title: Identification of a novel splice-site mutation in the CYP1A2 gene.
abstract: OBJECTIVE
  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.
authors.affiliation: EA 2679, Faculté de Médecine/Pôle Recherche, 1 place de Verdun, F-59045 Lille cedex, France. dallorge@University-lille2.fr
authors.forename: Delphine
authors.initials: D
authors.lastname: Allorge
authors.forename: Dany
authors.initials: D
authors.lastname: Chevalier
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Lo-Guidice
authors.forename: Christelle
authors.initials: C
authors.lastname: Cauffiez
authors.forename: Françoise
authors.initials: F
authors.lastname: Suard
authors.forename: Pierre
authors.initials: P
authors.lastname: Baumann
authors.forename: Chin B
authors.initials: CB
authors.lastname: Eap
authors.forename: Franck
authors.initials: F
authors.lastname: Broly
mesh_terms: D000368:Aged; D001483:Base Sequence / Q000235:genetics; D002110:Caffeine / Q000235:genetics; D003024:Clozapine / Q000097:blood; D019388:Cytochrome P-450 CYP1A2 / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction / Q000379:methods; D011110:Polymorphism, Genetic / Q000235:genetics; D018807:Polymorphism, Single-Stranded Conformational; D011618:Psychotic Disorders / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D022821:RNA Splice Sites / Q000235:genetics
chemical_list: D022821:RNA Splice Sites; D002110:Caffeine; D019388:Cytochrome P-450 CYP1A2; D003024:Clozapine