MDR1 - autosomal dominant

[gcv-border]

 

Denise MaherScottish-Collie Resource Page

Stmeptem2hb0er 188,3t 20218ed  ·

IMPORTANT MDR1 UPDATE

It has been officially confirmed that MDR1 which is a genetic mutuation (MDR1 is the abbreviated name of a gene called Multi-Drug Resistance 1) that causes sensitivity to Ivermectin and a number of other drugs in many herding breeds is determined to be AUTOSOMAL DOMINANT. This means that dogs need only carry one mutuant gene to be affected. Dogs will now be listed as carrier/affected rather than just carrier if they possess only one gene for MDR1.

Dogs with the mutation will react to certain drugs including Ivermectin. Whether a dog reacts depends on the dosage of the drug. A dog may not react to very low doses, as with the amount of Ivermectin found in heart worm products for dogs but dosages used for livestock are highly toxic. Typical doses of a variety of medications will cause reactions in dogs with two copies of the mutation, but some drugs – most notably several chemotherapy agents – can cause reactions in dogs with only one. Dogs with this mutation have a transport defect—the drug goes in to their brains, fails to be transported out, and builds up to toxic levels. This causes serious neurological problems including seizures or death in many herding breeds to include collies.

Please treat all carriers of MDR1 as affected.

Reference: http://www.ashgi.org/home-page/genetics-info/faq/mdr1-faqs

[Journey]

Thanks GCV...the HEF came out with a statement years ago wrt this. Unfortunately the barn door was blown wide open due to a popular sire being a single gene affected, along with EOAD and TNS. Now the MDR1 gene is more prevalent than once thought in the breed.

[Michael Parkey]

I am a little confused by terminology.  Since one copy of MDR1 (heterozygous) causes some sensitivity to drugs, and two copies (homozygous) increase that sensitivity, wouldn't MDR1 be classified as a codominant or incompletely dominant autosomal mutation?  The term "carrier" is no longer valid, of course, since the characteristic is expressed in the heterozygous condition.

[gcv-border]

3 hours ago, Michael Parkey said:

I am a little confused by terminology.  Since one copy of MDR1 (heterozygous) causes some sensitivity to drugs, and two copies (homozygous) increase that sensitivity, wouldn't MDR1 be classified as a codominant or incompletely dominant autosomal mutation?  The term "carrier" is no longer valid, of course, since the characteristic is expressed in the heterozygous condition.

You pose a good question. So, even though my PhD is in molecular genetics (so I had to take the classic genetics courses too), it has been decades since university. I decided to look up the meanings of each word/phrase.

Autosomal dominant: A pattern of inheritance in which an affected individual has one copy of a mutant gene and one normal gene on a pair of autosomal chromosomes. (In contrast, autosomal recessive diseases require that the individual have two copies of the mutant gene.)

Codominance is a relationship between two versions of a gene. Individuals receive one version of a gene, called an allele, from each parent. If the alleles are different, the dominant allele usually will be expressed, while the effect of the other allele, called recessive, is masked.

Incomplete dominance is a form of Gene interaction in which both alleles of a gene at a locus are partially expressed, often resulting in an intermediate or different phenotype. It is also known as partial dominance. For eg., in roses, the allele for red colour is dominant over the allele for white colour.

• Incomplete dominance and codominance are types of inheritance of traits where both alleles are neither dominant nor recessive. • In incomplete dominance, the resulting trait is a blend of the traits of parents whereas in codominance, both traits show up in the offspring.

My take-away is that codominance and incomplete dominance are subsets of autosomal dominance.

But, what I think is most important, is that there is no longer a recessive 'carrier' status. 

FWIW

[Michael Parkey]

9 hours ago, gcv-border said:

But, what I think is most important, is that there is no longer a recessive 'carrier' status.

Agreed!

[Eileen Stein]

There's an article called "Understanding the Multi-Drug Resistant Gene Mutation in Border Collies" on the ABCA Health & Education Foundation's website that y'all may find to be helpful:

https://bordercolliefoundation.org/wp-content/uploads/2020/08/Understanding_MDR1_Jul-2020.pdf

This is the meat of the explanation:

Quote

The MDR1 gene (also sometimes referred to as the ABCB1 gene) produces a protein that protects the brain from certain drugs and also aids in clearing these drugs from the body through organs such as the liver and kidneys. . . .  The MDR1-1Delta mutation interferes with this important protective function. Like most single gene mutations, a dog can have one mutated MDR1 gene and one normal gene (heterozygote) or two mutated genes (homozygote). One copy of the gene is contributed by each parent. A dog that carries two copies of the mutation will not produce any of the protective protein, and it will pass one copy of the mutated gene to all of its offspring. A dog that carries one copy of the mutation will pass on a copy of the mutation to roughly half of its offspring. But in one very important respect, the dog that carries a single copy of the mutated MDR1 gene is different from the "carrier" dogs who are heterozygous for other most commonly known mutations, such as CEA, where a heterozygote is an unaffected carrier:  The dog who is heterozygous for the MDR1-1Delta mutation may display symptoms of the disorder. Because each of the two genes separately produces the MDR1 protein, his normal gene will produce the protective protein, but the mutant gene will not. Depending on other regulating factors present in the body at the time, a “carrier” of the MDR1 gene mutation has the potential to produce only half or less of the normal MDR1 protein needed to protect its brain from certain drugs. As a result, these heterozygous dogs range from essentially normal to mildly affected to significantly affected, with the most being mildly affected.

I'm not sure that any variant of the "dominant/recessive" terminology is meaningful in this case.  Due to the function that the gene performs, I would say that the wild (normal) allele is doing its thing, which is to produce the protein, and the mutated allele is doing its thing, which is not to produce the protein.  It's not a case of the normal allele masking or suppressing the effect of the mutated allele.