinic in FloridaJennifer M. Gass - Mayo Clinic in FloridaNiCole A. Finch - Mayo Clinic in FloridaYa-Fei Xu - Mayo Clinic in FloridaHeather Stewart - Vancouver General HospitalBrendan J. Kelley - Mayo ClinicKaren Kuntz - Mayo ClinicRichard J. P. Crook - Mayo Clinic in FloridaJemeen Sreedharan - King's College LondonCaroline Vance - King's College LondonEric Sorenson - Mayo ClinicCarol Lippa - Drexel UniversityEileen H. Bigio - Northwestern UniversityDaniel H. Geschwind - University of California, Los AngelesDavid S. Knopman - Mayo ClinicHiroshi Mitsumoto - Columbia UniversityRonald C. Petersen - Mayo ClinicNeil R. Cashman - University of British ColumbiaMike Hutton - Mayo Clinic in FloridaChristopher E. Shaw - King's College LondonKevin B. Boylan - Mayo Clinic in FloridaBradley Boeve - Mayo ClinicNeill R. Graff-Radford - Mayo Clinic in FloridaZbigniew K. Wszolek - Mayo Clinic in FloridaRichard J. Caselli - Mayo Clinic in ArizonaDennis W. Dickson - Mayo Clinic in FloridaIan R. Mackenzie - University of British ColumbiaLeonard Petrucelli - Mayo Clinic in FloridaRosa Rademakers - Mayo Clinic in Florida
- Publication Details
- PLoS genetics, v 4(9), e1000193
- Publisher
- Public Library of Science
- Number of pages
- 8
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Neurology
- Web of Science ID
- WOS:000260411200011
- Scopus ID
- 2-s2.0-52949094629
- Other Identifier
- 991019312454804721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Genetics & Heredity