Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis

Luquin, Natasha; Yu, Bing; Saunderson, Rebecca B.; Trent, Ronald J.; Pamphlett, Roger

doi:10.1016/j.nmd.2009.07.005

Cited by 25 publications

(29 citation statements)

References 31 publications

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“…site for Egr nerve growth factor-induced protein C. 28 Our in silico analysis has confirmed that a potential binding site for SF2/ASF is lost following the G ? A change, but loss of enhancer sequences has not been detected by either RES-CUE-ESE or PESX.…”

Section: Discussionsupporting

confidence: 52%

TARDBP Mutations in Frontotemporal Lobar Degeneration: Frequency, Clinical Features, and Disease Course

Borroni

Archetti

et al. 2010

Rejuvenation Research

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The 43-kD transactive response (TAR)-DNA-binding protein (TARDBP) mutations have been demonstrated to be causative of sporadic and familial forms of amyotrophic lateral sclerosis. More recently, these mutations have been reported in cases of frontotemporal lobar degeneration (FTLD). The aim of this study was to evaluate the role of TARDBP genetic variations in a large sample of consecutive patients with FTLD. A total of 252 FTLD patients were investigated. Each subject had a clinical and neuropsychological evaluation and a brain imaging study. The clinical diagnosis was confirmed by at least 1 year of follow up. The entire TARDBP gene, the intronic flaking regions, and the 5'-untranslated region (5'-UTR) were screened. Six genetic variations were identified in patients with behavioral variant frontotemporal dementia (FTD) and FTD with motor neuron disease phenotypes. Two of these mutations, namely N267S and M359V, lead to amino acid changes within exon 6. We further identified three genetic variations, i.e., Y214Y, IVS-IV + 45C/T, and 5'-UTR G/A, that could potentially affect the normal splicing process as predicted by in silico analyses. None of these genetic variations was found in healthy age-matched controls. Moreover, we identified a previously described benign variant, A66A, in 5 patients. Our study has confirmed and extended the list of pathogenetic mutations in the TARDBP gene in both apparently sporadic and familial FTLD patients. This work further supports the need for TARDBP screening in FTLD. Also intronic splicing that affects mutations should be considered as well.

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Section: Discussionsupporting

confidence: 52%

TARDBP Mutations in Frontotemporal Lobar Degeneration: Frequency, Clinical Features, and Disease Course

Borroni

Archetti

et al. 2010

Rejuvenation Research

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“…Since then others have failed to find ALS brain-specific mutations involving either the length of androgen receptor triplet repeats [23], single nucleotide variants of coding and non-coding regions of TARDP [24], [25], or of all exons and the promoter of superoxide dismutase 1 [26]. ALS brain-situated genome-wide variants in chromosomal copy number [27] and in DNA methylation [28] have been reported, but these still require independent validation.…”

Section: Discussionmentioning

confidence: 99%

Can ALS-Associated C9orf72 Repeat Expansions Be Diagnosed on a Blood DNA Test Alone?

et al. 2013

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Gene mutations that preferentially affect the CNS have been implicated in a number of neurological disorders. This leads to the possibility that a disease-causing mutation present only in CNS tissues could be missed if it were tested in a blood DNA sample only. The commonest mutation in amyotrophic lateral sclerosis (ALS) is an expansion of the hexanucleotide repeats of C9orf72. To find out if CNS-specific mutations of this gene could cause some cases of ALS we looked for differences in the size of C9orf72 repeats between DNA from the CNS and from white blood cells (WBCs) of 38 sporadic ALS patients, using a repeat-primed PCR screening test. We also looked for differences in C9orf72 repeats in WBC DNA from 6 ALS-discordant and 1 ALS-concordant monozygotic twins. Abnormally expanded C9orf72 repeats were found in 13% of the ALS CNS samples, as well as in their paired WBC DNA. The 87% of ALS CNS samples with normal-sized C9orf72 repeats had the same number of repeats in paired WBC samples. All ALS-discordant twins had the same normal numbers of WBC C9orf72 repeats. Although previous work suggests some tissue mosaicism in C9orf72 repeat size is probably present, this study indicates that this is not likely to be of sufficient magnitude to result in a normal C9orf72 repeat length in blood but an abnormally expanded repeat length in the CNS. This suggests that a blood DNA test alone will usually be sufficient to make a diagnosis of C9orf72 repeat-related ALS.

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“…These results raise the possibility that altered expression of Wt TDP-43 may also be disease causing in sporadic ALS patients. Further studies are needed to elucidate if raised Wt TDP-43 levels are present in sporadic ALS patients, perhaps due to variations in the non-coding region of the gene [28].…”

Section: Discussionmentioning

confidence: 99%

Progranulin is Neurotrophic In Vivo and Protects against a Mutant TDP-43 Induced Axonopathy

et al. 2010

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Mislocalization, aberrant processing and aggregation of TAR DNA-binding protein 43 (TDP-43) is found in the neurons affected by two related diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal lobe dementia (FTLD). These TDP-43 abnormalities are seen when TDP-43 is mutated, such as in familial ALS, but also in FTLD, caused by null mutations in the progranulin gene. They are also found in many patients with sporadic ALS and FTLD, conditions in which only wild type TDP-43 is present. The common pathological hallmarks and symptomatic cross over between the two diseases suggest that TDP-43 and progranulin may be mechanistically linked. In this study we aimed to address this link by establishing whether overexpression of mutant TDP-43 or knock-down of progranulin in zebrafish embryos results in motor neuron phenotypes and whether human progranulin is neuroprotective against such phenotypes. Mutant TDP-43 (A315T mutation) induced a motor axonopathy characterized by short axonal outgrowth and aberrant branching, similar, but more severe, than that induced by mutant SOD1. Knockdown of the two zebrafish progranulin genes, grna and grnb, produced a substantial decrease in axonal length, with knockdown of grna alone producing a greater decrease in axonal length than grnb. Progranulin overexpression rescued the axonopathy induced by progranulin knockdown. Interestingly, progranulin also rescued the mutant TDP-43 induced axonopathy, whilst it failed to affect the mutant SOD1-induced phenotype. TDP-43 was found to be nuclear in all conditions described. The findings described here demonstrate that progranulin is neuroprotective in vivo and may have therapeutic potential for at least some forms of motor neuron degeneration.

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Genetic variants in the promoter of TARDBP in sporadic amyotrophic lateral sclerosis

Cited by 25 publications

References 31 publications

TARDBP Mutations in Frontotemporal Lobar Degeneration: Frequency, Clinical Features, and Disease Course

TARDBP Mutations in Frontotemporal Lobar Degeneration: Frequency, Clinical Features, and Disease Course

Can ALS-Associated C9orf72 Repeat Expansions Be Diagnosed on a Blood DNA Test Alone?

Progranulin is Neurotrophic In Vivo and Protects against a Mutant TDP-43 Induced Axonopathy

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