Identification of a novel splice-site mutation in the CYP1A2 gene.
Allorge, Delphine 1; Chevalier, Dany 1; Lo-Guidice, Jean-Marc 1; Cauffiez, Christelle 1; Suard, Francoise 2; Baumann, Pierre 3; Eap, Chin B. 3; Broly, Franck 1
[Report]
British Journal of Clinical Pharmacology.
56(3):341-344, September 2003.
(Format: HTML)
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.
(C) 2003 Blackwell Science Ltd.