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The Importance of the MRD1 gene in herding dogs

 

 

Why is MDR1 important:

 

MDR1 is important because it ‘codes for’ (i.e. makes) the P-glycoprotein nano-pump (P-gp). In nature these molecules are the ultimate ‘de-tox’, reducing the absorbtion of and also removing potentially harmful substances (toxins) from the body.

P-gp molecules are found all over the body in areas including the intestines (where they limit absorbtion), kidney, liver and brain (where they help to remove foreign substances). All these areas are, by their nature, regularly exposed to toxins and need to be ‘kept clean’ by functional P-gp pumps. They have been likened to nature’s vacuum cleaners.

Apart from this natural role P-gp pumps also handle and dispose of many drugs which in many cases are recognised as foreign substances. This can be a good thing or a bad thing depending on what one is trying to achieve with the drug.

In humans it is generally a bad thing (hence the research and the knockout mice) because of the problem of drug resistance which P-gp causes. In particular cancer cells over express the gene (i.e. the gene acts too strongly), causing resistance to chemo-therapeutic agents. Furthermore, as chemotherapeutic agents are used they will naturally tend to kill the cells with the least numbers of P-gp, thereby leaving (selecting for) the most resistant ones which will then multiply further, causing the whole tumour to become resistant. In addition bacteria also possess their own version of the MDR gene, and overexpression of this gene is associated with antibiotic resistance – another serious problem as we know from the MRSA so-called ‘superbug’ problem. Thus a lot of research is undertaken to find ways of stopping the action of MDR1 gene in human medicine to improve the treatment of cancer and other medical conditions.

In dogs though the significance is different, in sensitive collies it’s too little, not too much MDR1 (and therefore P-gp) which causes problems and the reason for this is a very special protective mechanism posessed uniquely by the brain itself.

One of the many things the P-gp pumps do is keep substances including drugs out of the brain, they do this by forming one of the active components of the Blood Brain Barrier (BBB).

This barrier means that the brain is protected from many drugs which other tissues are exposed to.  This is a problem if you are trying to treat the brain with, say antibiotics as in a case of meningitis, makind delivery of the drug to the brain difficult, but it is much more of a problem when a dog with MDR1 gene deletion doesn’t have enough P-gp pumps. In this case the brain becomes exposed to many times the normal, expected concentration of certain drugs and sometimes this causes unexpected side-effects.  The worst offender of course is ivermectin.

The avermectins generally and ivermectin in particular are problematic because they are so useful and (normally) very safe and therefore widespread and easy to get hold of.  They act as such effective parasite killers because they damage the nervous system causing paralysis.  The reason they are so lethal in insects and roundworms yet so safe in mammals is that the part of the nervous system the drug affects in mammals (GABA receptors) is safely locked away behind the normally highly efficient BBB where the drug can’t get to it.   So, in individuals which don’t have an effective BBB the drug will have the same effect on the nervous system as it does on insects – weakness, incoordination, reduced sensation, paralysis, coma and often, but not always, death; and those are all the signs which are described in dogs in the veterinary literature.

Other drugs which are involved:

 

The avermectins aren’t the only drugs involved in this condition.  There are many, lengthy lists of drugs pertaining to this condition available online but often with little explanation as to what they are or their likely significance.  The best one is at the WSU website (8).

Drugs on the lists are known substrates for P-gp and increased concentration can be demonstrated in brain tissue following administration to sensitive animals but, for many of them, the clinical significance of this is as yet unknown or actually not significant.  Thus lengthy lists of drugs given without accompanying explanation are useless as they say nothing about which of them are significant.  Fortunately the WSU list is excellent and gives detailed notes on the significance or otherwise of each one.

The situation today:

 

Ivermectin is still on the market, more popular than ever now under a variety of different trade names and is still occasionally used in dogs.

Other variants of the original ivermectin molecule are currently available and these have a far better safety profile in sensitive collies.  This means that with these newer compounds, whereas normal dogs would tolerate a 20 fold overdose, MDR1 deficient dogs would start to show signs at only a 5 times overdose.  Normally this is fine as long as the suggested dose is used.

Some of the preparations are considered so safe however, that they have wide dose ranges and therefore a limited number of tablet sizes.  In such cases there are potential implications for sensitive dogs.   If, for example a dog suspected of having the MDR1 deletion weighs 10 kg and the dose of a hypothetical drug is one tablet for a dog weighing from 10 to 50 kg then, by giving such a tablet to a 10kg dog you will be close to the five fold increase in dose at which adverse reactions might be expected. So here either the tablet would need to be divided (which would possibly go against data sheet guidelines), find another class of drug to do the job or, ideally, have such a dog tested for the presence or absence of the MDR1 gene defect so that a a fully informed decision can be made.

The newer drugs which have a better safety profile in sensitive collies include selamectin (Stronghold), moxidectin (Advocate) and milbemycin (Milbemax and Program Plus) and it is with these drugs that dosing must be more precise if MDR1 defect is known or suspected.

Ivermectin itself is still occasionally used, off license, in dogs as it is one of the most useful treatments we have for the severe skin problems caused by mange, particularly demodex but also sarcoptic (so-called fox) mange.  The doses required to treat these conditions, particularly demodecosis are high, up to 3 times the lethal dose for an MDR1 deficient collie.

Restricting the type of drugs used in dogs suspected of having the MDR1 defect is mere crisis management.  By making a blanket ban for certain drugs we run the risk of denying MDR1 normal dogs safe, effective treatment for some serious conditions.

To tackle the problem properly first we need to look at the incidence – how wide spread is this mutation?

Genome mapping has tracked the history of the gene as it progressed through the various breeds of collie as well as into some sight hounds such as the Longhaired Whippet and the Silken Windhound, and certain sheperding breeds including the Australian shepherd and the Swiss white shepherd which were also found also to be carrying the gene.  It looks like the gene first arose in Great Britain in one individual at or just before the formal establishment of the collie breed around 1873 (9).

There are various studies, some small, some large, which have looked at the incidence in the various collie types and, in the Sheltie, it is anything from 50 to 75%.  The various studies are not all comparable and it takes a while to work out that what is meant by “collie” in most of them is the rough collie and the closely related smooth coated collie – in these breeds the incidence of the defective mdr1 gene is anything up to 75%.

What would be ideal would be a met-analysis of all these studies to combine all the statistics into meaningful figures of incidence per breed.  Some of the best studies are Geyer, 2005 (10), Neff, 2004 (9) and Erkens, 2009 (11).  From these it appears the highest incidence is in the Shetland sheepdog and the rough and smooth coated collies.  The border collie has a relatively low incidence.

What can be done to address the problem?

 

In common with all genes MDR1 is inherited from the parents.

Every living thing, including the dog has two copies of each gene whether it’s for coat colour or length or eye colour. One of these genes comes from the mother, the other from the father.  Generally one gene will be dominant while the other is recessive so humans with one gene for blue eyes and another for brown will grow up with brown eyes as the brown gene is ‘dominant’ over the blue gene.

The MDR1 gene defect (written down as mdr1, using lower case to distinguish it from the functional MDR1) is inherited as what is called a recessive gene but with partial expression.  What that means is that a dog with 2 copies of MDR1 has the correct number of membrane pumps and will be normal and a dog with 2 copies of mdr1 will have non-functional pumps and have marked problems with drug sensitivity.  These individuals are known as homozygous as both the genes are the same.  But if a dog has one of each gene (i.e. MDR1 + mdr1 – what is known as a carrier or heterozygous) the normal MDR1 gene, though dominant, doesn’t completely have its own way and you get a halfway house where the individual is still likely to have problems though to a lesser degree than the completely affected individuals.

This knowledge of how the genes are inherited means that accurate predictions can be made about how breeding certain individuals with known genetic profiles will affect the offspring.  This means that, in theory, a simple and effective breeding programme can be devised.

A rational breeding programme of course can’t work without first testing breeding animals and a number of laboratories offer this test enabling owners to make informed decisions about drugs use and breeding.

A Kennel Club official testing scheme is in existence and comes with appropriate breeding advice:

  • Always pre-test breeding stock
  • If a carrier is identified, then only mate it to a DNA tested clear dog.  Ideally, the progeny should be then DNA tested to assign those that are clear and those that are carriers.  If one or more pups from such a mating are not DNA tested, then there progeny should be endorsed by the breeder  ‘progeny not eligible for registration’, under the condition that the endorsement will be lifted once the dog has been DNA tested.
  • Ideally affected dogs should not be bred from.

It is not enough to exclude every dog with the defective gene from a breeding programme as many carriers will also have ‘good’ genes which will benefit the breed.  Excluding such individuals would have a narrowing effect on the gene pool and there would be a risk of simply exchanging one genetic problem for another.  To assist breeders and potential owners the Kennel Club makes available lists of carriers as well as those affected and clear (12).

At the end of the day it is up to individual breeders to decide how serious they feel the problem is.  If it decided that it is serious enough to warrant action then this condition has a simple inheritance pattern, it is well researched, and there is an easily accessible, reliable test for it.  In theory it should be straightforward to deal effectively with the MDR1 defect.

 

 

Transcript from a presentation by Niall Taylor MRCVS 

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