Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis

  title={Mutations in the FUS/TLS Gene on Chromosome 16 Cause Familial Amyotrophic Lateral Sclerosis},
  author={Thomas J. Kwiatkowski and Daryl A. Bosco and Ashley Lyn Leclerc and Eric Tamrazian and C. Vanderburg and Carsten Russ and Adrian Davis and James M. Gilchrist and Edward J. Kasarskis and Theodore L. Munsat and Paul N. Valdmanis and Guy A. Rouleau and Betsy A. Hosler and Pietro Cortelli and Pieter J de Jong and Yuko Yoshinaga and Jonathan L. Haines and Margaret A. Pericak-Vance and J Yan and Nicola Ticozzi and Teepu Siddique and Diane M. McKenna-Yasek and Peter C. Sapp and H. Robert Horvitz and John E. Landers and R. H. Brown},
  pages={1205 - 1208}
Amyotrophic lateral sclerosis (ALS) is a fatal degenerative motor neuron disorder. Ten percent of cases are inherited; most involve unidentified genes. We report here 13 mutations in the fused in sarcoma/translated in liposarcoma (FUS/TLS) gene on chromosome 16 that were specific for familial ALS. The FUS/TLS protein binds to RNA, functions in diverse processes, and is normally located predominantly in the nucleus. In contrast, the mutant forms of FUS/TLS accumulated in the cytoplasm of neurons… 

Nuclear transport impairment of amyotrophic lateral sclerosis‐linked mutations in FUS/TLS

This work examined the biochemical and cellular characteristics of mutant FUS in expressing cells and found that ALS‐linked mutations of FUS are clustered in the C‐terminal region.

Molecular pathomechanisms of Amyotrophic Lateral Sclerosis caused by FUS mutations

A multi-step model where antiviral immune response serves as the "second hit" provoking FUSopathy is proposed, and the presence of endogenous mutant FUS protein in the nucleus causes hyper-assembly of structurally and functionally abnormal paraspeckles - nuclear bodies assembled on the long non-coding RNA called Nuclear Paraspeckle Assembly Transcript 1 (NEAT1).

TARDBP and FUS Mutations Associated with Amyotrophic Lateral Sclerosis: Summary and Update

The biological and clinical relevance of TARDBP and FUS mutations in ALS is summarized and functional characterization of these mutations in in vitro and in vivo systems is helping to better understand how motor neuron degeneration occurs.

[Amyotrophic lateral sclerosis (ALS) with the mutations in the fused in sarcoma/translocated in liposarcoma gene].

  • M. Aoki
  • Biology, Medicine
    Rinsho shinkeigaku = Clinical neurology
  • 2013
As the disease duration becomes longer, there were broader distributions of neuronal and glial FUS/TLS-immunoreactive inclusions, and neuropathological examination revealed remarkable atrophy of the brainstem tegmentum characterized by cytoplasmic basophilic inclusion bodies in the neurons of thebrainstem.

Mechanisms of FUS mutations in familial amyotrophic lateral sclerosis

Evidence for an oligogenic basis of amyotrophic lateral sclerosis.

Evidence for an oligogenic aetiology of ALS is provided and may have important implications for the interpretation of whole exome/genome experiments designed to identify new ALS-associated genes and for genetic counselling, especially of unaffected family members.

Fus gene mutations in familial and sporadic amyotrophic lateral sclerosis

It is demonstrated that the phenotype with FUS mutations extends beyond classical ALS cases, and there are specific clinicogenetic correlations and the first detailed neuropathological description is provided.



TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis

The evidence suggests a pathophysiological link between TDP-43 and ALS, and neighboring mutations in a highly conserved region of TARDBP in sporadic and familial ALS cases.

Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

Tight genetic linkage between FALS and a gene that encodes a cytosolic, Cu/Zn-binding superoxide dismutase (SOD1), a homodimeric metalloenzyme that catalyzes the dismutation of the toxic superoxide anion O–2 to O2 and H2O2 is reported.

Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration

Findings add to the growing body of evidence implicating the RNA processing pathway in neurodegeneration and suggest a critical role for ELP3 in neuron biology and of ELP 3 variants in ALS.

TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis

Findings further corroborate that TDP-43 is involved in ALS pathogenesis and reports eight missense mutations in nine individuals—six from individuals with sporadic ALS and three from those with familial ALS (FALS)—and a concurring increase of a smaller T DP-43 product.

Epidemiology of ALS.

  • L. Nelson
  • Medicine, Psychology
    Clinical neuroscience
  • 1995
Associations of sporadic ALS with work in occupations that involve toxicant exposure and genetic susceptibility to environmental toxicants are identified; however, genetically acquired biochemical defects have not been identified in sporadic ALS patients.

Fus deficiency in mice results in defective B-lymphocyte development and activation, high levels of chromosomal instability and perinatal death

The results indicate that Fus is essential for viability of neonatal animals, influences lymphocyte development in a non-cell-intrinsic manner, has an intrinsic role in the proliferative responses of B cells to specific mitogenic stimuli and is required for the maintenance of genomic stability.

Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma

The presence of an abnormal CHOP transcript and protein in these tumours is reported and Targeting of a conserved effector domain of RNA-binding proteins to DNA may play a role in tumour formation.

Fusion of the dominant negative transcription regulator CHOP with a novel gene FUS by translocation t(12;16) in malignant liposarcoma

It is shown that the translocation t(12;16)(q13:p11) in malignant myxoid liposarcoma can be a fusion of the CHOP dominant negative transcription factor gene with a novel gene, FUS, which can result in fusion of.