This allelic variant is also known as CYP2D6*4 or CYP2D6(B).
In 20 individuals with poor metabolism of debrisoquine (608902), Gough et al. (1990) identified a G-to-A transition at the first nucleotide of exon 4 in the CYP2D6 gene, resulting in a shift of the splice site and introduction of a premature termination codon. The mutant protein had no residual activity. Gough et al. (1990) presented preliminary data suggesting a reduction in the proportion of poor metabolizers among patients with lung or bladder cancer.
In leukocyte DNA of an individual who was deficient in debrisoquine metabolism, Hanioka et al. (1990) identified a 1934G-A transition at the junction of the third intron and fourth exon, resulting in an aberrant 3-prime splice recognition site and an mRNA with a single basepair deletion. The disrupted mRNA leads to a truncated protein without functional activity. The patient studied was a compound heterozygote: the allele with the 1934G-A mutation was identified by a 44-kb XbaI restriction fragment; the second allele was a complete deletion of the CYP2D6 gene (124030.0002). The dextromethorphan urinary metabolite ratio in this patient was 9.7, which is operationally defined as a poor metabolizer of debrisoquine.
Kagimoto et al. (1990) likewise concluded that the mutation at the 3-prime splice site of intron 3 is a common cause of the poor metabolizer phenotype.
Chen et al. (1995) found that Alzheimer disease (104300) patients who were either heterozygous or homozygous for the CYP2D6*4 allele had a smaller decline of the synaptic markers choline acetyltransferase (118490) and synaptophysin (313475) in the frontal cortex than those who did not. Senile plaques neurofibrillary tangles were not significantly affected. The authors had earlier shown an association of the CYP2D6*4 mutant allele with Lewy body formation (127750). The findings suggested different mechanisms of neurodegeneration in the 2 disorders.
