Aberrant Splicing Mutations and Ataluren

Question

My 14 year old daughter has the two mutations DF508 and 621 + 1G > T. It is my understanding that the 621 + 1G > T mutation causes aberrant splicing of mRNA. How is that different from a nonsense mutation?

Currently, I see that Ataluren trials are targeting nonsense mutations in Class I. Since 621 + 1G > T is in Class I as well, could Ataluren potentially help carriers of this mutation as well or will it work only on nonsense mutations?

Thank you.

Answer

Dear Parent
Thank you for your question. Firstly you ask how the splicing mutation 621+1G>T is different to that of a nonsense mutation (typically those mutations that end with an "X"). 621+1G>T has one thing in common with nonsense mutations in that it is also a Class I, as you say in your question. Class I mutations produce few or no functioning protein (in other words the CFTR chloride channels). The way in which 621+1G>T causes this lack of protein is different to nonsense mutations. Healthy protein synthesis can briefly be described as being a three stage process. 1) DNA is copied to make RNA (translation); 2) RNA is modified to produce mRNA (splicing; sections are removed and other sections joined up); 3) mRNA used as "blueprint" to build protein (translation). In nonsense mutations the third stage, translation, stops early due to a premature stop signal and therefore causes a shortened non-functional protein. Splicing defects occur when there are errors in the second stage. For example there may be disruptions in the parts of the mRNA which are removed and which are joined together.

This leads us to your second question. Will Ataluren work only in nonsense mutations or will it also work in patients with 621+1G>T? I'm afraid the answer is not straight forward. Ataluren is thought to have an effect on patients with splicing mutations which cause a premature stop signal. The results of the Phase III study in CF which included patients with such mutations are due this summer. It is currently unknown, however, whether this new molecule could target all splicing mutations.

Best wishes,
Lisa Kent
Stuart Elborn
Belfast

02.04.2012

The answer is edited by: PhD Lisa Kent