Canine mdr1 gene mutation in Japan

Area of Science:

• Veterinary Genetics
• Pharmacogenomics
• Molecular Biology

Background:

• The canine multidrug resistance (MDR1) gene plays a crucial role in drug transport.
• A specific 4-bp deletion mutation in the mdr1 gene is associated with adverse drug reactions in certain dog breeds.
• Understanding the frequency and functional impact of this mutation is vital for canine pharmacotherapy.

Purpose of the Study:

• To determine the frequency of the 4-bp deletion mutant in the canine mdr1 gene across eight breeds in Japan.
• To investigate the functional consequences of the mdr1 mutation on MDR1 protein expression and function.
• To assess the presence of functional MDR1 in dogs with different mdr1 genotypes.

Main Methods:

• Genotyping of 193 dogs from eight breeds for the 4-bp deletion in the mdr1 gene.
• Detection of MDR1 protein expression on peripheral blood mononuclear cells (PBMC).
• Functional assays using Rhodamine 123 (Rh123) extrusion from lymphocytes and inhibition by verapamil.

Main Results:

• The 4-bp deletion mutant mdr1 allele was identified in Collies (58.3%), Australian Shepherds (33.3%), and Shetland Sheepdogs (1.2%).
• MDR1 protein was absent in PBMC from a mdr1-1Delta/mdr1-1Delta Collie.
• Rh123 extrusion from lymphocytes was observed in MDR1/MDR1 dogs but not in mdr1-1Delta/mdr1-1Delta dogs, indicating loss of MDR1 function.

Conclusions:

• The mutant mdr1 allele is prevalent in Japanese Collie-breed dogs.
• Dogs homozygous for the mdr1-1Delta mutation (mdr1-1Delta/mdr1-1Delta) lack functional MDR1 protein.
• This genetic variation has significant implications for drug safety and efficacy in affected canine populations.