Frequency of the MDR1 mutant allele associated with multidrug sensitivity in dogs from Brazil

Abstract

To date, a 4-bp deletion in the MDR1 gene has been detected in more than ten dog breeds, as well as in mixed breed dogs, in several countries, however information regarding this mutation in dogs from Brazil is lacking. For this reason, 103 Collies, 77 Border Collies, 76 Shetland Sheepdogs, 20 Old English Sheepdogs, 55 German Shepherds, 16 Australian Shepherds, and 53 Whippets from Brazil were screened for the presence of the mutation. The heterozygous mutated genotype, MDR1 (+/−), frequency found for Collies, Australian Shepherd, and Shetland Sheepdog was 50.5% (95% CI =41.1%–59.9%), 31.3% (95% CI =8.6%–53.2%), and 15.8% (95% CI =7.7%–23.9%), respectively. Homozygous mutated genotype, MDR1 (−/−), was detected only in Collies 35.9%. The MDR1 allele mutant frequency found for Collies, Australian Shepherd, and Shetland Sheepdog was 61.2% (95% CI =54.8%–67.5%), 15.6% (95% CI =3.1%–28.2%), and 7.9% (95% CI =3.7%–12.1%), respectively. Additionally, even free of the mutant allele, the maximum mutant prevalence (MMP) in that population, with 95% CI, was 3.8%, 5.2%, 5.4%, and 13.8% for Border Collies, German Shepherds, Whippets, and Old English Sheepdogs, respectively. In this way, this information is important, not only for MDR1 genotype-based breeding programs and international exchange of breeding animals of predisposed breeds, but also for modification of drug therapy for breeds at risk.

Genotypic and allelic frequencies of MDR1 gene in dogs in Italy

“…11 Slightly lower results in MDR1 mutant frequency have been recorded in Germany: 59 per cent, 7 55 per cent, 12 in Japan 58.3 per cent, 13 Australia 56 per cent 14 and Brazil 61.2 per cent. 3 In AuS, the MDR1 mutated allele frequency in Italy was calculated to be 35 per cent, a mean value considering it ranged from 15.7 per cent in Brazil 2 to 46 per cent in UK. 4 In the USA, the country of origin of AuS breed, Neff et al 1 and Mealey and Meurs 10 reported a mutant allele frequency of 17 per cent and 29 per cent, respectively.…”

“…About Whi: the mutation has been described in the FCI as unrecognised long-haired whippet SiW in the USA with a 16-18 per cent frequency, 1 10 but no mutation was found in the 14 samples analysed in UK by Tappin et al in 2012 4 and in the 53 samples tested by Monobe and colleagues in Brazil. 3 MDR1 mutation test is available since 2008 when the first animals were tested for (2009 n=0, 2010 n=2, 2011 n=3). A clear increase in the number of animals tested has been recorded since 2012 (n=44).…”

“…The evident clinical signs of the neurotoxic effect promoted by the dysfunction of P-gp, caused by the expression of the mutant MDR1 gene, could even lead to coma and death. 3 P-gp plays an important role in physiological barriers. In the blood/brain barrier, it limits drug efflux in the central nervous system whereas in placental trophoblast it reduces drug access to fetal circulation and in Sertoli cells barrier it limits drug entry in gonads.…”

“…In the blood/brain barrier, it limits drug efflux in the central nervous system whereas in placental trophoblast it reduces drug access to fetal circulation and in Sertoli cells barrier it limits drug entry in gonads. 3 Pharmacogenetic investigation of MDR1 gene plays a pivotal role in purebred dog breed studies considering the basic function of P-gp in restricting the xenobiotics' access. 4 The risk of intrinsic and acquired multidrug resistance in clinical therapy with particular attention to cancer treatment has been first described more than 30 years ago by Ueda and colleagues.…”

DRUG TOLERANCE/INTOLERANCE IN DOMESTIC DOG (Canis lupus familiaris) WITH MDR1 GENE DEFECT

“…al. 2010;Mizukami et al 2012;Mizukami et al 2013;Monobe et al 2015), yet the most important mutation remains the one which leads to a loss of four base pairs in 227-230 nucleotide, known as MDR1 (c.227-230del) or ABCB1-1Δ (Mizukami et al 2012).…”