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UniProtKB/Swiss-Prot O00519: Variant p.Pro129Thr

Fatty-acid amide hydrolase 1
Gene: FAAH
Chromosomal location: 1p34-p35
Variant information

Variant position:  129
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Type of variant:  Polymorphism
The variants are classified into three categories: Disease, Polymorphism and Unclassified.
  • Disease: Variants implicated in disease according to literature reports.
  • Polymorphism: Variants not reported to be implicated in disease.
  • Unclassified: Variants with uncertain implication in disease according to literature reports. Evidence against or in favor of a pathogenic role is limited and/or conflicting.

Residue change:  From Proline (P) to Threonine (T) at position 129 (P129T, p.Pro129Thr).
Indicates the amino acid change of the variant. The one-letter and three-letter codes for amino acids used in UniProtKB/Swiss-Prot are those adopted by the commission on Biochemical Nomenclature of the IUPAC-IUB.

Physico-chemical properties:  Change from medium size and hydrophobic (P) to medium size and polar (T)
The physico-chemical property of the reference and variant residues and the change implicated.

BLOSUM score:  -1
The score within a Blosum matrix for the corresponding wild-type to variant amino acid change. The log-odds score measures the logarithm for the ratio of the likelihood of two amino acids appearing by chance. The Blosum62 substitution matrix is used. This substitution matrix contains scores for all possible exchanges of one amino acid with another:
  • Lowest score: -4 (low probability of substitution).
  • Highest score: 11 (high probability of substitution).
More information can be found on the following page

Polymorphism:  Genetic variations in FAAH can be associated with susceptibility to polysubstance abuse [MIM:606581]. At homozygosity, variant Thr-129 is strongly associated with drug and alcohol abuse, and methamphetamine dependence.
Additional information on the polymorphism described.

Variant description:  Polymorphism associated with susceptibility to drug abuse; the mutant enzyme is more sensitive to proteolytic degradation; displays reduced cellular expression probably due to a post-translational mechanism preceding productive folding.
Any additional useful information about the variant.

Other resources:  
Links to websites of interest for the variant.



Sequence information

Variant position:  129
The position of the amino-acid change on the UniProtKB canonical protein sequence.

Protein sequence length:  579
The length of the canonical sequence.

Location on the sequence:   KGTNCVTSYLADCETQLSQA  P RQGLLYGVPVSLKECFTYKG
The residue change on the sequence. Unless the variant is located at the beginning or at the end of the protein sequence, both residues upstream (20) and downstream (20) of the variant will be shown.

Residue conservation: 
The multiple alignment of the region surrounding the variant against various orthologous sequences.

Human                         KGTNCVTSYLADCETQLSQAPRQG--------LLYGVPVSLKECFTYKG

Mouse                         KGTNCVTSYLTDCETQLSQAPRQG--------LLYGVPVSL

Rat                           KGTNCVTSYLTDCETQLSQAPRQG--------LLYGVPVSL

Pig                           RGTNCVTTYLADCEAQLCQAPGQG--------LLYGVPVSL

Caenorhabditis elegans        EKTNAVTCFILDAERQAEELDEQAKLPYYVKPPLFGVPLSL

Sequence annotation in neighborhood:  
The regions or sites of interest surrounding the variant. In general the features listed are posttranslational modifications, binding sites, enzyme active sites, local secondary structure or other characteristics reported in the cited references. The "Sequence annotation in neighborhood" lines have a fixed format:
  • Type: the type of sequence feature.
  • Positions: endpoints of the sequence feature.
  • Description: contains additional information about the feature.

TypePositionsDescription
Chain 1 – 579 Fatty-acid amide hydrolase 1
Topological domain 30 – 403 Cytoplasmic
Active site 142 – 142 Charge relay system


Literature citations

Submission
NIEHS SNPs program;
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA]; VARIANT THR-129;

Submission
Mural R.J.; Istrail S.; Sutton G.G.; Florea L.; Halpern A.L.; Mobarry C.M.; Lippert R.; Walenz B.; Shatkay H.; Dew I.; Miller J.R.; Flanigan M.J.; Edwards N.J.; Bolanos R.; Fasulo D.; Halldorsson B.V.; Hannenhalli S.; Turner R.; Yooseph S.; Lu F.; Nusskern D.R.; Shue B.C.; Zheng X.H.; Zhong F.; Delcher A.L.; Huson D.H.; Kravitz S.A.; Mouchard L.; Reinert K.; Remington K.A.; Clark A.G.; Waterman M.S.; Eichler E.E.; Adams M.D.; Hunkapiller M.W.; Myers E.W.; Venter J.C.;
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]; VARIANT THR-129;

A missense mutation in human fatty acid amide hydrolase associated with problem drug use.
Sipe J.C.; Chiang K.; Gerber A.L.; Beutler E.; Cravatt B.F.;
Proc. Natl. Acad. Sci. U.S.A. 99:8394-8399(2002)
Cited for: POLYMORPHISM; ASSOCIATION OF VARIANT THR-129 WITH SUSCEPTIBILITY TO POLYSUBSTANCE ABUSE; CHARACTERIZATION OF VARIANT THR-129;

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.
Chiang K.P.; Gerber A.L.; Sipe J.C.; Cravatt B.F.;
Hum. Mol. Genet. 13:2113-2119(2004)
Cited for: CHARACTERIZATION OF VARIANT THR-129;

The fatty acid amide hydrolase 385 A/A (P129T) variant: haplotype analysis of an ancient missense mutation and validation of risk for drug addiction.
Flanagan J.M.; Gerber A.L.; Cadet J.L.; Beutler E.; Sipe J.C.;
Hum. Genet. 120:581-588(2006)
Cited for: ASSOCIATION OF VARIANT THR-129 WITH SUSCEPTIBILITY TO POLYSUBSTANCE ABUSE;

Association of a functional FAAH polymorphism with methamphetamine-induced symptoms and dependence in a Malaysian population.
Sim M.S.; Hatim A.; Reynolds G.P.; Mohamed Z.;
Pharmacogenomics 14:505-514(2013)
Cited for: ASSOCIATION OF VARIANT THR-129 WITH SUSCEPTIBILITY TO METHAMPHETAMINE DEPENDENCE;

Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.