Snapshot: What is RAN translation?

In many diseases caused by repeat expansion mutations in the DNA, harmful proteins containing repetitive stretches are found to build up in the brain. The repeat expansion mutation, when translated into a protein, results in an abnormally expanded repeat tract that can affect the function of the protein and have harmful consequences for the cells. Following a study published in 2011, we know that repeat expansion mutations can make additional harmful repeat-containing proteins by a process called Repeat Associated Non-AUG translation or RAN translation.

How are proteins made?

To get from DNA to protein, there are two main steps. The first step involves the conversion of a gene in the DNA into an instructional file called messenger RNA (mRNA). The second step is translation, this is where the cellular machinery responsible for making proteins uses mRNA as a template to make the protein encoded by the gene.

During translation mRNA is “read” in sets of three bases. Each set of three bases is called a codon and each codon codes for one amino acid. There is a specific codon that signals where to start making the protein, this codon is AUG. From the point where the cellular machinery “reads” the start codon, the mRNA is “read” one codon at a time and the matching amino acid is added onto the growing protein.

What happens when there is a repeat expansion mutation?

As the name suggests, Repeat Associated Non-AUG (RAN) translation is a protein translation mechanism that happens without a start codon. RAN translation occurs when the mRNA contains a repeat expansion that causes the mRNA to fold into RAN-promoting secondary structures. Because RAN translation starts without an AUG start codon, the mRNA can be “read” in different ways.

Let’s consider a CAG repeat expansion to illustrate this process. In the CAG “reading frame” a polyglutamine containing protein would be made because the codon CAG leads to incorporation of the amino acid glutamine. But a CAG repeat expansion could also be “read” as an AGC or a GCA repeat expansion if you don’t know where in the sequence to start “reading”. When “read” as AGC, the cellular machinery would incorporate the amino acid serine, making a polyserine repeat protein. In the GCA frame a polyalanine repeat protein would be made. This has been shown to happen in Huntington’s disease (HD). In HD, RAN-translated polyserine and polyalanine proteins accumulate in HD patients’ brains, along with the AUG-initiated mutant huntingtin protein containing a polyglutamine expansion.

Diagram show how different DNA sequences can be "read" and translated as different proteins
Overview of repeat proteins that can be produced by RAN-translation from a CAG expansion transcript. Designed by Mónica Bañez-Coronel.

To complicate matters more, RAN translation can happen from different repeat expansions, including those in regions of the DNA that aren’t normally made into proteins at all. Through the process of RAN translation, repeat expansion mutations in the DNA can give rise to multiple different proteins that aren’t made in healthy individuals. RAN proteins have now been identified in several neurodegenerative diseases where they have been shown to be toxic to cells, including in HD, spinocerebellar ataxia type 8, myotonic dystrophy type 1 and 2, and C9orf72 amyotrophic lateral sclerosis (ALS).

To learn more about the implications of RAN proteins for repeat expansion diseases see this article by Stanford Medicine News Center.

To learn more about the process of translation see this article by Nature.

https://www.nature.com/scitable/topicpage/translation-dna-to-mrna-to-protein-393/

For the original article describing RAN translation see this article by PNAS, and this article by Neuron about RAN translated proteins in Huntington’s disease.

Snapshot written by Dr. Hannah Shorrock and edited by Dr. Mónica Bañez-Coronel.

The Discovery of SCA8

Written by Dr. Hannah K Shorrock Edited by Dr. Judit M Perez Ortiz

How one team uncovered the first SCA known to be caused by a CTG repeat expansion mutation

Identifying the gene that causes a type of ataxia not only gives patients and their families a clearer diagnosis and prognosis, but also allows scientists to model the disease. Through genetic animal models of ataxia, researchers can study how a single mutation causes a disease and how we can try to slow, halt, or even reverse this process. It is this path through research that may eventually lead from gene discovery to the development of effective therapies.

The gene that causes spinocerebellar ataxia type 8 (SCA8) was first described in a research article published in 1999. Since then, many research articles on SCA8 have been published, including research into the DNA repeat expansions that cause the ataxia, the cellular processes that lead to ataxia, and the development of multiple animal models of SCA8. Together, these move the scientific community further along the road of research.

mother with her two children looking at a mountain
Image of mother with her children. SCA8 was initially identified in a mother and daughter. SCA8 also shows maternal penetrance bias. Photo by Josh Willink on Pexels.com

Continue reading “The Discovery of SCA8”