Expansion Repeat Disorders
DNA carries the genetic code that ultimately dictates the growth, development, and function of each of our cells. It is comprised of distinct arrangements of four DNA building blocks called nucleotides: adenine (A), guanine (G), thymine (T), and cytosine (C). The arrangement of nucleotides ultimately dictates the type of protein produced. Generally, this process can be simplified into two steps. First, DNA is transcribed into another molecule called messenger RNA (mRNA), and mRNAs are then translated into the encoded proteins.
Everyone’s genome is slightly different, and most of the time, we think of these differences as single alterations in nucleotide sequence. However, there exist other types of genetic variation as well. All individuals carry stretches of 1-6 nucleotide-long repeating sequences, termed “microsatellites”, throughout their genome. Although microsatellites do not cause disease by themselves, they can change in length over the lifespan of an individual, or across successive generations (Fan & Chu, Genom Prot Bioinf, 2007). In fact, the specific length and pattern of microsatellites is commonly used in forensics to uniquely identify individuals.
5’ ATG GGC TAC CAG GCC 3’
3’ TAC CCG ATG GTC CGG 5’
5’ ATG GGC TAC CAG CAG CAG CAG GCC 3’
3’ TAC CCG ATG GTC GTC GTC GTC CGG 5’
5’ AUG GGC UAC CAG CAG CAG CAG GCC 3’
NH2-Met Gln Tyr Gln Gln Gln Gln Ala-COOH
Expansion Repeat Disorders
An important class of genetic diseases, expansion repeat disorders (also known as repeat expansion disorders or trinucleotide repeat disorders) occur when microsatellite repeats expand beyond a threshold length. Currently, at least 30 genetic diseases are believed to be caused by repeat expansions.
Our understanding of this diverse group of disorders exploded in the early 1990’s with the discovery that trinucleotide repeats underlie several major inherited conditions, including Fragile X, Spinal and Bulbar Muscular Atrophy, Myotonic Dystrophy, and Huntington’s disease (Nelson et al, Neuron, 2013). Microsatellite repeat instability was found to be a hallmark of these conditions, as was anticipation – the phenomenon in which repeat expansion can occur with each successive generation, which leads to a more severe phenotype and earlier age of onset in the offspring.
Repeat expansions are believed to cause disease via several different mechanisms. Namely, expansions may interfere with cellular functioning at the level of the gene, the mRNA transcript, and/or the encoded protein. In some conditions, mutations act via a loss-of-function mechanism by silencing repeat-containing genes. In others, disease results from gain-of-function mechanisms, whereby either the mRNA transcript or protein takes on new, aberrant functions.
Role of Toxic mRNAs in Disease Pathogenesis
Understanding the role of toxic mRNAs in the development of disease has gained attention in recent years in part due to opportunities for therapeutic intervention. In several cases, mutant mRNAs sequester RNA binding proteins and inappropriately accumulate in the nucleus of the cell. These proteins are crucial for the regulation of mRNA processing (“splicing”), stability, and function. The relative loss of RNA binding proteins can lead to aberrant splicing of other RNA transcripts and consequently altered expression of many different proteins. Such pleiotropic effects may explain, at least in part, the multi-organ system dysfunction observed in repeat expansion disorders.
The strongest evidence to support a role for toxic mRNA to drive disease lies in myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2). Toxic mRNAs may represent a viable therapeutic target that is at the root of and central to disease pathogenesis.