Partial deletion of CYP2B6 owing to unequal crossover with CYP2B7.
OBJECTIVE
To evaluate the possibility of copy number variation (CNV) of CYP2B6.


METHODS
We investigated CNV in 226 HIV-1-infected individuals by quantitative PCR. Identification of a candidate CNV prompted characterization of the size of deletion by assessment of absence of exons, mapping of the recombination site by sequencing, and by southern blot. The functional consequences of CNV were assessed in silico (predicted protein), and in vivo, by evaluation of plasma drug levels of the CYP2B6 substrate efavirenz.


RESULTS
Analyses identified one white individual carrying a heterozygous deletion of exons 1-4 of CYP2B6. We identified a approximately 68 kb deletion between CYP2B7 and CYP2B6, and mapped the crossover to a homologous region in intron 4 of both genes. The new hybrid allele, named CYP2B6*29, carries two amino acid substitutions, Q172H and M198T, previously associated with impaired enzyme function. Consistent with the functional prediction, the average of efavirenz area under the curve values of the patient was mean+/-SD, 81.64+/-23.62, versus 47.75+/-19.73 mug h/ml for individuals with an extensive metabolizer phenotype.


CONCLUSIONS
CYP2B6*29 represents a new mechanism of genetic variation at the CYP2B6 locus, underscoring the highly polymorphic nature of this isoenzyme.
Rotger
Margalida
M
Institute of Microbiology, University Hospital Center and University of Lausanne, Lausanne; Switzerland.
Saumoy
Maria
M
Zhang
Kunlin
K
Flepp
Markus
M
Sahli
Roland
R
Decosterd
Laurent
L
Telenti
Amalio
A
D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D002874:Chromosome Mapping; D003434:Crossing Over, Genetic / Q000235:genetics*; D065702:Cytochrome P-450 CYP2B6; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D000072467:Cytochrome P450 Family 2; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage; D006801:Humans; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011995:Recombination, Genetic / Q000235:genetics
D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; C107082:CYP2B7P protein, human; D065702:Cytochrome P-450 CYP2B6; D000072467:Cytochrome P450 Family 2; D010089:Oxidoreductases, N-Demethylating