Potentiate the residual wild type CFTR!


Mutations associated with Cystic Fibrosis are grouped into VI classes
to better identify the basic defect generating the disease.
There can be issues in the folding mechanism, problems in protein
synthesis or in its conductance, or errors in the splicing machinery
(see e.g. Rowntree & Harris, Ann.Hum Genet. 2003)
Link to PubMed reference http://www.ncbi.nlm.nih.gov/pubmed/12940920
Link to PDF http://www.colorado.edu/MCDB/MCDB4600/1ReviewPhenotype.pdf ).
Some mutations in Class I and in Class V have a common defect: Splicing.
A splicing mutation alters or abolishes the specific sequence denoting
the site at which the splicing of an intron takes place. Such
mutations result in one or more introns remaining in the mature
messenger RNA (or in one or more exons skipped)and can disrupt the generation of the correct protein product.
This means the defect leads to the formation of more than one protein
isoforms, but only one is "normal". Generally mutations that allow
more "normal" CFTR to be built are associated with milder phenotypes, as
in this case more chloride (and other anions) can be moved through the
channel.
In the case where almost no normal CFTR is synthesized, a splicing
mutation is grouped into class I (together with stop mutations, that
produce merely a truncated, useless protein).
On the other hand, Splicing-Class V mutations instead produce a
variable amount of normal protein, and are usually associated with
"pancreas sufficiency" in CF patients and a milder phenotype in
general.

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