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Diseases

I have mild cystic fibrosis on both sides of my family. I have all the symptoms of CF -- bronchectiasis, malabsorption, diabetes, chronic sinus infections and polyps that have been surgically removed 7 times! My sweat test is normal.

My DNA analysis reveals DF508, M470V, 7T/9T polyvariant. Do you know if this would be considered CF now? What is M470V responsible for doing in the human body? Is it now considered a CF gene? If not why? I have every symptom of this disease there is and can't get the diagnosis. This leads to me no longer being able to get the drug Pulmozyme for my lungs.

-A curious adult from Ohio

October 20, 2005

How frustrating this all must be! To have many of the symptoms but not enough of them to qualify for medicine that might be helping you.

The quick answer is that by traditional standards, you do not have classic cystic fibrosis (CF). The sweat test is a hallmark of CF and you pass yours.

But given your symptoms, you may have either variant CF or CFTR-related disease. With both of these, you have some but not all of the symptoms of CF.

The difference between these two forms is which gene is mutated. For CFTR-related disease, the standard CF gene, CFTR, is mutated. People with variant CF have many CF symptoms but their CFTR gene is normal.

Not enough is known about variant CF to explain where the symptoms are coming from. But we do know that CFTR-related disease has fewer symptoms than CF because of different mutations in the CFTR gene.

Classic CF happens when both copies of your CFTR gene have mutations that disable the gene completely. CFTR-related disease often happens when one copy has this kind of a mutation and the other a mild one. (Remember, we have two copies of most of our genes -- one from mom and one from dad.)

What is the difference between these two types of mutations? To understand this, we need to go a bit deeper into what a gene is and how it works.

A gene is really just a string of the letters A, G, C, and T in a certain order. Contained in this specific set of letters in their proper order are the instructions for making a protein.

Proteins are the workhorses of the cell. Pretty much if anything needs to be done, a protein does it. Proteins carry oxygen to your cells, give you brown eyes and, when lots of them work together, let you see, breathe and even think.

To do all of this, a protein has to be put together just right. In other words, changes in the instructions (or mutations) can have a big effect in how a protein works.

Some changes just wreck the protein completely. Your DF508 mutation is one of these. This small change removes three letters from the 4400 or so that make up the CFTR gene. Because of this mutation, most of the DF508 protein ends up in the wrong place in the cell. And the little bit that does make it to the right place doesn't work too well anyway.

All mutations are not as clear-cut as DF508, though. Some are milder and just make the protein work less well. Your M470V mutation is in this category.

Let's think about a gene as the instructions for a car. The DF508 mutation is like a car without wheels. It is broken and isn't going anywhere.

The M470V mutation is more like a car with flat tires. The car doesn't run as well, but it'll get you there in a pinch.

As I said earlier, if both copies of your CFTR gene have mutations that disable the protein completely, you'll have classic CF. People with CFTR-related disease have one of these and a mild mutation. Your DF508 definitely counts as a mutation that wrecks the CFTR gene. But what about M470V and the 7T/9T polyvariant? Do these count as mild? Or do they have no effect at all?

It is important to note that lots of mutations have little or no effect on a protein. These are called silent mutations. So it is possible to have mutations in the CFTR gene and to have no effect on the protein.

Recent data suggests that the M470V mutation is not a silent one. The M470V mutation results in a CFTR protein that doesn't work as well -- it is about half as good as the "normal" protein. If your M470V and DF508 mutations are in different copies of your CFTR gene, then you have around 25% of the normal amount of working CFTR.

Is this enough to cause CFTR-related disease? No one knows for sure. We know that the classic disease happens when less than 1% of the protein is working. From around 1-4.5%, you end up with progressive pulmonary disease, around 5% a sweat abnormality and around 10%, male infertility (CABVD). The 10-49% area is the gray area.

Your 25% falls smack dab in the middle of the gray area. No one knows yet if that is enough to cause CFTR-related disease, though.

So your symptoms may have nothing to do with your M470V mutation and may have more to do with a different gene. If that is the case, then you would be a candidate for variant CF not CFTR-related disease.

In any case, if you have the symptoms and the drug is helping it seems like you should be able to argue for getting the drug. It may be that your insurance company and/or doctor are unaware of these CF-like diseases. Worth bringing up anyway...


Some mutations in the CFTR
gene can lead to CF