MDR 1

MDR1 – what´s it all about?

There is plenty of information about the MDR1 mutation on the web these days.  Look up the Washington State University web site, for an example, or the German but multilingual MDR1-Informationsplattform…..
The long and short of it is this.

Collies, Rough and Smooth, along with several related breeds – and a couple of not so obviously related ones, such as the Silken Windhound – quite frequently have a genetic change, a mutation, disturbing the function of a protein that serves as a transport mechanism for molecules not wanted. It´s a bouncer, waiting at the door of a cell to throw unwelcome visitors back out into the blood stream.

The name of this bouncer protein is glucoprotein Gp-70; and the gene which makes it is known as MDR1. And yes, MDR stands for MultiDrug Resistance. Prominent names in current research: Professor Joachim Geyer, Germany, and Dr. Katrina Mealey, U S A.

Vets have known for a long time that some dogs react very badly to some medications – and that many of those dogs are Collies, Shelties and Aussies.  The coming of ivermectin, used against parasites – heartworm, mange and tapeworm – made it  obvious some twenty years ago.

A few years back, a research group found out just what was wrong with these dogs. They had a bit missing in the MDR1 gene, a deletion, making the bouncer an invalid. After that, research has made headway. Every now and then, another drug is added to the list of risk medicines on the sites that offer genetic testing. Naturally dog owners worry.  

Dogs with the non-functioning Gp-70 protein in the cell membranes of their gut absorb much more of a certain class of drugs. The armless bouncer cannot throw the drug molecules back out into the gut, so the drugs will pass through the gut cells and get into the blood. The cells of the bile ducts and the kidneys for the same reason cannot excrete them; so blood levels of the drugs will be high. And worse than that, the cells lining the blood vessels of the brain and of the uterus cannot bounce that type of drug out either. A fetus growing in the womb will be exposed to them, and so of course will the brain. And that is precisely why some Collies have had convulsions, and some have even died, of these drugs.

Now surely this is frightening? Surely it is best to test?

Well….Is it?  Take a look at the drugs first!

Many of the drugs on the list of stuff known or suspected to be unsafe for MDR1-mutant dogs are medications that very few dogs indeed will ever need. And if they do, they certainly will have a prescription first. Because this is stuff like cytostatics for cancer, rifampicine against human tuberculosis, a medicine for heart failure …  The few that are likely to come the dog-owner´s way, such as ivermectin and similar formulas against parasites, the vets can find good substitutes for.

So if you plan to feed your dog, or pregnant bitch, a course of cytostatics; or digitalis ; or rifampicin, or any other of the prescription drugs on the list - and you do not plan to consult your vet first… well …then the MDR1 mutation would be a big problem.

But what if you don´t?  In what way is the MDR1 mutant dog at risk then?

Not known.

So what´s the commotion? I`m not sure. Is there anything in the MDR1 scare? Possibly, but it´s hard to know.

In 2007, a research group headed by Dr Katrina Mealey of the Washington State University published a very interesting study, comparing three MDR1 normal to four MDR1 mutant Collies. They were all healthy. But it turned out that compared to the MDR1 normal Collies, the MDR1 mutant dogs in this study had difficulties in raising their cortisol levels. They could rally less of an important hormone, which puts the body into high gear, when there is serious stress – that is, major illness or major surgery. Sadly, Dr. Mealey says on a mail to us that she is not aware of any research being done or being planned to find out whether MDR1 mutant dogs respond in the same way to everyday, normal-life stress.

Critical  illness or  major surgery hopefully will not come your dog´s way any more often than cancer. One might well reason, therefore, that this discovery too is of less importance than all the other genes which decide your dog´s ability to lead a long, active life under ordinary circumstances. But it leads us on to the intriguing question:

The MDR1 gene and its bouncer protein have existed in mice, men and dogs for millions of years. They did not develop because mammals anticipated late 20ieth century  medicines. So what are they for?

What is the naturally occurring stuff for which this gene has gone on producing a bouncer during all these years?

There does not seem to be a good answer to that one just yet. It´s just possible that nobody knows the answer. There is none on the web sites advertising the DNA test for dog breeds. And until we have a good answer, why must all of us queue up to spend our money on the gene test? Being MDR1 normal/normal is not a merit in a dog. It´s a matter of practical interest to the vets under certain circumstances.

The figures quoted for number of MDR1 mutant dogs from different countries are quite high. Professor Geyer found 33% homozygous mutant/mutant in tested  German Collies. A study of French Collies in 2005 turned up with only 20% MDR1 normal/normal and 48% homozygous mutant/mutant. If the MDR1 mutation caused a major disadvantage, medicines apart, for the dogs who carry it,  would we not have known much earlier that something was seriously wrong with many of them? But Collies lived active and long lives for very many years before ivermectin caused us to discover the mutation.

The high figures of MDR1 mutant dogs in themselves would make it very difficult to follow suggestions to select against them in breeding. It´s not reasonable to reject so large a section of your breeding basis to hunt down a single gene pair of uncertain significance. If we try, and breed the MDR1 out – what other mutation would we discover we had accidentally bred in?

If we restrict our breeding basis to the small number of normal/normal dogs ( 25 % at best?), we risk a repeat of the very error which got us into this spot in the first place. If we take our time about it, breed normal/mutant to normal/mutant and weed the successive generations of mutants out by repeated testing, we have invested an enormous amount of money and effort, as if we could be certain that this single gene is indeed the major threat to the Collie.

How about selecting for good general health, good hips, and good personality? Just by doing that, you will have secured in one sweep a very great number of functional gene pairs of obvious importance to the dog´s quality and length of life.

The MDR1 gene is only one out of the thirty to forty thousand genes in a dog. The labs offering their services know exactly where it is to be found and what version of it your dog carries. But the fact that they can do that is not reason enough to boost the significance of it.

On April, 25^th 2009, Professor Geyer will lead a seminar on the MDR1 question in Germany. This web site will be back with a report. So far, we agree with the position of the Swedish Collie Club:  there is no need to recommend general DNA-testing of Collies. Breeders have more urgent matters to focus on.