Sunday, December 29, 2013

Laura Ranum to the Rescue

I previously mentioned that several different C9ORF72 ALS-FTD groups have published that there is an antisense transcript at the repeat region, but only used FISH targeting the antisense transcript.  I was surprised that the claims made it through the review process, given my experience in the trinucleotide repeat field.  More specifically, my most recent grants were returned with harsh reviews suggesting that antisense transcripts at repeat regions are spurious and unimportant.  But the ALS-crowd embraces the prospect whole heartedly.  Additionally, the ALS-crowd embraces Repeat-Associated Non-ATG (RAN) translation, a story that should be solely credited to Laura Ranum.  OK, I am certain there are others who suggested non-ATG translation is possible.  However, Laura realized it was a critical feature of trinucleotide repeat expansion diseases.  As the repeat expands, there is a longer transcript generated from the repeat region.  This transcript can generate longer or more polypeptides, in multiple frames. Dr. Ranum took a great deal of heat for this line of research, but she opted to move through the critiques rather than give up.  Here is a link to a great review by John Cleary and Laura Ranum.

Why is RAN-translation important?  It opens a window to a new field of study.  An important window.  There have been mumblings about "aberrant" peptides that are generated by our cells.  Of course, they are passed off as unimportant.  After all, if something does not adhere to the central dogma:
it cannot be real/important/possible/likely/useful (pick your favorite word).

What is wrong with scientists?  It seems as though there is a great population of scientists who cannot think outside of the core classes they took as undergrads or graduate students.  I am always puzzled.  In a discipline with a history of searching for the novel, the current "research-leaders" shun the brilliant observations and celebrate the popular studies.  Of course, as a scientist, it is as much my responsibility to highlight good science as it is to recognize the bad.  On that note: here is another paper on C9ORF72 ALS-FTD, this time from the Ranum lab.  Because it is from a veteran repeat-expansion disease lab, there is actual analysis of the sense and antisense transcripts.  Note: while my work on the antisense transcript at the C9ORF72 locus is still not published, I will point out that I have different results. Of course, I am fairly sure I know why and I am looking forward to addressing the question myself.

Laura's paper is a reminder of what I find interesting about bidirectional transcription, as well as a reminder to not give up on a pursuit that is important.


  1. Dear, I have a question to ask regarding C9orf72 not sure if it is right place to ask. Do we know already from other such repeat expansion cases, what is mechanism of anti sense transcription, are these transcripts also made by RNA Pol II? What would be best technique to detect them as they span the repeat regions which might be difficult to sequence or detect via RT-PCR?

  2. Fortunately, you can access Ranum's paper for the protocol and primer location. Or access 2007 ladd, pd, et al for the general protocol and figure out the primers you want to use.

    As far as function---no, we do not yet understand function. That is the point of detection, now that we have the transcript to monitor, we can assay for function.