Reduced cellular expression and activity of the P129T mutant of human fatty acid amide hydrolase: evidence for a link between defects in the endocannabinoid system and problem drug use

Hum Mol Genet. 2004 Sep 15;13(18):2113-9. doi: 10.1093/hmg/ddh216. Epub 2004 Jul 14.


Fatty acid amide hydrolase (FAAH) inactivates the endogenous cannabinoid (endocannabinoid) anandamide and related lipid transmitters in vivo. A single nucleotide polymorphism (SNP) in the human FAAH gene (385C to A) has recently been described that, in homozygous form, is over-represented in subjects with problem drug use. This SNP, which converts a conserved proline residue in FAAH to threonine (P129T), suggests a potential role for the FAAH-endocannabinoid system in regulating addictive behavior. Nonetheless, the impact of the 385A mutation on the biochemical and cellular function of FAAH remains unknown. Here, we report that T-lymphocytes isolated from patients homozygous for the P129T-FAAH variant express less than half of the FAAH protein and activity observed in wild-type (WT) lymphocytes. Transfected COS-7 cells also expressed significantly lower levels of P129T-FAAH compared with WT-FAAH, indicating that the aberrant expression of the former protein is not a cell type-specific phenomenon. A comparison of the transcription/translation efficiencies and cellular stabilities of WT- and P129T-FAAH proteins revealed that the reduced expression of the mutant enzyme is due to a post-translational mechanism that precedes productive folding. These findings indicate that the natural 385A SNP in the human FAAH gene produces a mutant enzyme with reduced cellular stability, thus fortifying a potential link between functional abnormalities in the endocannabinoid system and drug abuse and dependence.

Publication types

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

MeSH terms

  • Amidohydrolases / analysis
  • Amidohydrolases / genetics*
  • Amidohydrolases / metabolism*
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cannabinoid Receptor Modulators / metabolism
  • Chlorocebus aethiops
  • Endocannabinoids
  • Gene Expression
  • Half-Life
  • Humans
  • Molecular Sequence Data
  • Mutation / genetics
  • Polymorphism, Single Nucleotide
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Conformation
  • Substance-Related Disorders / enzymology*
  • Substance-Related Disorders / genetics*
  • T-Lymphocytes / chemistry
  • T-Lymphocytes / metabolism
  • Transfection


  • Cannabinoid Receptor Modulators
  • Endocannabinoids
  • Proteasome Endopeptidase Complex
  • Amidohydrolases
  • fatty-acid amide hydrolase