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Identification of a novel splice‐site mutation in the CYP1A2 gene
Author(s) -
Allorge Delphine,
Chevalier Dany,
LoGuidice JeanMarc,
Cauffiez Christelle,
Suard Françoise,
Baumann Pierre,
Eap Chin B.,
Broly Franck
Publication year - 2003
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.2003.01858.x
Subject(s) - genetics , splice site mutation , splice , mutation , gene , identification (biology) , computational biology , biology , rna splicing , rna , botany
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 (3534 G > 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.