mutation classes and effects

Question

My daughter has a h1054d, often classified in articles as a missense class 4 mutation.

Her 2nd mutation is 4021inst. I have been told that it was a frameshift mutation. In my web researches, frameshift mutations are said to be class 1 mutations. Mutations 2, 3 and 4 are always missense mutations: am-I right? I do not rely completely on the web, even if the papers I read were in French and English.

Moreover, the gene has 2 different mutations. How does the cell deal with the CFTR production process? It produces a troncated protein that is eliminated because it’s not well synthesized (thanks to the class 4 mutation) or/and it produces a defective protein because of the class 4? How does the cell know what to do?

Thanks for your help, regards.

Answer

Hello,

As you’ve highlighted, several CFTR gene mutations exist and have variable consequences on the CFTR protein and its functions. Over 1800 CFTR gene mutations are described actually. Most of these mutations are punctual mutations, and the most frequent ones are missense mutations (42%). The CFTR class 2, 3 and 4 are frequently but not necessarily missense mutations.

Among CFTR functions, the most important is to be a chloride channel. A classification of the gene mutations has further been proposed, based on the mutation’s consequences on the protein function (“functional” classification). Six mutations classes are generally described, resulting in quantitative or qualitative CFTR abnormalities.

Your daughter has 2 CFTR gene mutations: h1054d and 4021inst.

The first one (h1054d) is a mutation classified as ‘4th class’. It’s a missense mutation that results in a CFTR protein well positioned and with a chloride channel activity. However, the protein characteristics (and, consequently, the channel characteristics) are different from that of a non-mutated protein and the ions efflux might be little decreased. This mutation is classically associated with a mild form of the disease, which could include infertility in males, delayed respiratory symptoms and rarely gastrointestinal tract symptoms.

The second mutation (4021inst) is classified as ‘1st class’. It’s a frameshift mutation which alters the protein production. The mutation leads indeed to a premature end of the protein fabrication process (premature stop codon). It results in the absence of the protein, and, consequently, of the chloride channel activity.

Your daughter has these 2 different CFTR mutations. In the cell, the 2 mutated alleles are expressed and: one part of the produced protein is immediately eliminated (the part that results from the class 1 mutation expression) and the other part (that results from the class 4 mutation) results in functional proteins. As such, a chloride channel activity persists in the cells. That is why the disease form is considered as “mild”. You may ask to consult a geneticist or a geneticist counselor who will be able to explain these rather complexes processes. Some French-speaking websites may also be of interests, but some remain very medical and rather hard to follow: fr.wikipedia.org/wiki/Mucoviscidose#Origine_des_mutations, fr.wikipedia.org/wiki/Mucoviscidose#La_prot.C3.A9ine_CFTR, atlasgeneticsoncology.org/Educ/CisticFibFr.html, www.123bio.net/revues/vchappe/sommaire.html.


I hope to have answer your questions and do please fill free to reply if you do have more questions.

Best regards

Harriet Corvol

22.03.2012