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

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.

DOI: 10.1046/j.1365-2125.2003.01858.x

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