De novo FUS gene mutations are associated with juvenile-onset sporadic amyotrophic lateral sclerosis in China

Zou, Zhang‐Yu; Cui, Liying; Sun, Qing; Li, Xiaoguang; Liu, Mingsheng; Xu, Yan; Zhou, Yongan; Yang, Xunzhe

doi:10.1016/j.neurobiolaging.2012.09.005

Cited by 67 publications

(83 citation statements)

References 57 publications

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“…The phenotypes observed in our transgenic models phenocopy aspects of adult cases of ALS. However, the onset of phenotypes in the mouse models is earlier, more closely reflecting FUS-linked juvenile ALS (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Sephton

Tang

Kulkarni

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

120

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The RNA-binding protein fused-in-sarcoma (FUS) has been associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), two neurodegenerative disorders that share similar clinical and pathological features. Both missense mutations and overexpression of wild-type FUS protein can be pathogenic in human patients. To study the molecular and cellular basis by which FUS mutations and overexpression cause disease, we generated novel transgenic mice globally expressing low levels of human wild-type protein (FUS WT ) and a pathological mutation (FUS R521G A myotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons, leading to muscle weakness, paralysis, and death within 3-5 y of onset. Interestingly, ∼10-15% of ALS patients have clinical features of frontotemporal lobar degeneration (FTLD), marked by a decline in decision-making, behavioral control, emotion, and language, and as many as half have mild-to-moderate cognitive or behavioral abnormalities (1). FTLD comprises a group of heterogeneous diseases characterized by progressive neurodegeneration of the frontal and temporal lobes and clinically by frontotemporal dementia (FTD) with or without motor neuron disease. There is no cure or effective therapy for those who suffer from ALS or FTLD, and the mechanisms by which these diseases occur are not well understood.The clinical, pathological, and genetic overlap between ALS and FTLD suggests that there are mechanisms shared by these diseases. The RNA-binding proteins fused in sarcoma (FUS) and transactive response DNA-binding protein-43 (TDP-43) are the major protein components of inclusions that are characteristic of ALS and FTLD-U (FTLD with ubiquitinated inclusions) (2). More than 50 genetic FUS mutations have been identified in these related neurodegenerative disorders (3). Similarly, more than 40 dominant mutations in the TDP-43 gene have been linked to ALS cases and, to a lesser extent, to FTLD (4). The identification of mutations in the FUS and TDP-43 genes has provided insights for uncovering the disease mechanisms for ALS and FTLD.FUS is a ubiquitously expressed RNA-binding protein that exists in dynamic ribonucleoprotein complexes involved in pre-mRNA splicing, mRNA stability, and mRNA transport. FUS is a member of the FET family of proteins that bind RNAs (5) and contains an RNA recognition motif, three arginine-glycine-glycine (RGG) boxes, and a zinc finger (ZnF) (6). RGG2-ZnF-RGG3 is the major RNA-binding domain, which has a preference for GUrich sequences (7,8). The N terminus of FUS contains a lowcomplexity sequence domain involved in RNA granule formation (9). Nucleocytoplasmic shuttling of FUS occurs by a nonclassical proline-tyrosine nuclear localization signal (PY-NLS) and a nuclear export signal (NES) (10). Methylation of the C-terminal RGG3 domain of FUS is necessary for transportin 1 interaction and nuclear localization (11).The majority of clinical ALS/FTLD-associated FUS mutations occur in its C-terminal PY-NLS seque...

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Section: Discussionmentioning

confidence: 99%

Activity-dependent FUS dysregulation disrupts synaptic homeostasis

Sephton

Tang

Kulkarni

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

120

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“…Juvenile‐onset ALS is associated with the great majority of the kindreds, with both autosomal recessive and autosomal dominant pattern of inheritance (Conte et al., 2012), and mutations in several genes such as alsin (ALS2), SETX, spatacsin (SPG11), SOD1 (Orban, Devon, Hayden, & Leavitt, 2007), and FUS (Belzil et al., 2012; Conte et al., 2012; Zou et al., 2013). In Chinese Han families with JALS, FUS mutations were reported to be the most common genetic determinant with an aggressive phenotype (Liu et al., 2017), especially the de novo ones (Zou et al., 2013).…”

Section: Discussionmentioning

confidence: 99%

“…In Chinese Han families with JALS, FUS mutations were reported to be the most common genetic determinant with an aggressive phenotype (Liu et al., 2017), especially the de novo ones (Zou et al., 2013). Mutations in the SETX gene are associated with a rare and autosomal dominant form of JALS, also known as ALS4, which is characterized by motor neuron dysfunction of early onset, slow progression, acute muscle weakness and pyramidal tract signs, and the absence of bulbar and sensory abnormalities (Orban et al., 2007).…”

Section: Discussionmentioning

confidence: 99%

A novel SETX gene mutation associated with Juvenile amyotrophic lateral sclerosis

Shi

Chen

et al. 2018

Brain and Behavior

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ObjectsThis study aimed to report a novel point mutation associated with juvenile amyotrophic lateral sclerosis (JALS) in a Chinese Han family.MethodsDetailed clinical assessment was applied to two patients, including proband (II‐2) and his mother (I‐2). Next‐generation sequencing (NGS), also known as high‐throughput sequencing in whole exon sequence, was performed in the proband to reach the target region. Sanger sequencing was also used to detect DNA sequence variants of the proband and other three members of his family.ResultsThe proband (II‐2) and his mother (I‐2) were successfully diagnosed according to the clinical manifestations and physical examination. A novel point mutation c.1157T > C in the exon 10 of the SETX gene was identified in II‐2 and I‐2, resulting in a substitution of methionine (ATG) to threonine (ACG). However, we ultimately did not find the same variant in the other two normal members of his family in addition to 100 unrelated normal subjects.ConclusionWe presented a novel probably pathogenic missense mutation in exon 10 of SETX gene in a Chinese Han family with JALS.

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“…3 Given the potentially large impact of increasing subspecialization, it is important to monitor the effects of new accreditations that are being created for neurology fellowship programs by the American Board of Psychiatry and Neurology and United Council for Neurologic Subspecialties. 4 Author Response: William D. Freeman, Jacksonville, FL; Kenneth A. Vatz, Chicago; Robert C. Griggs, Rochester, NY; Timothy Pedley, New York: We appreciate the comments by Drs. Hodgson and Lukas concerning factors that affect decisions trainees make about choice of subspecialties and the potential impact of those decisions on the composition of future neurology workforces.…”

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confidence: 99%

“…Juvenile sporadic ALS is a rare form of motor neuron disease occurring in patients younger than 25 years of age. Zou et al 4 reported association of FAS mutation with juvenile ALS in Chinese patients.…”

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confidence: 99%