A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis

J Biol Chem. 2004 Oct 29;279(44):45951-6. doi: 10.1074/jbc.M408139200. Epub 2004 Aug 17.


Peripherin is a neuronal intermediate filament associated with inclusion bodies in motor neurons of patients with amyotrophic lateral sclerosis (ALS). A possible peripherin involvement in ALS pathogenesis has been suggested based on studies with transgenic mouse overexpressors and with a toxic splicing variant of the mouse peripherin gene. However, the existence of peripherin gene mutations in human ALS has not yet been documented. Therefore, we screened for sequence variants of the peripherin gene (PRPH) in a cohort of ALS patients including familial and sporadic cases. We identified 18 polymorphic variants of PRPH detected in both ALS and age-matched control populations. Two additional PRPH variants were discovered in ALS cases but not in 380 control individuals. One variant consisted of a nucleotide insertion in intron 8 (PRPH(IVS8)(-36insA)), whereas the other one consisted of a 1-bp deletion within exon 1 (PRPH(228delC)), predicting a truncated peripherin species of 85 amino acids. Remarkably, expression of this frameshift peripherin mutant in SW13 cells resulted in disruption of neurofilament network assembly. These results suggest that PRPH mutations may be responsible for a small percentage of ALS, cases and they provide further support of the view that neurofilament disorganization may contribute to pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / etiology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Base Sequence
  • Frameshift Mutation*
  • Humans
  • Intermediate Filament Proteins / genetics*
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Nerve Tissue Proteins / genetics*
  • Neurofilament Proteins / chemistry
  • Peripherins


  • Intermediate Filament Proteins
  • Membrane Glycoproteins
  • Nerve Tissue Proteins
  • Neurofilament Proteins
  • PRPH protein, human
  • Peripherins
  • Prph protein, mouse
  • neurofilament protein L
  • neurofilament protein M