Neuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS

doi:10.1016/j.neurobiolaging.2007.11.002

Neurobiology of Aging

Volume 30, Issue 8, August 2009, Pages 1329-1331

https://doi.org/10.1016/j.neurobiolaging.2007.11.002 Get rights and content

Abstract

The nuclear TAR DNA binding protein (TDP-43) is deposited in ubiquitin-positive inclusions in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), two clinicopathologically overlapping neurodegenerative diseases. In this study we excluded mutations and copy number variations in the gene encoding TDP-43 (TARDBP) from an extended series of 173 FTD and 237 ALS patients. Further, we did not identify association of common genetic variants in these patients. Our data implicate that TDP-43 has no primary genetic role in the pathophysiological mechanisms underlying central nervous system neurodegeneration in these diseases.

Introduction

The TAR DNA binding protein 43 (TDP-43) was recently identified as a major constituent of poly-ubiquitinated neuronal inclusions in brain of frontotemporal dementia (FTDU) and spinal cord of amyotrophic lateral sclerosis (ALS) patients (Arai et al., 2006, Neumann et al., 2006), two neurodegenerative diseases belonging to a clinicopathological spectrum of overlapping central nervous system (CNS) disorders. Mutations in genes encoding the major protein component of characteristic pathological deposits can be a direct cause of CNS neurodegeneration. Therefore, we investigated whether the gene encoding TDP-43 (TARDBP) is genetically involved in the development of CNS diseases of the FTD–ALS spectrum.

Section snippets

Materials and methods

We analyzed TARDBP in a Belgian series of 173 genealogically unrelated FTD patients (mean age at onset 64.4 ± 10.1 years) and 237 sporadic ALS patients (mean age at onset 57.6 ± 12.3 years). Positive family history was recorded for 50 FTD patients. Screening of the known dementia genes (APP, PSEN1, PSEN2, PRNP, MAPT, PGRN, CHMP2B and VCP) in the FTD series revealed mutations in 19 FTD patients while in the ALS series no SOD1 mutations were found. For details see Supplementary material.

We sequenced

Results and discussion

TARDBP sequencing in the FTD and ALS sample revealed 16 sequence variants, none of which was predicted to affect the encoded protein: two coding SNPs resulting in silent mutations, ten intronic variants of which none was located in or near a splice site, one in the 3′UTR and three in the upstream region (Supplementary material Fig. 1 and Supplementary material Table 2). Dosage analysis did not reveal any copy number variation.

Association analysis of all eight common SNPs did not reveal

Conflict of interest statement

None.

Acknowledgments

The authors are grateful to Virginia M. Lee and John Q. Trojanowski (University of Pennsylvania School of Medicine, Philadelphia, USA) for sharing prepublication of the data on TDP-43, to the patients and family members for their kind cooperation in this study, and to the personnel of the VIB Genetic Service Facility (http://www.vibgeneticservicefacility.be) and the Biobank of the Institute Born-Bunge. This research was in part funded by the Special Research Fund of the University of Antwerp,

References (4)

T. Arai et al.
TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis
Biochem. Biophys. Res. Commun.
(2006)
S. Rollinson et al.
TDP-43 gene analysis in frontotemporal lobar degeneration
Neurosci. Lett.
(2007)

There are more references available in the full text version of this article.

Cited by (56)

Investigation of next-generation sequencing technologies as a diagnostic tool for amyotrophic lateral sclerosis
2015, Neurobiology of Aging
The future of genetic diagnostics will see a move toward massively parallel next-generation sequencing of a patient's DNA. Amyotrophic lateral sclerosis (ALS) is one of the diseases that would benefit from this prospect. Exploring this idea, we designed a screening panel to sequence 25 ALS-linked genes and examined samples from 95 patients with both familial and sporadic ALS. Forty-three rare polymorphisms were detected in this cohort. A third of these have already been reported with respect to ALS, leaving 28 novel variants all open for further investigation. This study highlights the potential benefits of next-generation sequencing as a reliable, cost and time efficient, diagnostic, and research tool for ALS.
Two distinct clinical features and cognitive impairment in amyotrophic lateral sclerosis patients with TARDBP gene mutations in the Chinese population
2015, Neurobiology of Aging
Citation Excerpt :
Among Caucasian populations, the percentage of Sardinian SOD1-negative FALS patients and SALS patients carrying TARDBP mutations was 63.9% (74 of 161) and 17.5% (30 of 171), respectively (Chio et al., 2011; Orru et al., 2012). Notably, several reports looking at large cohorts of SALS patients did not identify any mutations in TARDBP, including the Chinese cohort (Gijselinck et al., 2009; Guerreiro et al., 2008; Kwon et al., 2012; Ye et al., 2013); thus, more studies are needed to determine the precise frequency of TARDBP mutations in SALS patients. The p.M337 V mutation was previously reported in patients from Caucasian and Japanese populations with typical ALS (Corrado et al., 2009; Kirby et al., 2010; Rutherford et al., 2008; Sreedharan et al., 2008; Tamaoka et al., 2010; Tsai et al., 2011).
Mutations in the TARDBP gene have been identified as a major causative factor in amyotrophic lateral sclerosis (ALS). However, few reports have analyzed the relationship of genotype–phenotype, especially in Chinese ALS patients. Our study investigated the presence and frequency of TARDBP mutations in Chinese patients with ALS. Additionally, we investigated correlations among clinical features and TARDBP gene mutations in a large ALS family with the p.M337 V mutation and one sporadic ALS (SALS) patient with the p.S393 L mutation. The pedigree with the p.M337 V mutation showed variable clinical features with a long lifespan, particularly cognitive impairment. One patient carrying the p.S393 L mutation experienced ALS with cognitive impairment; the patient also had a family history of frontotemporal dementia (FTD). This is the first report of detailed genetic and clinical characterizations of the TARDBP gene in a Chinese population. This research is also the first to demonstrate that the p.M337 V and the p.S393 L mutations are related to cognitive impairment in ALS patients. The mutation frequency of TARDBP was 5.6% in Chinese, SOD1-negative familial ALS (FALS), which was much higher than that reported in previous studies conducted with Caucasian populations, whereas the TARDBP mutation frequency was lower in the Chinese population with regard to SALS patients. Our results emphasize the importance of the genetic and clinical characterization of TARDBP mutations in ALS, which allows us to understand the genotype–phenotype relationship and relative frequencies in different populations.
Targeted high-throughput sequencing identifies a TARDBP mutation as a cause of early-onset FTD without motor neuron disease
2014, Neurobiology of Aging
Targeted high-throughput sequencing of many amyotrophic lateral sclerosis (ALS) and fronto-temporal dementia (FTD) genes in parallel has the potential to reveal novel ALS- and/or FTD-phenotypes and to provide missing links on the ALS-FTD continuum. For example, although the 43-kDa transactive response DNA binding protein is the major pathologic hallmark linking ALS and FTD, mutations in the gene encoding 43-kDa transactive response DNA binding protein (TARDBP) have been appreciated only as a cause of ALS-phenotypes, but not yet of pure FTD. Thus, the genetic link is not yet well substantiated that TARDBP mutations can cause the full spectrum of the ALS-FTD continuum. High-throughput sequencing of 18 ALS and FTD genes in an index patient presenting with early-onset pure (behavioral) FTD and a positive family history for ALS revealed an established TARDBP mutation, A382T. This finding demonstrates that a TARDPB mutation can cause early-onset pure FTD without evidence for ALS even in advanced FTD disease stages. Moreover, it indicates that TARDPB screening might be considered even in young patients with “pure” neuropsychiatric disturbances and without evidence of neurodegenerative disease in the parental generation.
Screening of the TARDBP gene in familial and sporadic amyotrophic lateral sclerosis patients of Chinese origin
2012, Neurobiology of Aging
Citation Excerpt :
The pathological findings led to genetic screening for TAR DNA-binding protein (TARDBP) gene mutations in ALS and frontotemporal dementia (FTD) patients. Although two groups (Guerreiro et al., 2008; Gijselinck et al., 2009) did not find TARDBP mutations or linkage of ALS with the TARDBP gene, in 2008, one group identified missense mutations in the TARDBP gene in both SALS and FALS patients, providing evidence of a direct pathogenic role for TDP-43 in ALS (Sreedharan et al., 2008). To date, 41 different TDP-43 pathogenic mutations (40 missense and one frameshift mutation) (Supplementary Table S1) have been reported in ALS patients of different ethnicities, mainly in White populations (Baumer et al., 2009; Benajiba et al., 2009; Chiò et al., 2010, 2011; Conforti et al., 2011; Corrado et al., 2009; Daoud et al., 2008; Del Bo et al., 2009; Gitcho et al., 2008; Huang et al., 2012; Iida et al., 2012; Kabashi et al., 2008; Kamada et al., 2009; Kirby et al., 2009; Kühnlein et al., 2008; Lemmens et al., 2009; Millecamps et al., 2010; Origone et al., 2010; Orrù et al., 2012; Piaceri et al., in press; Rutherford et al., 2008; Sreedharan et al., 2008; Ticozzi et al., 2011; Tsai et al., 2011; Van Deerlin et al., 2008; Williams et al., 2009; Xiong et al., 2010; Yokoseki et al., 2008).
TAR DNA-binding protein (TARDBP) mutations have been reported in patients with amyotrophic lateral sclerosis (ALS) in different populations. Only a few studies have screened for TARDBP mutations in Chinese populations. Here, we sequenced the coding region of all five TARDBP exons for mutations in 13 familial ALS (FALS) pedigrees and 312 sporadic ALS (SALS) patients of Chinese origin, as well as 245 healthy control subjects. Two heterozygous missense mutations, c.875G>A (p.S292N) and c.1043G>T (p.G348V), were identified in two and one SALS patients, respectively. One synonymous substitution, c.1098C>G (p.A366A), was identified in two SALS patients. None of the substitutions were found in healthy control subjects. In Chinese populations, the estimated frequency of TARDBP mutations in SALS patients (0.73%) is higher than Japanese and lower than White populations, whereas the estimated mutation frequency in superoxide dismutase 1 (SOD1)-negative FALS patients (15.2%) is higher than both Japanese and White populations. Our findings provide an overview of the occurrence of TARDBP mutations in Chinese ALS patients and highlight the importance of TARDBP mutation screening in Chinese ALS patients.
FUS and TDP43 genetic variability in FTD and CBS
2012, Neurobiology of Aging
This study aimed to evaluate genetic variability in the FUS and TDP-43 genes, known to be mainly associated with amyotrophic lateral sclerosis (ALS), in patients with the diagnoses of frontotemporal lobar degeneration (FTLD) and corticobasal syndrome (CBS). We screened the DNA of 228 patients for all the exons and flanking introns of FUS and TDP-43 genes. We identified 2 novel heterozygous missense mutations in FUS: P106L (g.22508384C>T) in a patient with behavioral variant frontotemporal dementia (bvFTD) and Q179H in several members of a family with behavioral variant FTD. We also identified the N267S mutation in TDP-43 in a CBS patient, previously only reported in 1 ALS family and 1 FTD patient. Additionally, we identified 2 previously reported heterozygous insertion and deletion mutations in Exon 5 of FUS; Gly174-Gly175 del GG (g. 4180-4185 delGAGGTG) in an FTD patient and Gly175-Gly176 ins GG (g. 4185-4186 insGAGGTG) in a patient with diagnosis of CBS. Not least, we have found a series of variants in FUS also in neurologically normal controls. In summary, we report that genetic variability in FUS and TDP-43 encompasses a wide range of phenotypes (including ALS, FTD, and CBS) and that there is substantial genetic variability in FUS gene in neurologically normal controls.
Large-scale screening of TARDBP mutation in amyotrophic lateral sclerosis in Japanese
2012, Neurobiology of Aging
Citation Excerpt :
Overall, the frequencies of the TARDBP mutations in ALS are low and have considerable difference even among Caucasian populations. For examples, TARDBP mutations are found in 5.0% of French Canadian and French ALSs (Kabashi et al., 2008), 2.2% in Italian ALSs (Corrado et al., 2009), but no mutations are found in north American (Guerreiro et al., 2008) and Belgian ALSs (Gijselinck et al., 2009). There are only a few studies for TARDBP mutations in non-Caucasian populations.
Mutations in TARDBP encoding TDP (TAR DNA binding protein)-43 have been reported in familial and sporadic amyotrophic lateral sclerosis (ALS), but mostly in Caucasians. In other ethnic groups, four types of mutations are found in familial ALS. In sporadic ALS, the TARDBP mutations frequency is low in Caucasians (0–5%) and no mutation has been found in other ethnic groups. To examine spectrum of TARDBP mutations and its frequency in Japanese, we screened the TARDBP mutation in 721 Japanese ALS by direct sequencing. We identified a novel mutation, c.1069G > A (p.Gly357Ser) and a known mutation in sporadic ALS. One patient was homozygous for p.Gly357Ser, which was the first for TARDBP mutation. Our study showed that TARDBP mutations also occur in non-Caucasian sporadic ALS. The estimated frequency of the TARDBP mutation in sporadic ALS is 0.29% in Japanese. The mutation frequency in familial ALS in Japanese is also similar to that in Caucasian, and is ∼10 times higher than that in Japanese sporadic ALS.

View all citing articles on Scopus

View full text

Negative ResultsNeuronal inclusion protein TDP-43 has no primary genetic role in FTD and ALS