MDR1 defect
The MDR1 defect is a defect in the MDR1 gene that can occur in some breeds of dogs and in humans. This leads to a deficient or missing synthesis of a certain protein ( P-glycoprotein , P-gp), which is an important component of the blood-brain barrier , which leads to hypersensitivity to some drugs . The cause of the defect is presumably a single dog that was significantly involved in the consolidation of the Collie breed ( long-haired collie / Kurzhaarcollie ) around the middle of the 19th century . Therefore, the defect occurs in dog breeds related to the collie. In other breeds affected by the defect, the mutation serves as evidence of the relationship. Animals without an MDR system can show similar drug sensitivities.
An intact MDR1 system is very old in evolutionary terms in mammals and humans.
Discovery of the genetic defect
Since the 1990s, hypersensitivity to certain drugs has been noticed in some dog breeds, especially the Ivermectin hypersensitivity of the Collies. When given ivermectin or various other drugs, these dogs can experience neurotoxic symptoms such as movement and coordination disorders, tremors, drowsiness, vomiting, disorientation and increased salivation; higher doses can also lead to comatose states and even death of the animal .
It was only with the generation of a knockout mouse in which the MDR1A gene was switched off that the hypersensitivity could be clarified. When ivermectin was administered as an anti- parasite agent , deaths occurred in mdr1a (- / -) mice, but not in mdr1a (+/-) or mdr1a (+ / +) mice. An 87-fold higher concentration of ivermectin was found in the brain of deceased mice. An examination of a Collie who died of ivermectin also showed a greatly increased ivermectin concentration in the brain. The suspicion that some dogs have a mutation in the MDR1 gene was therefore obvious.
When the gene sequences of the MDR1 of a beagle and seven ivermectin-sensitive collies were examined, mutations in the MDR1 sequence were found. One of them causes the synthesis of the MDR1 protein to stop. Because of its location in the reading frame for the MDR1 protein, the defect is referred to as the nt230 (del4) MDR1 mutation. Further investigations revealed the genetic defect in various breeds of dog.
Symptoms, diagnosis and consequences for the animal
The defect in the MDR1 gene leads to deficient or absent synthesis of the P-glycoprotein. The protein enables ATP-dependent transport processes between blood and tissue. It is found in the brain , liver , kidneys , intestines , placenta, and testes . In addition to its function in the transport of exogenous substances, it limits the transport of hormones from the adrenal cortex ( cortisol , corticosterone ) into the brain. It thus influences the hypothalamus - pituitary- adrenal cortex axis. In the case of an MDR1 defect, there is an increased transfer of the adrenal cortex hormones to the higher-level centers and, due to the negative feedback, decreased cortisol levels in the blood. Another consequence of the defect is a higher susceptibility to chronic inflammatory bowel diseases.
In animals not affected by the defect, the protein u. a. to transport foreign substances like drugs out of the body. So there is a kind of resistance to undesirable side effects - the so-called Multiple Drug Resistance .
The effects on the blood-brain barrier are known so far . At this boundary between the cerebral blood vessels and the cranial nerve tissue, a so-called MDR1 transporter represents a protective barrier for the brain. As part of the blood-brain barrier, the transporter is located on the surface of the endothelial cells (cells that line the walls of the blood vessels ) . It ensures that toxins and drugs are retained in the brain capillaries and do not penetrate the brain.
In the case of an animal with an MDR1 defect, the transporter is missing and protection fails. As a result, severe brain and nerve damage can occur after the administration of certain antiparasitic and cytostatic agents such as acepromazine , butorphanol , loperamide , ondansetron and erythromycin - up to and including death. In mice whose MDR1 transporter was switched off, there was a 90-fold higher amount of ivermectin and other drugs in the brain than in comparison animals with an intact blood-brain barrier. These substances endanger dogs affected by the MDR1 defect.
The possible consequence of the genetic defect is hypersensitivity to certain drugs . Because some of these agents can kill an affected dog, genetic testing of all affected breeds of dogs is recommended. The University of Giessen offers a test for the MDR1 defect. To do this, a veterinarian takes some blood from the dog (1 ml EDTA blood) and sends the sample to the university. The blood sample is examined for the presence of the MDR1 mutation, and the result is communicated to the dog owner.
If the dog is affected by the defect, the dog owner may no longer administer certain wormer cures and flea repellants, for example. Medicines used for diarrhea or heart disease can also have far-reaching undesirable side effects. A hypersensitivity z. B. for the active ingredients ivermectin , doramectin , moxidectin (only for oral use) and loperamide . Milbemycin oxime and emodepside may only be used with exact doses. Many other active ingredients are suspected of causing undesirable side effects. The attending veterinarian should therefore be informed of the defect. The dog itself is considered a risk patient.
When walking, it is important to ensure that the dog does not ingest faeces from horses , for example , as it may contain ivermectin in unchanged form.
So far, hypersensitivity has been known mainly in dogs with homozygous inheritance of the MDR1 defect (MDR1 - / -), but reactions have also been observed in carriers (MDR1 +/-). In a US study (see links), the carriers are therefore referred to as "sensitive", the dogs affected by the defect (MDR1 - / -) as "super sensitive". Also in the USA, the dogs affected by the defect have meanwhile been discovered by research as test animals.
Effects on Breeding
Due to the problems in drug therapy for dogs with the genotype MDR1 (- / -), z. B. recommended by the University of Giessen to consider the genetic defect in the breeding of affected dog breeds and to mate so that no offspring affected by the defect arise. The MDR1 genotype of a dog results from the combination of a trait inherited from the paternal (+ or -) and one from the maternal (+ or -) trait. “+” Stands for an intact MDR1 gene and “-” for a defective MDR1 gene based on the characteristic MDR1 nt230 (del4). There are three options for the MDR1 genotype of a dog: Not affected - MDR1 (+ / +), carriers - MDR1 (+/-) and affected - MDR1 (- / -).
If the MDR1 genotype of two breeding animals is known, a theoretical prediction can be made about the MDR1 genotypes of the offspring generation. Affected animals with genotype MDR1 (- / -) can be obtained from a cross of genotypes MDR1 (+/−) x MDR1 (+/−), MDR1 (+/−) x MDR1 (- / -) or MDR1 (- / -) x MDR1 (- / -) arise. If the genotypes MDR1 (+ / +) x MDR1 (- / -), MDR1 (+ / +) x MDR1 (+/-), and MDR1 (+ / +) x MDR1 (+ / +) are crossed, there are no affected genotypes MDR1 (- / -) animals, but with the exception of MDR1 (+ / +) x MDR1 (+ / +) possibly again bearers of characteristics.
After some of the breed clubs affiliated to the Verband für das Deutsche Hundewesen (VDH) voluntarily observed these mating rules, the VDH imposed these on the collie and Sheltie breed clubs affiliated with it in June 2009. From November 2009, all breeding animals must be tested for the MDR1 defect in order not to produce any offspring affected by the defect.
| Bitch MDR genotype | |||
|---|---|---|---|
| MDR genotype of the male dog | MDR1 (+ / +) | MDR1 (+/−) | MDR1 (- / -) |
| MDR1 (+ / +) | 100% MDR1 (+ / +) | 50% MDR1 (+ / +) 50% MDR1 (+/−) |
100% MDR1 (+/-) |
| MDR1 (+/−) | 50% MDR1 (+ / +) 50% MDR1 (+/−) |
25% MDR1 (+ / +) 50% MDR1 (+/−) 25% MDR1 (- / -) |
50% MDR1 (+/−) 50% MDR1 (- / -) |
| MDR1 (- / -) | 100% MDR1 (+/-) | 50% MDR1 (+/−) 50% MDR1 (- / -) |
100% MDR1 (- / -) |
Affected races
In 2004, the project group MDR1 Defect in Collies at the Justus Liebig University in Gießen examined dogs from 30 breeds and 10 European countries as part of a study on the frequency of MDR1 Defects. The defect in the MDR1 gene was found in the following dog breeds, among others: Collie ( short-haired collie and long-haired collie ), Shetland sheepdog , Australian shepherd , bobtail and border collie . Although no nt230 (del4) mutation has yet been detected in the Bearded Collie , the small number of samples does not yet allow a final assessment. In the Waller and Bobtail breeds , only heterozygous dogs affected by the defect (MDR1 +/-) have been detected so far, but homozygous mutations are also to be expected in these breeds. Breeding animals must be tested at the Wäller. When mating, a carrier animal should only be mated with a free one so that homozygous pups do not occur. The defect is also known in the following breeds: German Shepherd Dog , English Shepherd , McNab , Silken Windhound , Longhair Whippet , Berger Blanc Suisse and some rare breeds. Since the beginning of 2008, the Borzoi , Belgian Shepherd and Kelpie breeds have also been examined for defects.
Race distribution of the MDR1 defect
| race | MDR genotype (%) | ||
|---|---|---|---|
| MDR1 (+ / +) | MDR1 (+/−) | MDR1 (- / -) | |
| collie | 19th | 45 | 36 |
| Shetland Sheepdog | 49 | 43 | 8th |
| Australian Shepherd | 62 | 32 | 6th |
| Miniature Australian Shepherd | 54 | 43 | 3 |
| Waller | 65 | 35 | 0 |
| Bobtail (Old English Sheepdog) |
92 | 8th | 0 |
| Border collie | 98.7 | 0.9 | 0.4 |
| Bearded Collie | 100 | 0 | 0 |
| Long-haired whippet | 25th | 60 | 15th |
| White Swiss Shepherd Dog | 75 | 23 | 2 |
Sources and literature
- KL Mealey, SA Bentjen, et al .: Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. In: Pharmacogenetics 2001 11 (8). Pp. 727-733.
- JD Pulliam, RL Seward, RT Henry, SA Steinberg: Investigating ivermectin toxicity in collies. In: Vet Med. 1985, 80, pp. 33-40.
- AH Schinkel, JJ Smit, O. van Tellingen, JH Beijnen et al .: Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. In: Cell. 1994, 77, pp. 491-502.
- J. Geyer et al.: MDR1 defect. Multiple drug hypersensitivity in British Sheepdogs. In: Small animal specifically. 9 (3) / 2006, pp. 16-20.
- Ivermectin intolerance: genetic defect not only in the collie. In: VETimpulse. 17/2006, p. 5.
- I. Gramer, R. Leidolf, B. Döring et al .: Breed distribution of the nt230 (del4) MDR1 mutation in dogs. In: Veterinary journal (London, England: 1997). Volume 189, number 1, July 2011, pp. 67-71, doi: 10.1016 / j.tvjl.2010.06.012 . PMID 20655253 .
Individual evidence
- ↑ KL Mealey, SA Bentjen, et al .: Ivermectin sensitivity in collies is associated with a deletion mutation of the mdr1 gene. In: Pharmacogenetics 2001 11 (8). Pp. 727-733.
- ↑ Katrina L. Mealey et al .: Comparison of the hypothalamic-pituitary-adrenal axis in MDR1-1Δ and MDR1 wildtype dogs . In: Journal of Veterinary Emergency and Critical Care. 17 (2007), pp. 61-66. (pdf; 135 kB)
- ↑ TransMIT Center for Pharmacogenetic Diagnostics: MDR1 Defect in Dogs and Drug Intolerance with an overview of the breeds affected.
- ↑ Irina Gramer et al .: Breed distribution of the nt230 (del4) MDR1 mutation in dogs. In: Veterinary Journal. 189 (2011), pp. 67-71, doi: 10.1016 / j.tvjl.2010.06.012 . PMID 20655253 .
Web links
- MDR1 defect in dogs and drug intolerance
- US statistics (English)
- Japanese study and statistics ( Memento from June 30, 2010 in the Internet Archive ) (English; PDF file; 204 kB)
