Identification of novel &lt;i&gt;FUS&lt;/i&gt; and &lt;i&gt;TARDBP&lt;/i&gt; gene mutations in Chinese amyotrophic lateral sclerosis patients with HRM analysis

Wang, Zhen; Fu, Shengyu; Lei, Jianfan; Wu, Hongchen; Shi, Shugui; Chen, Kangning; Hu, Jun; Xu, Xueqing

doi:10.18632/aging.103967

Cited by 5 publications

(11 citation statements)

References 17 publications

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“…However, TDP-43 granules did not colocalize with PSs, PML, or NSs, which suggests that FUS and TDP-43 may utilize different mechanisms in response to hyperosmotic stress. Besides, a recent study showed that TDP-43 and PSs showed co-localization under arsenite treatment (Wang et al, 2020a(Wang et al, , 2020b, suggesting that different stresses may also possess a distinctive mechanism triggering protein LLPS in cells.…”

Section: Discussionmentioning

confidence: 99%

“…Next, we examined the LLPS of hnRNPA1 and FUS-R521H (one of the highest proportions of FUS mutation, which could lead to aberrant trafficking and retention of the mutant FUS protein in the cytoplasm [Wang et al, 2020a[Wang et al, , 2020b), which also assembled into granules in both nucleus and cytoplasm induced by 0.15 M NaCl for 60 min (Figures S6A and S6B), and the granules of FUS-R521H and hnRNPA1 mainly assembled in the nucleus with the increase of hypertonic solution concentration (Figures S6C and S6D). In addition, we investigated the nuclear phase separation induced by hyperosmotic stress in neuron cells.…”

Section: The Formation Mechanism Of Fus and Tdp-43 Granules Is Differentmentioning

confidence: 99%

“…The amyotrophic lateral sclerosis (ALS)-and frontotemporal dementia (FTD)-associated proteins fused in sarcoma (FUS) (Liu et al, 2020;Murakami et al, 2015;Patel et al, 2015), heterogeneous nuclear ribonucleoproteins (hnRNPs) (Gui et al, 2019;Maharana et al, 2018) and TAR DNA-binding protein 43 (TDP-43) (Wang et al, 2020a(Wang et al, , 2020bYu et al, 2021) can condense into droplets under diverse stress (Anderson and Kedersha, 2009;Gu et al, 2020;Kedersha et al, 2005). Moreover, abnormal stress will destroy the homeostasis of droplets and accelerate those liquid compartments to form pathological aggregates via liquid-to-solid phase transition (McGurk et al, 2018;Molliex et al, 2015;Wang et al, 2020aWang et al, , 2020b. Therefore, a better understanding mechanism of LLPS under stress not only helps to reveal the function of MLOs but also to uncover the pathogenesis of neurodegenerative diseases.…”

Section: Introductionmentioning

confidence: 99%

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Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus

Gao¹,

Gu²,

Zhang³

et al. 2022

Cell Reports

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Section: Discussionmentioning

confidence: 99%

Section: The Formation Mechanism Of Fus and Tdp-43 Granules Is Differentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus

Gao¹,

Gu²,

Zhang³

et al. 2022

Cell Reports

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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 (1/21) (Liu et al, 2019), and 2.74% (4/146) (Wang et al, 2020) in Chinese SALS patients. At the same time, several previous studies did not identify any Chinese SALS patients with TARDBP missense mutations (Deng et al, 2019;Hou et al, 2016;Lin et al, 2020;Liu et al, 2016;Liu et al, 2017;Soong et al, 2014;Xiong et al, 2010;Xu et al, 2018;Ye et al, 2013).…”

Section: Discussionmentioning

confidence: 94%

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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“…The most distinctive phenotypic feature is a more frequent onset in the upper extremities, but with a similar evolution to the sporadic ALS, including the extension to other regions and bulbar involvement. To our knowledge, only four cases of JALS associated with three different variants in the TARDBP gene have been described [ 25 , 26 , 27 , 28 ] ( Table 1 ). An overview of the clinical data of these cases reveals the following.…”

Section: Discussionmentioning

confidence: 99%

An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature

Sánchez-Tejerina¹,

Restrepo-Vera²,

Rovira-Moreno

et al. 2022

Genes

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that can rarely affect young individuals. Juvenile ALS (JALS) is defined for individuals with an onset of the disease before the age of 25. The contribution of genetics to ALS pathology is a field of growing interest. One of the differences between adult-onset ALS and JALS is their genetic background, with a higher contribution of genetic causes in JALS. We report a patient with JALS and a pathogenic variant in the TARDBP gene (c.1035C > G; p.Asn345Lys), previously reported only in adult-onset ALS, and with an atypical phenotype of marked upper motor neuron predominance. In addition, the proband presented an additional variant in the NEK1 gene, c.2961C > G (p.Phe987Leu), which is classified as a variant of unknown significance. Segregation studies showed a paternal origin of the TARDBP variant, while the variant in NEK1 was inherited from the mother. We hypothesize that the NEK1 variant acts as a disease modifier and suggests the possibility of a functional interaction between both genes in our case. This hypothesis could explain the peculiarities of the phenotype, penetrance, and the age of onset. This report highlights the heterogeneity of the phenotypic presentation of ALS associated with diverse pathogenic genetic variants

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Identification of novel <i>FUS</i> and <i>TARDBP</i> gene mutations in Chinese amyotrophic lateral sclerosis patients with HRM analysis

Cited by 5 publications

References 17 publications

Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus

Hyperosmotic-stress-induced liquid-liquid phase separation of ALS-related proteins in the nucleus

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

An Atypical Presentation of Upper Motor Neuron Predominant Juvenile Amyotrophic Lateral Sclerosis Associated with TARDBP Gene: A Case Report and Review of the Literature

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