Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders

Science. 2014 Jan 31;343(6170):506-511. doi: 10.1126/science.1247363.


Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease.

Publication types

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

MeSH terms

  • Animals
  • Axons / physiology
  • Biological Transport / genetics
  • Cohort Studies
  • Exome / genetics*
  • Gene Regulatory Networks
  • Genetic Association Studies*
  • Humans
  • Motor Neuron Disease / genetics*
  • Mutation
  • Neurons / metabolism*
  • Nucleotides / genetics
  • Nucleotides / metabolism
  • Pyramidal Tracts / metabolism*
  • Sequence Analysis, DNA
  • Spastic Paraplegia, Hereditary / genetics*
  • Synapses / physiology
  • Transcriptome
  • Zebrafish


  • Nucleotides

Associated data

  • dbGaP/PHS000288