Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase

Proc Natl Acad Sci U S A. 2010 Apr 20;107(16):7556-61. doi: 10.1073/pnas.0914128107. Epub 2010 Apr 5.


We report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein. Similarly, lentiviral-mediated expression of R199W DAO in primary motor neuron cultures caused increased TUNEL labeling. This effect was also observed when motor neurons were cocultured on transduced astrocytes expressing R199W, indicating that the motor neuron cell death induced by this mutation is mediated by both cell autonomous and noncell autonomous processes. DAO controls the level of D-serine, which accumulates in the spinal cord in cases of sporadic ALS and in a mouse model of ALS, indicating that this abnormality may represent a fundamental component of ALS pathogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / enzymology*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Animals
  • Apoptosis
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • D-Amino-Acid Oxidase / genetics*
  • D-Amino-Acid Oxidase / physiology*
  • Female
  • Genetic Linkage
  • Male
  • Mice
  • Microsatellite Repeats
  • Motor Neurons / metabolism
  • Mutation*
  • Neurodegenerative Diseases / genetics
  • Neurons / metabolism
  • Rats


  • D-Amino-Acid Oxidase