The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans.

TLDR

Mephenytoin metabolism shows a genetic polymorphism with an autosomal recessive poor metabolizer trait, large interracial frequency differences, and is linked to a defect in CYP2C19, though its molecular basis had remained elusive. The study reports that the principal defect in poor metabolizers is a single G→A mutation in exon 5 of CYP2C19 that creates an aberrant splice site. The mutation shifts the mRNA reading frame from amino acid 215, introduces a premature stop codon 20 residues downstream, and yields a truncated, non‑functional protein. Homozygosity for this mutation was observed in 7/10 Caucasian and 10/17 Japanese poor metabolizers, and the allele’s inheritance matched the phenotypic trait, confirming it as the major defect.

Abstract

The metabolism of the anticonvulsant drug mephenytoin exhibits a genetic polymorphism in humans, with the poor metabolizer trait being inherited in an autosomal recessive fashion. There are large interracial differences in the frequency of the poor metabolizer phenotype, with Oriental populations having a 5-fold greater frequency compared to Caucasians. Impaired metabolism of mephenytoin and a number of other currently used drugs results from a defect in a cytochrome P450 enzyme recently identified as CYP2C19. Attempts over the past decade to define the molecular genetic basis of the polymorphism have, however, been unsuccessful. We now report that the principal defect in poor metabolizers is a single base pair (G–>A) mutation in exon 5 of CYP2C19, which creates an aberrant splice site. This change alters the reading frame of the mRNA starting with amino acid 215 and produces a premature stop codon 20 amino acids downstream, which results in a truncated, non-functional protein. We further demonstrate that 7/10 Caucasian and 10/17 Japanese poor metabolizers are homozygous for this defect, indicating that this is the major defect responsible for the poor metabolizer phenotype. Finally, the familial inheritance of the deficient allele was found to be concordant with that of the phenotypic trait.