Monday, November 28, 2011

Mutation Matters

I want to use this blog to revisit a topic that was featured in so many different talks at the NACFC this year--Individualized medicine.  As more and more is learned about the genetics of cystic fibrosis, researchers are learning that each person's case of CF is truly unique.  This "genetic signature" is the product of your CF genotype plus a slew of other modifying genes.  At the Vertex Pharmaceuticals booth, they were giving out all sorts of awesome info on CFTR science and classes of mutations.  Inside one of these books, they discuss this information as a "Call to Action" to our physicians to review their knowledge of CFTR science, and embrace the new idea of using genetic mutations as a guide individualized treatment for each CF patient.  Then it dawned on me...this is new for everyone, patients and doctors alike.  With these big chages on the horizon, I think it is more important than ever for CF patients and families to be involved with their care team and stay in the loop about new research information.  I also realized that I blogged in some detail about the misfolding problems associated with the DF508 mutation, and that it might be a good idea to pull back a little and really break this mutation business down.  Let's talk about mutation classes and CFTR function.

I learned that there are have found close to 1900 different CF causing mutations.  There are many individuals that have one common mutation and another extremely rare one.  Many older patients may not have any genotype information, as it wasn't part of the diagnosis protocol 20 years ago.  Many other patients might have that genotype info sitting in their chart somewhere, but it never really useful information before. Now is the time to figure it out. 

The CFF and Vertex both divide CF causing mutations into 6 classes.  Mutations within each class have a similar CFTR dysfunction.  When assessing CFTR function, researcher basically examine two aspects:

1) How much CFTR reaches the cell surface
2) How much Chloride transport activity the existing CFTR exhibits. 

Researchers believe the key to controlling this disease is to increase the amount of functional CFTR for each patient using small-molecule drugs (like VX-770).  They believe if they can activate 20-30% function, that they will see a significant drop in clinical symptoms of CF.  They really hit the jackpot with VX-770, which activates about 50% CFTR function in G551D patients.  In essence, when Brady is able to take this drug, he will achieve about the same level of functional CFTR that I have as a symptomless carrier--50%. 

I want to make one important point before moving along to the mutation classes.  In new information being published about CF mutations, as well as in the CFTR2 project, you are going to start seeing genotype-phenotype correlations.  In other words, they are attempting to make correlations between CF mutation and clincal presentation of things like pancreatic sufficiency, liver disease, CFRD, etc... These correlations were made by performing a statistical analysis on National Registry (and European) data and is NOT MEANT IN ANY WAY TO BE USED AS A TOOL TO PREDICT INDIVIDUAL OUTCOMES!  Basically, if you are in the group that has little to no functional CFTR, you will see associations with more CF complications.  If you are in the groups with some functional CFTR, there will be fewer associated complications.  I encourage everyone to visit and watch the archived Plenary Session 2, entitled CFTR2, from year's Conference.  They describe exactly how these correlations are made and how they might be used.  For some variables like pancreatic sufficiency, they are able to use genotype to make a fairly accurate prediction about whether or not a patient will need enzymes based on their genotype.  For other variables, especially lung function, the correlation is very weak (their own words!).  In fact, I sat through a talk at the Conference all about how siblings or even twins with the exact same genotype and environment can have drastically different cases of CF.  In other words, DO NOT FREAK OUT ABOUT THE CLINICAL ASSOCIATIONS.  Think of it as a snapshot of what has happened in the past--not a tool for predicting the future.  Modifier genes (that might affect the body's inflammation response, cell death, etc...) and countless other non-genetic factors(age of onset of chronic infection, level of care, nutritional support, exposure to secondhand smoke) all play a role in determing clinical variability.  Honestly, I don't pay much attention to the clinical associations.  I'm much more interested in the TREATMENT ASSOCIATIONS!

Ok.  Here we go.  This can be extremely confusing because some people call the classes by numbers.  Other times you might here jargon related to the CFTR dysfunction like, "gating," "deletion," "non-sense," etc...

Class 1 (Nonsense, Stop, X-mutations, premature splice mutations)

Mutation Effect:  Protein synthesis defect causing failure to synthesize full length protein

Cell Surface Expression: Little to no functional CFTR

Channel Function: Little to no function
Example Mutations:  W1282X, G542X, R553X, R1162X, 2184delA, 3659delC, 621 + 1G-T,  711 + 1 G-T, 1717 – 1 G-A, 1898 + 1 G-A

Clinical Associations: Related to more complications of CF like MI, PI, liver disease, etc…

Class 2 (Misfolding/Trafficking, Deletion)

Mutation Effect: Protein processing defect often resulting from improper folding and trafficking to cell membrane.

Cell surface expression: Little to no functional CFTR

Channel Function: Little to no Chloride channel activity

Example Mutations: F508del, N1303K, 1507del, R560T

Clinical Associations: Related to more complications of CF like MI, PI, liver disease, etc…

Class 3 (Gating, Missense)

Mutation Effect: Defect in regulation impairs opening of channel.
Cell Surface Expression: Normal quantity of dysfunctional CFTR at cell surface.
Channel Function: Little to none
Example Mutations: G551D, G551S, S1255P, G178R, G970R, G1244E, G1349D
Clinical Associations: Related to more complications of CF like MI, PI, liver disease, etc…

Class 4 (Channel, Conductance)
Mutation Effect: Insufficient amounts of Chloride move through the channel
Cell Surface Expression: Normal quantity of dysfunctional CFTR
Channel function: Some
Example Mutations: R117H, R334W, R347P
Clinical Associations: fewer CF related complications

Class 5 (Splicing)
Mutation Effect: Splicing error causes variable synthesis of protein, CFTR is produced in smaller than normal quantities.
Cell Surface Expression: Some (variable) functional CFTR at the cell surface
Channel Function: Some
Example Mutations: 3120 + 1 G-A, 3849 + 10 kb C-T, 2789 + 5 G-A, A455E
Clinical associations: fewer CF related complications

Class 6 (Stability, Protein truncation)
Mutation Effect: CFTR degrades too fast.  Not enough functional protein present. Protein truncation causes increased cell-surface turnover.
Cell Surface Expression: Unstable
Channel Function: Some
Example Mutations: 4326delTC, N287Y, 4279insA

Clinical Associations: fewer CF related complications

Learn More
Until CFTR2 goes online sometime next year, I think the best resource out there is the website associated with Vertex called
You can go to this site and watch animated videos showing the unique dysfunction that different classes of mutations exhibit.  You can page through amazing slide presentations with all sorts of great graphics.  You can go to the "educational resources" tab and request that they send you all the booklets that they gave your Dr. at the Conference this year.  I have been geeking out hard on this website and I hope everyone takes the time to pay them a visit.  This is basically the tool that they are using to educate/refresh the memory of CF physicians about CFTR, so let's see what they are learning!  Of course, you can always go to and do a general search for mutation classes.  This will bring up a short 2 page article about Targeting CF Mutations and is a lot less technical.  In closing, I think this information is crucial for patients to embrace because it is a huge change for Doctors to approach CF care this way.  Genotype information is going to be crucial to find and enroll in the huge number of mutation specific clincal trials coming our way.  My hope is that everyone gets to obsess over their mutation specific therapy as it comes down the pipeline, as I've been able to do with VX-770 for Brady.  I will never forget the day that I first read about VX-770 (Brady was an infant).  I had to go to Brady's medical information file and dig out a letter that listed his specific mutations (they were nothing but a jumble of letters and numbers to me before). 
All of a sudden, it became significant.  Extremely significant.  I believe now, more than ever that they are on track to developing drugs to control CF like VX-770, for other classes of mutations.  MUTATION MATTERS!


What if my insurance doesn't want to cover genetic testing?
--The CFF is planning a patient assistance program to help cover genetic panel costs.  This program is set to begin next year, alongside CFTR2

What if I had the test, but they only identified 1 of my mutations?
--Of course, it is best to know both mutations, but knowing only 1 is much better than knowing none.  In the case of VX-770, only a single patient in that trial was homozygous for G551D.  In other words, they were treating only one of each patient's mutations and still had great success with treatment.  Also, as more mutations are discovered, those genetic panels will include more and more mutations...increasing the chances that they will be able to find that elusive second one.

I know both my mutations, but didn't see them listed in the example mutations
--With close to 1900 CF mutations, this represents just a small fraction of them.  Please ask your Dr. to help you determine which class and the specific type of CFTR dysfunctions that are associated with your mutations.   

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