Polymorphisms in the ABCB1 gene in phenobarbital responsive and resistant idiopathic epileptic Border Collies

J Vet Intern Med. May-Jun 2011;25(3):484-9. doi: 10.1111/j.1939-1676.2011.0718.x. Epub 2011 Apr 12.

Abstract

Background: Variation in the ABCB1 gene is believed to play a role in drug resistance in epilepsy.

Hypothesis/objectives: Variation in the ABCB1 gene encoding the permeability-glycoprotein could have an influence on phenobarbital (PB) resistance, which occurs with high frequency in idiopathic epileptic Border Collies (BCs).

Animals: Two hundred and thirty-six client-owned BCs from Switzerland and Germany including 25 with idiopathic epilepsy, of which 13 were resistant to PB treatment.

Methods: Prospective and retrospective case-control study. Data were collected retrospectively regarding disease status, antiepileptic drug (AED) therapy, and drug responsiveness. The frequency of a known mutation in the ABCB1 gene (4 base-pair deletion in the ABCB1 gene [c.296_299del]) was determined in all BCs. Additionally, the ABCB1 coding exons and flanking sequences were completely sequenced to search for additional variation in 41 BCs. Association analyses were performed in 2 case-control studies: idiopathic epileptic and control BCs and PB-responsive and resistant idiopathic epileptic BCs.

Results: One of 236 BCs (0.4%) was heterozygous for the mutation in the ABCB1 gene (c.296_299del). A total of 23 variations were identified in the ABCB1 gene: 4 in exons and 19 in introns. The G-allele of the c.-6-180T > G variation in intron 1 was significantly more frequent in epileptic BCs resistant to PB treatment than in epileptic BCs responsive to PB treatment (P(raw) = .0025).

Conclusions and clinical importance: A variation in intron 1 of the ABCB1 gene is associated with drug responsiveness in BCs. This might indicate that regulatory mutations affecting the expression level of ABCB1 could exist, which may influence the reaction of a dog to AEDs.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Alleles
  • Animals
  • Anticonvulsants / therapeutic use*
  • Dog Diseases / drug therapy
  • Dog Diseases / genetics*
  • Dogs
  • Drug Resistance / genetics
  • Epilepsies, Myoclonic / drug therapy
  • Epilepsies, Myoclonic / genetics
  • Epilepsies, Myoclonic / veterinary*
  • Gene Expression Regulation
  • Phenobarbital / therapeutic use*
  • Polymorphism, Genetic*

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anticonvulsants
  • Phenobarbital