R1158X Mutation

[hikingmomde]

My daughter (17 months) was diagnosed with CF less than a month ago. My pregnancy screening indicated that I was most likely not a carrier, so this came as quite a shock. Both mutations have been identified in the expanded panel--one is the 508 (probably from her dad) and one is R1158X (probably from me).
Our dr has indicated that there is not much recent research on the latter--does anyone know much about it or have a child with the same mutation? We're anxious to learn all that we can.
She is doing great--on the small side with a BIG belly, a great smile that melts the world, and the sweetest disposition. Meds already seem to be helping (she's on creon, adeks, and pulmozyme in addition to the pulmicort and albuterol that she's been on when the docs thought she had asthma) which is a great relief, although we know there is a long road ahead. Just taking it day by day . . .

 

[CFHockeyMom]

Here's a link to a article with some info...

<a target=_blank class=ftalternatingbarlinklarge href="http://www.clinchem.org/cgi/content/full/45/7/957">Link 1</a>

It is a nonsense mutation (ends in x) which means it result in the absence of functional CFTR (Class I). Here's a link to a previous discussion on nonsense mutations...

<a target=_blank class=ftalternatingbarlinklarge href="http://forums.cysticfibrosis.com/messageview.cfm?catid=5&threadid=8908&highlight_key=y&keyword1=cf%20mutations">Link 2</a>

I copied this info from a previous post...

<div class="FTQUOTE"><begin quote>Class I mutations lead to defects in the synthesis of stable CFTR mRNA transcripts resulting in absence of the CFTR protein. About half of all mutations in CFTR (encompassing premature termination, exon skipping, aberrant mRNA splicing, and frameshifts) are thought to fall into this class and result in complete loss of CFTR protein/function.

Class II mutations, including F508, complete protein translation but produce an abnormal protein that fails to escape the endoplasmic reticulum. Little or no CFTR reaches the plasma membrane, and the absence of all surface CFTR results in a severe phenotype. It is being increasingly recognized that mutations in unrelated genes can create defective proteins, which fail to traffic properly through the cell. Classically, missense mutations creating an abnormal protein were thought to be relatively benign or less consequential than nonsense mutations (null) or large deletions. This is no longer strictly the case because examples from CF and other inherited disorders demonstrate that a synthesized protein that fails to mature along the normal biosynthetic pathway often becomes quite destructive (7).

Class III mutations disrupt activation and regulation of CFTR at the plasma membrane. Thus biosynthesis, trafficking, and processing are undisturbed, but the channel may be defective with respect to ATP binding and hydrolysis, or phosphorylation. Mutations, such as G551D, tend to be associated with a severe phenotype.

Class IV mutations affect chloride conductance or channel gating and thus result in reduced chloride current. As might be expected, mutations in this class, such as R117H or P574H, are thought to confer a milder phenotype.

Class V mutations reduce the level of normal CFTR protein by alterations in the promoter or by altering splicing. Currently it is thought that a reduction in mRNA to less than 10% of normal results in disease in CF. Examples of Class V mutations include 3849 + 10kb CT, A455E, and 5T.
</end quote></div>

It wasn't detected in a prenatal screening because R1158X isn't in the top 32 (routine panel) but in the top 70 (extended panel).

The big belly is a trait of CFers. She'll probably have it her whole life. Sean's belly ranges from mildly distended to very distended depending on what he eats.

 

[sweetwhite30]

<img src="i/expressions/face-icon-small-smile.gif" border="0">I just wanted to share with you a few things i do know of the delta f508 gene.it is a common north american gene 70 to 75 have this gene and do not know it. Its main affect is a pancreatic insuffiency. From what i read in your topic your child has 2 different types of genes that came to be a positive c.f test out. Which they consider to be called a CF heterozygote.... I have done a ton of reading on c.f since my child was diagnosed at 7 weeks for it. But of course the reading was on the f508 gene only .... But there are over 1000 different types of c.f genes ...

 

[hikingmomde]

thank you for your response. i think it helped . . . i am having to bring up information stored in my brain from hs biology that i didn't even know was still in there!
i think i understand the science of nonsense v missense, but what does it all mean for my daughter?
just trying to learn all i can--i feel like if i can understand what's happening to her body, i can do a better job caring for her. crazy, i guess.
anyway, thanks!

 

[stella]

hallo my brother has the double f 508 mutation and i would like to send me any infos about this mutation my brother has digestive problems he was diagnosed at 20 ywars old now he is 26 he doesnt have many lung problems.i worry very much about the future,what will happen?


stella from greece.my mail stelask@in.gr.

 

[erinbrien]

Hello - My son was just diagnosed with CF at 8 weeks. His mutations are F508 and also R1158x ... It is a challenge to find meaningful information on the R1158x mutation in terms of what this means for my son. I was so happy to see that you had the same questions and I see that you posted this 6 years ago. Is there anything you have learned that I may find helpful. I - like you - just want to help my son in the best ways possible. Thank You

 

[Tyler's Mom]

My son was born on 10/13/13 and was diagnosed with CF on Day 16 of his life. He has G551D (Class 3) and R1158X (Class 1 - Nonsense). I would love to talk to anyone that also has R1158X as I would like to find out what this mutation means for my son.

 

[GodLovesMe]

If anyone has acquired more info on mutation R1158X I would really want to hear from you. Please share!

 

[Tyler's Mom]

In the John Hopkin's database that tracks CF mutations in the United States, there are 89 people documented with R1158X. That means it is a very rare mutation since 30,000 US people have CF and 70,000 worldwide. My son has R1158X and G551D. For anyone that has R1158X, please email me at jwesner@tampabay.rr.com I would love to talk with you and compare symptoms of our children and at least exchange contact info so we can at least try to find others with this same mutation!

 

[LittleLab4CF]

Anecdotal evidence with such a small population is going to be the best way to gather information and compare notes. I am interested in how this plays out for several reasons. R1158X has been regarded as a nonsense mutation in a number of scientific research papers. It seems that nonsense label is pretty old, referenced in a 1996 article which in turn has been referenced by a few more. None were challenging the accuracy of it being truly benign until recently.

I can't find the seminal study that actually determined its virulence category of nonsense but 1990 was a big year for CF and the terminology used fits the time. The methods used to determine how damaging or what symptoms would be expected for all the known mutations has been evolving.

Animal studies are amongst the oldest and slowest methods and ultimately we need to do such studies as they are the gold standard in disease genetics. Supercomputers will be able long before all the mutations and mutation combinations are tested this way. Predicted gene behavior is the fast method and tests involving a series of biochemical interactions run in series to determine how they behave. The quality of this testing is improving but it is worth very little without the very information you're wanting to develop. Consider posting a summary of your discoveries. And anybody with this mutation join in!

The little bit I found in scientific papers paints the mutation as one that doesn't interfere with a good gene except an odd allele that causes pancreatic cystic fibrosis. For what it's worth, I see the possible benefit for CFers sharing a mutation or two to discuss the health history and arrive at a better sense of how the genetics could play out.

Remember, genetics is never all black or all white. How it presents is far from predictable with certain exceptions. I encourage like mutation or mutations to work together and make our own database.

LL