Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis

Nature. 2012 Aug 23;488(7412):499-503. doi: 10.1038/nature11280.

Abstract

Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative disorder resulting from motor neuron death. Approximately 10% of cases are familial (FALS), typically with a dominant inheritance mode. Despite numerous advances in recent years, nearly 50% of FALS cases have unknown genetic aetiology. Here we show that mutations within the profilin 1 (PFN1) gene can cause FALS. PFN1 is crucial for the conversion of monomeric (G)-actin to filamentous (F)-actin. Exome sequencing of two large ALS families showed different mutations within the PFN1 gene. Further sequence analysis identified 4 mutations in 7 out of 274 FALS cases. Cells expressing PFN1 mutants contain ubiquitinated, insoluble aggregates that in many cases contain the ALS-associated protein TDP-43. PFN1 mutants also display decreased bound actin levels and can inhibit axon outgrowth. Furthermore, primary motor neurons expressing mutant PFN1 display smaller growth cones with a reduced F/G-actin ratio. These observations further document that cytoskeletal pathway alterations contribute to ALS pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / diagnosis
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Axons / metabolism
  • Axons / pathology
  • Cells, Cultured
  • European Continental Ancestry Group / genetics
  • Exome / genetics
  • Female
  • Genetic Predisposition to Disease / genetics*
  • Growth Cones / metabolism
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Jews / genetics
  • Male
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Motor Neurons / cytology
  • Motor Neurons / metabolism
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism*
  • Mutation / genetics*
  • Pedigree
  • Profilins / genetics*
  • Profilins / metabolism*
  • Protein Conformation
  • Ubiquitination

Substances

  • Actins
  • Mutant Proteins
  • PFN1 protein, human
  • Profilins