Mutations in FUS, an RNA Processing Protein, Cause Familial Amyotrophic Lateral Sclerosis Type 6

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is familial in 10% of cases. We have identified a missense mutation in the gene encoding fused in sarcoma (FUS) in a British kindred, linked to ALS6. In a survey of 197 familial ALS index cases, we identified two further missense mutations in eight families. Postmortem analysis of three cases with FUS mutations showed FUS-immunoreactive cytoplasmic inclusions and predominantly lower motor neuron degeneration. Cellular expression studies revealed aberrant localization of mutant FUS protein. FUS is involved in the regulation of transcription and RNA splicing and transport, and it has functional homology to another ALS gene, TARDBP, which suggests that a common mechanism may underlie motor neuron degeneration.

[1]  V. Meininger,et al.  Mutations of the ANG gene in French patients with sporadic amyotrophic lateral sclerosis. , 2008, Archives of neurology.

[2]  A. Grierson,et al.  Role of axonal transport in neurodegenerative diseases. , 2008, Annual review of neuroscience.

[3]  B. McConkey,et al.  TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis , 2008, Nature Genetics.

[4]  Murray Grossman,et al.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis , 2008, The Lancet Neurology.

[5]  J. Morris,et al.  TDP‐43 A315T mutation in familial motor neuron disease , 2008, Annals of neurology.

[6]  Xun Hu,et al.  TDP-43 Mutations in Familial and Sporadic Amyotrophic Lateral Sclerosis , 2008, Science.

[7]  A. Tessitore,et al.  A novel Angiogenin gene mutation in a sporadic patient with amyotrophic lateral sclerosis from southern Italy , 2008, Neuromuscular Disorders.

[8]  J. Trojanowski,et al.  Pathological TDP‐43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations , 2007, Annals of neurology.

[9]  V. Meininger,et al.  Three families with amyotrophic lateral sclerosis and frontotemporal dementia with evidence of linkage to chromosome 9p. , 2007, Archives of neurology.

[10]  T. Takumi,et al.  Myosin-Va Facilitates the Accumulation of mRNA/Protein Complex in Dendritic Spines , 2006, Current Biology.

[11]  Bruce L. Miller,et al.  Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis , 2006, Science.

[12]  G. Kollias,et al.  Onset and Progression in Inherited ALS Determined by Motor Neurons and Microglia , 2006, Science.

[13]  F. Baas,et al.  Familial amyotrophic lateral sclerosis with frontotemporal dementia is linked to a locus on chromosome 9p13.2-21.3. , 2006, Brain : a journal of neurology.

[14]  H. Horvitz,et al.  A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia , 2006, Neurology.

[15]  G. Hicks,et al.  TLS, EWS and TAF15: a model for transcriptional integration of gene expression. , 2006, Briefings in functional genomics & proteomics.

[16]  S. Ennis,et al.  ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis , 2006, Nature Genetics.

[17]  Nobutaka Hirokawa,et al.  Kinesin Transports RNA Isolation and Characterization of an RNA-Transporting Granule , 2004, Neuron.

[18]  C. Lewis,et al.  Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. , 2003, American journal of human genetics.

[19]  J. Haines,et al.  Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. , 2003, American journal of human genetics.

[20]  D. Borchelt,et al.  High Molecular Weight Complexes of Mutant Superoxide Dismutase 1: Age-Dependent and Tissue-Specific Accumulation , 2002, Neurobiology of Disease.

[21]  Robert H. Brown,et al.  A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. , 2002, American journal of human genetics.

[22]  A. Al-Chalabi,et al.  Progress in the pathogenesis of amyotrophic lateral sclerosis , 2001, Current neurology and neuroscience reports.

[23]  J. Haines,et al.  Linkage of familial amyotrophic lateral sclerosis with frontotemporal dementia to chromosome 9q21-q22. , 2000, JAMA.

[24]  J. Powell,et al.  Mutations in all five exons of SOD‐1 may cause ALS , 1998, Annals of neurology.

[25]  J. Powell,et al.  Familial amyotrophic lateral sclerosis , 1997, Neurology.

[26]  M. Gurney,et al.  Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. , 1994, Science.

[27]  D. C. Carter,et al.  Atomic structure and chemistry of human serum albumin , 1993, Nature.

[28]  J. Haines,et al.  Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis , 1993, Nature.