Two distinct clinical features and cognitive impairment in amyotrophic lateral sclerosis patients with TARDBP gene mutations in the Chinese population

Ju, Xiaodong; Liu, WenChao; Li, Yong; Liu, Na; Zhang, Nan; Liu, Tao; Deng, Min

doi:10.1016/j.neurobiolaging.2015.10.032

Cited by 9 publications

(11 citation statements)

References 32 publications

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“…In our cohort, a total of 391 Chinese SALS patients from Han populations were screened for mutations in TARDBP gene. Two missense The frequency of TARDBP missense mutations in the current cohort was 0.77% (3/391), resembling previous results of 0.61% (1/165) (Huang et al, 2012), 0.93% (3/324) (Zou et al, 2016), 0.50% (1/200) (Ju et al, 2016), and 1.19% (3/253) (Chen et al, 2020), except for 4.76%…”

Section: Discussionsupporting

confidence: 89%

“…I G U R E 2 18 F-FDG PET/MR images of patient 3 Note the obvious hypometabolism, predominantly on the left side, without distinct atrophy in the bilateral frontal lobes (a, b), and severe, "blade-like" atrophy in the bilateral temporal lobes along with significant hypometabolism, especially in the anterior and lateral parts (c-h) mutations, c.1132A > G (p.N378D) and c.1147A > G (p.I383V), were identified in three patients.The frequency of TARDBP missense mutations in the current cohort was 0.77% (3/391), resembling previous results of 0.61% (1/165)(Huang et al, 2012), 0.93% (3/324)(Zou et al, 2016), 0.50% (1/200)(Ju et al, 2016), and 1.19% (3/253)(Chen et al, 2020), except for 4.76%…”

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confidence: 89%

“…Even in SALS patients with the same missense mutation, duration also varied widely (Table 1). Last, despite one patient with p.S393L (Ju et al, 2016) and one patient with p.I383V in our study presented ALS with FTD, the majority of Chinese SALS patients with TARDBP missense mutations displayed a phenotype of pure ALS (Table 1).…”

Section: Discussionmentioning

confidence: 62%

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Genetic and clinical features of Chinese sporadic amyotrophic lateral sclerosis patients with TARDBP mutations

et al. 2021

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To investigate the genetic and clinical features of Chinese sporadic amyotrophic lateral sclerosis (SALS) patients with TARDBP mutations, we carried out a genetic analysis in a cohort of 391 SALS patients and explored the clinical manifestations of patients with TARDBP variants. Materials and methods: The coding region of all five coding exons of TARDBP, exons 2-6, were sequenced for mutations in 391 Chinese SALS patients. The clinical features of patients with TARDBP mutations were described and compared with cases in literatures. Results: Two missense mutations in TARDBP gene, c.1132A > G (p.N378D) and c.1147A > G (p.I383V), were detected in three cases, showing a low frequency (0.77%, 3/391) of TARDBP missense mutations in Chinese SALS patients. Based on a retrospective analysis of literatures, p.N378D mutation mainly presents a phenotype of early onset, whereas p.I383V mutation presents pure ALS or ALS alongside semantic variant primary progressive aphasia (svPPA), a type of frontotemporal dementia (FTD). Conclusions:Our results demonstrate that TARDBP mutation is a rare cause of Chinese SALS patients and expand the spectrum of phenotype. It is implied that genetic analysis of SALS patients plays a crucial role in uncovering the cause of disease, especially for cases developing early onset or alongside FTD.

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Section: Discussionsupporting

confidence: 89%

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confidence: 89%

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Genetic and clinical features of Chinese sporadic amyotrophic lateral sclerosis patients with TARDBP mutations

et al. 2021

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“…TDP-43 is 414 amino acid residues in length and is comprised of an N-terminal domain (NTD, residues 1–102) that includes a predicted nuclear localization signal (NLS, residues 82–98), two RNA recognition motifs (RRMs) composed of residues 106–177 (RRM1), and residues 192–259 (RRM2), including a nuclear export signal (NES) from residue 239 to 250 and a C-terminal domain (CTD, residues 274–414) (Figure A). , In vitro biophysical characterization and cross-linking studies in cell culture and mouse brains all suggest that TDP-43 is intrinsically a dimeric protein and that dimer formation may be mediated by a number of regions across the entirety of TDP-43, including the NTD, RRM2, and/or the CTD. ,,− The CTD is particularly relevant to disease, as it is where nearly all ALS/FTD-associated mutations are found. ,− This is a flexible region containing only a transient α-helical structure and contains QN-rich residues implicated in aggregation (Figure D). The structural study of full length TDP-43 has been difficult because of its strong aggregation propensity and difficulty of purification, as well as its flexible CTD .…”

Section: Insights Into Tdp-43 Aggregation From Structural Studiesmentioning

confidence: 99%

Phase to Phase with TDP-43

Sun

Chakrabartty

2017

Biochemistry

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TDP-43 is a dimeric nuclear protein that plays a central role in RNA metabolism. In recent years, this protein has become a focal point of research in the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, as pathognomonic inclusions within affected neurons contain post-translationally modified TDP-43. A key question in TDP-43 research involves determining the mechanisms and triggers that cause TDP-43 to form pathological aggregates. This review gives a brief overview of the physiological and pathological roles of TDP-43 and focuses on the structural features of its protein domains and how they may contribute to normal protein function and to disease. A special emphasis is placed on the C-terminal prion-like region thought to be implicated in pathology, as it is where nearly all ALS/FTD-associated mutations reside. Recent structural studies of this domain revealed its crucial role in the formation of phase-separated liquid droplets through a partially populated α-helix. This new discovery provides further support for the theory that liquid droplets such as stress granules may be precursors to pathological aggregates, linking environmental effects such as stress to the potential etiology of the disease. The transition of TDP-43 among soluble, droplet, and aggregate phases and the implications of these transitions for pathological aggregation are summarized and discussed.

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“…However, large-scale screening for mutations of the common causative genes is less common in Chinese patients than in Caucasians. Previous studies have shown that in Chinese SALS patients, the frequency of TARDBP is 0–0.93% 9 10 11 12 13 14 , that of FUS is 1.55–1.85% 9 11 , that of ANG is 0.31% 9 , that of VCP is 0% 9 , that of SQSTM1 is 0.98–1.38% 15 16 , that of PFN1 is 0–0.19% 9 17 , that of matrin 3 ( MATR3 ) is 0.20% 18 , that of TANK-binding kinase 1 ( TBK1 ) is 0.57% 19 and that of coiled-coil-helix-coiled-coil-helix domain-containing protein 10 ( CHCHD10 ) is 0–0.41% 20 21 . For the C9orf72 HRE, five independent studies have revealed that its frequency in SALS is 0–1.53% 9 11 22 23 24 .…”

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confidence: 99%

Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review

Wei

Zhou

Chen

et al. 2017

Sci Rep

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Although the copper/zinc superoxide dismutase-1 (SOD1) gene has been identified in both familial ALS (FALS) and sporadic ALS (SALS), it has rarely been studied in Chinese patients with ALS, and there are few studies with large samples. This study sought to assess the prevalence of SOD1 mutations in Chinese ALS patients. We screened a cohort of 499 ALS patients (487 SALS and 12 FALS) from the Department of Neurology at the West China Hospital of Sichuan University and analyzed all coding exons of SOD1 by Sanger sequencing. In addition, we reviewed the mutation frequencies of common ALS causative genes in Chinese populations. Eight missense mutations in SOD1 were found in 8 ALS individuals: two novel mutations (p.G73D and p.V120F) and six previously reported mutations. The frequencies of SOD1 mutations were 1.03% (5/487) in SALS and 25% (3/12) in FALS from Southwest China. A literature review indicated that the mutation rates of major ALS causative genes were 53.55% in FALS and 6.29% in SALS. In Chinese SALS and FALS, the highest mutation frequency was in the SOD1 gene. Our results suggest that SOD1 mutation is the most common cause of ALS in Chinese populations and that the mutation spectrum of ALS varies among different ethnic populations.

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Two distinct clinical features and cognitive impairment in amyotrophic lateral sclerosis patients with TARDBP gene mutations in the Chinese population

Cited by 9 publications

References 32 publications

Genetic and clinical features of Chinese sporadic amyotrophic lateral sclerosis patients with TARDBP mutations

Genetic and clinical features of Chinese sporadic amyotrophic lateral sclerosis patients with TARDBP mutations

Phase to Phase with TDP-43

Analysis of SOD1 mutations in a Chinese population with amyotrophic lateral sclerosis: a case-control study and literature review

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