CYP2D7 splice variants in human liver and brain: does CYP2D7 encode functional protein?

Area of Science:

• Pharmacogenomics
• Molecular Biology
• Drug Metabolism

Background:

• A brain-specific CYP2D7 protein variant, involved in codeine metabolism, was previously identified in Indian subjects.
• The existence and functionality of this variant in other ethnic groups remain largely unexplored.

Purpose of the Study:

• To investigate the presence and potential functionality of CYP2D7 and CYP2D6 splice variants in liver and brain tissues across diverse ethnic backgrounds.
• To determine if the previously described CYP2D7 alternate mRNA is present and functional in non-Indian populations.

Main Methods:

• Analysis of full-length CYP2D7 and CYP2D6 splice products in liver and brain tissues.
• CYP2D7 splice variant-specific PCR was performed on samples from 13 subjects.
• Genotyping of 285 additional subjects was conducted to assess specific genetic variations (138delT and g.14408G > C SNP).

Main Results:

• A minor CYP2D7 splice variant, containing a partial intron 6, was detected in both liver and brain tissues.
• This transcript is unlikely to encode a functional protein due to the absence of a frame-shift-reverting deletion (138delT).
• The specific SNP (g.14408G > C) required for a functional transcript was not observed; individuals with g.14408G/G genotype showed premature stop codons in splice variants with the intron 6 insertion.

Conclusions:

• No evidence of functional CYP2D7 transcripts was found in the analyzed Asian, Caucasian, or African American individuals.
• The previously reported functional CYP2D7 variant appears to be specific to the Indian population studied.
• Further research is needed to fully understand the ethnic variations in CYP2D7 and CYP2D6 gene expression and function.