Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis

Hum Mol Genet. 1994 Oct;3(10):1757-61. doi: 10.1093/hmg/3.10.1757.


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder primarily affecting motor neurons. The etiology of the majority of cases remains unknown. Recent findings from several laboratories suggest a role for neurofilaments in the development of motor neuron disorders. The C-terminal region of the human neurofilament heavy subunit (NEFH) contains a unique functional domain consisting of 43 repeat motifs of the amino acids Lys-Ser-Pro (KSP). This C-terminal region of NEFH forms the sidearm projections which cross-link the neurofilaments. Previously, we have demonstrated polymorphism in the C-terminal region of the human NEFH: an allelic variant of a slightly larger molecular size, containing an additional KSP phosphorylation motif. Novel mutations in this region were found in five ALS patients. We propose that changes in the KSP-repeat domain may affect the cross-linking properties of the heavy neurofilament subunit and perhaps contribute to the development of neurofilamentous swellings in motor neurons, a hallmark of ALS.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Amino Acid Sequence
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / physiopathology
  • Base Sequence
  • Cloning, Molecular
  • DNA / blood
  • DNA Primers
  • Female
  • Genetic Variation*
  • Humans
  • Macromolecular Substances
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Neurofilament Proteins / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Genetic
  • Repetitive Sequences, Nucleic Acid


  • DNA Primers
  • Macromolecular Substances
  • Neurofilament Proteins
  • DNA