Identification of a novel splice-site mutation in the CYP1A2 gene

Br J Clin Pharmacol. 2003 Sep;56(3):341-4. doi: 10.1046/j.1365-2125.2003.01858.x.


Aims: To identify the molecular basis for a low CYP1A2 metabolic status, as determined by a caffeine phenotyping test, in a 71-year-old, nonsmoking, Caucasian woman who presented with very high clozapine concentrations despite being administered a standard dose of the drug.

Methods: The nucleotide sequence of the 7 exons, exon-intron boundaries and 5'-flanking region of the CYP1A2 gene was analysed by direct sequencing.

Results: Only one heterozygous point mutation was identified in the donor splice site of intron 6 (3534G > A) of CYP1A2. This mutation could cause abnormal RNA splicing and therefore lead to a truncated nonfunctional enzyme. No other carrier of this mutation was identified in a population of 100 unrelated healthy Caucasians.

Conclusions: This is the first report of a splice-site mutation affecting the CYP1A2 gene. This polymorphism is a likely explanation for the low CYP1A2 activity associated with high clozapine concentrations in this patient.

Publication types

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

MeSH terms

  • Aged
  • Base Sequence / genetics
  • Caffeine / genetics
  • Clozapine / blood
  • Cytochrome P-450 CYP1A2 / genetics*
  • Exons / genetics
  • Female
  • Humans
  • Introns / genetics
  • Mutation / genetics*
  • Phenotype
  • Polymerase Chain Reaction / methods
  • Polymorphism, Genetic / genetics
  • Polymorphism, Single-Stranded Conformational
  • Psychotic Disorders / blood
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / genetics
  • RNA Splice Sites / genetics


  • RNA Splice Sites
  • Caffeine
  • Cytochrome P-450 CYP1A2
  • Clozapine