OMIA 001402-9615 : Multidrug resistance 1 in Canis lupus familiaris

In other species: domestic cat

Possibly relevant human trait(s) and/or gene(s) (MIM number): 171050

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2001

Species-specific name: Invermectin sensitivity

Species-specific description: Multidrug resistance 1 is caused by a lack of P-glycoprotein drug transporter in the blood-brain barrier, which is characterized by neurotoxicity after administration of certain drugs. A genetic test is available.

Molecular basis: By cloning and sequencing a very likely candidate gene (based on knowledge of the biochemistry and physiology of the disorder) Mealey et al. (2001) identified the causative mutation as a 4 bp deletion (c.296_299del4) in the ABCB1 (MDR1) gene, which encodes P-glycoprotein drug transporter (P-gp). The deletion causes a frame shift, introducing several stop codons, which cause premature protein truncation. P-gp is an ATP-driven drug transporter that binds a variety of drugs in the endothelial cells and transports them back into the blood, preventing them from diffusing into the brain. P-gp is expressed in brain capillaries, renal proximal tubules, liver, small bowel, colon, placenta, and brain endothelium. P-gp is also expressed at high levels in tumor cells, allowing them to resist a spectrum of chemotherapeutic drugs (Mealey et al., 2001, Gramer et al., 2011).

Han et al. (2010) reported a different causal mutation, c.73insAAT, in an ivermectin-sensitive Border Collie.

Alves et al. (2011) reported a base substitution (c.-6-180T>G) in intron 1 that "was significantly more frequent in epileptic [Border Collies] resistant to [phenobarbital] treatment than in epileptic BCs responsive to PB treatment".

Clinical features: Neurotoxicity following drug administration, which varies according to dose, is the main sign. Dogs may show ataxia, tremors, seizures, excessive salivation, obtundation, bradycardia, mydriasis, loss of menace, loss of papillary light responses, coma and respiratory arrest (Mealey et al., 2001). P-gp normally transports some chemotherapeutic agents (Vinca alkaloids, doxorubicin), immunosuppressants (cyclosporine, tacrolimus), macrocyclic lactone antiparasitic drugs (ivermectin, loperamide, milbemycin, selamectin, moxidectin), HIV-1 protease inhibitors, and steroid hormones.

Pathology: Animals with the causative mutation lack P-glycoprotein (P-gp), so, they cannot clear certain compounds from the brain as quickly as normal animals., and accumulation of high drug levels in the brain leads to toxicity (Mealey, 2008).

Prevalence: In the USA, the frequency of the 4bp deletion allele was reported as 56-75% in collies, 7% in Shetland sheepdogs, 29% in Australian shepherds, 1% in Border collies, 1% in old English sheepdogs, 20% in miniature Australian shepherds, 29% in longhaired whippets, 16% in silken windhounds, and 6% in German shepherds (Mealey and Meurs, 2008, Mealey, 2008). In Germany, the frequency of the same allele was reported as 59% in collies, 45% in longhaired whippets, 30% in Shetland sheepdogs, 24% in miniature Australian shepherds, 22% in Australian shepherds, 17% in Wällers, 14% in white Swiss shepherds, 4% in old English sheepdogs, 1% in Border collies, 8% in herding breed mixes, and 2% in mixed breeds (Gramer et al., 2011).

Mizukami et al. (2013) developed a PCR-RFLP genotyping test for the c.-6-180T>G mutation, and in 472 Border Collies in Japan "demonstrated the frequencies of the T/T wild type, T/G heterozygote, and G/G mutant homozygote to be 60.0%, 30.3%, and 9.8%, respectively, indicating that the frequency of the mutant G allele is extremely high (24.9%) in Border Collies. The results suggest that this high mutation frequency of the mutation is likely to cause a high prevalence of phenobarbital-resistant epilepsy in Border Collies."

Mizukami et al. (2016) reported the frequency of the 4bp deletion allele as 0.002 in 500 Border collies in Japan.

Control: Breeding of affected dogs, regardless of breed, should be avoided. In breeds with high allelic frequency, carriers should be bred only to noncarriers. In breeds with low allelic frequency, breeding of carriers should be avoided.

Breeds: Australian Shepherd, Border Collie, Collie, German Shepherd Dog, Longhaired whippet, McNab shepherd, mixed breed, Old English Sheepdog, Shetland Sheepdog, Silken windhound, Waller, White Swiss shepherd.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
ABCB1 ATP-binding cassette, sub-family B (MDR/TAP), member 1 Canis lupus familiaris 14 NC_006596.3 (13852829..13644891) ABCB1 Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective.

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Breed(s) Variant Phenotype Gene Allele Type of Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
Border Collie Multidrug resistance 1 ABCB1 regulatory c.-6-180T>G 2011 21488961
Australian Shepherd Border Collie Collie German Shepherd Dog Longhaired whippet Miniature Australian shepherd Old English Sheepdog Shetland Sheepdog Silken windhound Waller White Swiss shepherd Multidrug resistance 1 ABCB1 deletion, small (<=20) c.295_298delAGAT p.Asp75fs 2001 11692082 Variant information gleaned from or confirmed by Donner et al. (2016) PLoS One 11:e0161005
Border Collie Multidrug resistance 1 ABCB1 insertion, small (<=20) c.73insAAT 2010 21113104

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2018 Myers, M.J., Martinez, M., Li, F., Howard, K., Yancy, H.F., Troutman, L., Sharkey, M. :
Impact of ABCB1 genotype in Collies on the pharmacokinetics of R- and S-fexofenadine. J Vet Pharmacol Ther :, 2018. Pubmed reference: 30020547. DOI: 10.1111/jvp.12696.
2016 Donner, J., Kaukonen, M., Anderson, H., Möller, F., Kyöstilä, K., Sankari, S., Hytönen, M., Giger, U., Lohi, H. :
Genetic Panel Screening of Nearly 100 Mutations Reveals New Insights into the Breed Distribution of Risk Variants for Canine Hereditary Disorders. PLoS One 11:e0161005, 2016. Pubmed reference: 27525650. DOI: 10.1371/journal.pone.0161005.
Mizukami, K., Yabuki, A., Kohyama, M., Kushida, K., Rahman, M.M., Uddin, M.M., Sawa, M., Yamato, O. :
Molecular prevalence of multiple genetic disorders in Border collies in Japan and recommendations for genetic counselling. Vet J 214:21-3, 2016. Pubmed reference: 27387721. DOI: 10.1016/j.tvjl.2016.05.004.
2015 Myers, M.J., Martinez, M., Li, H., Qiu, J., Troutman, L., Sharkey, M., Yancy, H.F. :
Influence of ABCB1 Genotype in Collies on the Pharmacokinetics and Pharmacodynamics of Loperamide in a Dose-Escalation Study. Drug Metab Dispos 43:1392-407, 2015. Pubmed reference: 26153274. DOI: 10.1124/dmd.115.063735.
2013 Mizukami, K., Yabuki, A., Chang, H.S., Uddin, M.M., Rahman, M.M., Kushida, K., Kohyama, M., Yamato, O. :
High Frequency of a Single Nucleotide Substitution (c.-6-180T>G) of the Canine MDR1/ABCB1 Gene Associated with Phenobarbital-Resistant Idiopathic Epilepsy in Border Collie Dogs. Dis Markers 35:669-72, 2013. Pubmed reference: 24302812. DOI: 10.1155/2013/695918.
Tomiyasu, H., Goto-Koshino, Y., Fujino, Y., Ohno, K., Tsujimoto, H. :
Epigenetic regulation of the ABCB1 gene in drug-sensitive and drug-resistant lymphoid tumour cell lines obtained from canine patients. Vet J :, 2013. Pubmed reference: 24332606. DOI: 10.1016/j.tvjl.2013.10.022.
2012 Geyer, J., Janko, C. :
Treatment of MDR1 mutant dogs with macrocyclic lactones. Curr Pharm Biotechnol 13:969-86, 2012. Pubmed reference: 22039792.
Mizukami, K., Chang, H.S., Yabuki, A., Kawamichi, T., Hossain, M.A., Rahman, M.M., Uddin, M.M., Yamato, O. :
Rapid genotyping assays for the 4-base pair deletion of canine MDR1/ABCB1 gene and low frequency of the mutant allele in Border Collie dogs. J Vet Diagn Invest 24:127-34, 2012. Pubmed reference: 22362942. DOI: 10.1177/1040638711425591.
Parton, K., Wiffen, E.M., Haglund, N.D., Cave, N.J. :
Macrocyclic lactone toxicity due to abamectin in farm dogs without the ABCB1 gene mutation. N Z Vet J 60:194-7, 2012. Pubmed reference: 22329447. DOI: 10.1080/00480169.2011.642770.
Tappin, S.W., Goodfellow, M.R., Peters, I.R., Day, M.J., Hall, E.J., Mealey, K.L. :
Frequency of the mutant MDR1 allele in dogs in the UK. Vet Rec 171:72, 2012. Pubmed reference: 22735986. DOI: 10.1136/vr.100633.
2011 Alves, L., Hülsmeyer, V., Jaggy, A., Fischer, A., Leeb, T., Drögemüller, M. :
Polymorphisms in the ABCB1 gene in phenobarbital responsive and resistant idiopathic epileptic Border Collies. J Vet Intern Med 25:484-9, 2011. Pubmed reference: 21488961. DOI: 10.1111/j.1939-1676.2011.0718.x.
Gramer, I., Leidolf, R., Doring, B., Klintzsch, S., Kramer, EM., Yalcin, E., Petzinger, E., Geyer, J. :
Breed distribution of the nt230(del4) MDR1 mutation in dogs. Vet J 189:67-71, 2011. Pubmed reference: 20655253. DOI: 10.1016/j.tvjl.2010.06.012.
2010 Han, JI., Son, HW., Park, SC., Na, KJ. :
Novel insertion mutation of ABCB1 gene in an ivermectin-sensitive Border Collie. J Vet Sci 11:341-4, 2010. Pubmed reference: 21113104.
Hülsmeyer, V., Zimmermann, R., Brauer, C., Sauter-Louis, C., Fischer, A. :
Epilepsy in Border Collies: clinical manifestation, outcome, and mode of inheritance. J Vet Intern Med 24:171-8, 2010. Pubmed reference: 20391637.
Klintzsch, S., Meerkamp, K., Doring, B., Geyer, J. :
Detection of the nt230[del4] MDR1 mutation in dogs by a fluorogenic 5' nuclease TaqMan allelic discrimination method. Vet J 185:272-277, 2010. Pubmed reference: 19733104. DOI: 10.1016/j.tvjl.2009.07.018.
Sherman, JG., Paul, AJ., Firkins, LD. :
Evaluation of the safety of spinosad and milbemycin 5-oxime orally administered to Collies with the MDR1 gene mutation. Am J Vet Res 71:115-9, 2010. Pubmed reference: 20043790. DOI: 10.2460/ajvr.71.1.115.
2009 Barbet, JL., Snook, T., Gay, JM., Mealey, KL. :
ABCB1-1 Delta (MDR1-1 Delta) genotype is associated with adverse reactions in dogs treated with milbemycin oxime for generalized demodicosis. Vet Dermatol 20:111-4, 2009. Pubmed reference: 19171022. DOI: 10.1111/j.1365-3164.2008.00725.x.
Bissonnette, S., Paradis, M., Daneau, I., Silversides, DW. :
The ABCB1-1Delta mutation is not responsible for subchronic neurotoxicity seen in dogs of non-collie breeds following macrocyclic lactone treatment for generalized demodicosis. Vet Dermatol 20:60-6, 2009. Pubmed reference: 19152588. DOI: 10.1111/j.1365-3164.2008.00731.x.
2008 Baars, C., Leeb, T., von Klopmann, T., Tipold, A., Potschka, H. :
Allele-specific polymerase chain reaction diagnostic test for the functional MDR1 polymorphism in dogs. Veterinary Journal 177:394-7, 2008. Pubmed reference: 17644437. DOI: 10.1016/j.tvjl.2007.05.020.
Fecht, S., Distl, O. :
Review of prevalence, genetic aspects and adverse effects of the mdr1-1Delta mutation in dogs. Dtsch Tierarztl Wochenschr 115:212-9, 2008. Pubmed reference: 18605373.
Fecht, S., Wöhlke, A., Distl, O. :
Haplotype analysis of the MDR1 flanking region in the dog breed Elo. Berl Munch Tierarztl Wochenschr 121:211-5, 2008. Pubmed reference: 18557525.
Mealey, K.L., Meurs, K.M. :
Breed distribution of the ABCB1-1Delta (multidrug sensitivity) polymorphism among dogs undergoing ABCB1 genotyping. J Am Vet Med Assoc 233:921-4, 2008. Pubmed reference: 18795852. DOI: 10.2460/javma.233.6.921.
Mealey, KL. :
Canine ABCB1 and macrocyclic lactones: heartworm prevention and pharmacogenetics. Vet Parasitol 158:215-22, 2008. Pubmed reference: 18922637. DOI: 10.1016/j.vetpar.2008.09.009.
2007 Fecht, S., Wöhlke, A., Hamann, H., Distl, O. :
Analysis of the canine mdr1-1Delta mutation in the dog breed Elo. J Vet Med A Physiol Pathol Clin Med 54:401-5, 2007. Pubmed reference: 17877579. DOI: 10.1111/j.1439-0442.2007.00966.x.
Geyer, J., Klintzsch, S., Meerkamp, K., Wöhlke, A., Distl, O., Moritz, A., Petzinger, E. :
Detection of the nt230(del4) MDR1 mutation in White Swiss Shepherd dogs: case reports of doramectin toxicosis, breed predisposition, and microsatellite analysis. J Vet Pharmacol Ther 30:482-5, 2007. Pubmed reference: 17803743. DOI: 10.1111/j.1365-2885.2007.00885.x.
Matsuura, S., Koto, H., Ide, K., Fujino, Y., Setoguchi-Mukai, A., Ohno, K., Tsujimoto, H. :
Induction of chemoresistance in a cultured canine cell line by retroviral transduction of the canine multidrug resistance 1 gene. Am J Vet Res 68:95-100, 2007. Pubmed reference: 17199425. DOI: 10.2460/ajvr.68.1.95.
2006 Henik, RA., Kellum, HB., Bentjen, SA., Mealey, KL. :
Digoxin and mexiletine sensitivity in a Collie with the MDR1 mutation. J Vet Intern Med 20:415-7, 2006. Pubmed reference: 16594604.
2005 Doering, B., Geyer, J., Godoy, J. R., Moritz, A., Petzinger, E. :
Ivermectin neurotoxicity in dogs: A consequence of a mutation in the canine MDR 1 gene Naunyn-Schmiedeberg's Archives of Pharmacology 371:R2 only, 2005.
Geyer, J., Doring, B., Godoy, JR., Leidolf, R., Moritz, A., Petzinger, E. :
Frequency of the nt230 (del4) MDR1 mutation in Collies and related dog breeds in Germany. J Vet Pharmacol Ther 28:545-51, 2005. Pubmed reference: 16343287. DOI: 10.1111/j.1365-2885.2005.00692.x.
Hugnet, C. :
Veterinary pharmacogenetics: example of MDR1 mutation in Collie dogs Bulletin de l'Academie Veterinaire de France 158:67-70, 2005.
Kawabata, A., Momoi, Y., Inoue-Murayama, M., Iwasaki, T. :
Canine mdr1 gene mutation in Japan. J Vet Med Sci 67:1103-7, 2005. Pubmed reference: 16327220.
Mealey, KL., Munyard, KA., Bentjen, SA. :
Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of herding breed dogs living in Australia. Vet Parasitol 131:193-6, 2005. Pubmed reference: 15975717. DOI: 10.1016/j.vetpar.2005.05.004.
Turba, ME., Binns, M., Mellersh, C., Godoy, JR. :
Canine microsatellites associated with genes known to cause progressive retinal atrophy in dogs or retinitis pigmentosa in humans. Anim Genet 36:259-61, 2005. Pubmed reference: 15932411. DOI: 10.1111/j.1365-2052.2005.01271.x.
2004 Hugnet, C., Bentjen, SA., Mealey, KL. :
Frequency of the mutant MDR1 allele associated with multidrug sensitivity in a sample of collies from France. J Vet Pharmacol Ther 27:227-9, 2004. Pubmed reference: 15305851. DOI: 10.1111/j.1365-2885.2004.00585.x.
Neff, MW., Robertson, KR., Wong, AK., Safra, N., Broman, KW., Slatkin, M., Mealey, KL., Pedersen, NC. :
Breed distribution and history of canine mdr1-1Delta, a pharmacogenetic mutation that marks the emergence of breeds from the collie lineage. Proc Natl Acad Sci U S A 101:11725-30, 2004. Pubmed reference: 15289602. DOI: 10.1073/pnas.0402374101.
Sartor, LL., Bentjen, SA., Trepanier, L., Mealey, KL. :
Loperamide toxicity in a collie with the MDR1 mutation associated with ivermectin sensitivity. J Vet Intern Med 18:117-8, 2004. Pubmed reference: 14765742.
2003 Mealey, K. L., Bentjen, S. A. :
Sequence and structural analysis of the presumed downstream promoter of the canine mdr1 gene Veterinary and Comparative Oncology 1:30-35, 2003.
Mealey, KL., Northrup, NC., Bentjen, SA. :
Increased toxicity of P-glycoprotein-substrate chemotherapeutic agents in a dog with the MDR1 deletion mutation associated with ivermectin sensitivity. J Am Vet Med Assoc 223:1453-5, 1434, 2003. Pubmed reference: 14627096.
Nelson, OL., Carsten, E., Bentjen, SA., Mealey, KL. :
Ivermectin toxicity in an Australian Shepherd dog with the MDR1 mutation associated with ivermectin sensitivity in Collies. J Vet Intern Med 17:354-6, 2003. Pubmed reference: 12774979.
Roulet, A., Puel, O., Gesta, S., Lepage, JF., Drag, M., Soll, M., Alvinerie, M., Pineau, T. :
MDR1-deficient genotype in Collie dogs hypersensitive to the P-glycoprotein substrate ivermectin. Eur J Pharmacol 460:85-91, 2003. Pubmed reference: 12559367.
2002 Mealey, KL., Bentjen, SA., Waiting, DK. :
Frequency of the mutant MDR1 allele associated with ivermectin sensitivity in a sample population of collies from the northwestern United States. Am J Vet Res 63:479-81, 2002. Pubmed reference: 11939306.
2001 Mealey, KL., Bentjen, SA., Gay, JM., Cantor, GH. :
Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. Pharmacogenetics 11:727-33, 2001. Pubmed reference: 11692082.
2000 Mealey, K. L., Bentjen, S. A., Cantor, G. H. :
Isolation and sequence of the promoter region of the canine multidrug resistance (P-glycoprotein) gene, MDR1 Journal of Veterinary Internal Medicine 14:359 only, 2000.
Paul, A.J., Tranquilli, W.J., Hutchens, D.E. :
Safety of moxidectin in avermectin-sensitive collies. Am J Vet Res 61:482-3, 2000. Pubmed reference: 10803640.
1996 Steingold, S.S., Sharp, N.J., Fuller, F., Page, R.L. :
Semi-quantitative assessment of canine MDR1 mRNA using RT-PCR Proceedings of the American Association for Cancer Research Annual Meeting 37:310 only, 1996.
1995 Hadrick, M.K., Bunch, S.E., Kornegay, J.N. :
Ivermectin toxicosis in two Australian shepherds. J Am Vet Med Assoc 206:1147-50; discussion 1150-2, 1995. Pubmed reference: 7768734.
1991 Fassler, P.E., Tranquilli, W.J., Paul, A.J., Soll, M.D., DiPietro, J.A., Todd, K.S. :
Evaluation of the safety of ivermectin administered in a beef-based formulation to ivermectin-sensitive Collies. J Am Vet Med Assoc 199:457-60, 1991. Pubmed reference: 1917657.
1990 Rohrer, S.P., Evans, D.V. :
Binding characteristics of ivermectin in plasma from collie dogs. Vet Res Commun 14:157-65, 1990. Pubmed reference: 2345955.
1989 Hsu, W.H., Wellborn, S.G., Schaffer, C.B. :
The safety of ivermectin. Comp Contin Educat Vet 11:584-589, 1989.
Vaughn, D.M., Simpson, S.T., Blagburn, B.L., Whitmer, W.L., Heddens-Mysinger, R., Hendrix, C.M. :
Determination of homovanillic acid, 5-hydroxyindoleacetic acid and pressure in the cerebrospinal fluid of collie dogs following administration of ivermectin. Vet Res Commun 13:47-55, 1989. Pubmed reference: 2475964.
1987 Paul, A.J., Tranquilli, W.J., Seward, R.L., Todd, K.S., DiPietro, J.A. :
Clinical observations in collies given ivermectin orally. Am J Vet Res 48:684-5, 1987. Pubmed reference: 3592367.
1985 Pulliam, J.D., Seward, R.L., Henry, R.T., Steinberg, S.A. :
Investigating ivermectin toxicity in collies. Veterinary Medicine 7:33-40, 1985.
1984 Campbell, W.C., Benz, G.W. :
Ivermectin: a review of efficacy and safety. J Vet Pharmacol Ther 7:1-16, 1984. Pubmed reference: 6368862.

Edit History


  • Created by Frank Nicholas on 22 Sep 2008
  • Changed by Vicki Meyers-Wallen on 18 Sep 2011
  • Changed by Vicki Meyers-Wallen on 19 Sep 2011
  • Changed by Frank Nicholas on 28 Sep 2011
  • Changed by Frank Nicholas on 12 Dec 2011
  • Changed by Frank Nicholas on 18 Sep 2012
  • Changed by Frank Nicholas on 06 Dec 2013
  • Changed by Frank Nicholas on 18 Oct 2016