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Identification of a novel splice-site mutation in the CYP1A2 gene
Delphine Allorge1, Dany Chevalier, Jean-Marc Lo-Guidice
1EA 2679, Faculté de Médecine/Pôle Recherche, 1 place de Verdun, F-59045 Lille cedex, France. dallorge@University-lille2.fr
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.