Trinucleotide Repeat Disorders


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What are Trinucleotide Repeat Disorders?

Many inherited diseases are the result of a single difference in the genetic code for a particular protein. As a result of that difference, either a protein is not made at all, made in inadequate amounts, or made in a defective form. The disease is a result of a person either not making enough of a protein or having a defective version of it.

In the early 1990's, researchers identified a new type of mutation called dynamic or expansion mutations. Actually there had been previous evidence for such mutations but the underlying cause was not understood. Researchers had noted that in a variety of diseases, there was an increase in severity of a disease or earlier onset of a disease over several generations. Today we understand these diseases to be trinucleotide repeat disorders.

Ball and Stick

Used with permission of
Paul Thiessen
Chemical Graphics

The DNA is made up of a chain of nucleotides which differ in their bases. Adenine, thymine, guanine, and cytosine (A, T, G, and C) are the four bases present in DNA. We can write out the genetic information in DNA in the form of a sequence of letters such as AATGACCCGTAG. This genetic information codes for the different proteins which result in our genetic differences from each other and from other living things.

Within the DNA, it is common to have a repeating triplet such as CGG CGG CGG CGG. All combinations of triplets (AGG, ACC, etc.) occur but CGG and CAG are more common than others. These sequences are a normal part of our DNA and may play a variety of regulatory roles.

However, something can go wrong. If the number of repeats is too large, it can trigger a problem that results in an identifiable disease.

Huntington disease is an inherited neurodegeneration that often occurs in the fourth or fifth generation of life. In the gene that controls Huntington disease, there is a series of CAG repeats. When that number of repeats is too large, it results in the synthesis of a protein that has an odd shape because a section of it is expanded. As a result, the abnormal protein causes the deterioration in neurological function that is associated with Huntington disease. As the size of the repeat section increases over generations, the age of onset of the disease becomes earlier.

Friedreich ataxia is also a neurodegenerative disorder. The mutation occurs in a series of GAA repeats that are located in an intron. Introns are sections of genetic code that are initially copied but the section is edited out before a protein is synthesized. As a result, an expansion in this GAA series does not result in an abnormally large protein as seen in Huntington disease. Instead, the expansion messes up the regulation of protein synthesis so there is a decreased amount of protein synthesized. The shortage of the protein causes the characteristics of Friedreich ataxia.

Atomic Force Microscopy of Fragile X chromosome

Used with permission of
Rob Willemsen, Ph.D., Erasmus University

Fragile X syndrome fits in with this family of repeat expansion disorders. It involves an expansion of the CGG repeats normally in the FMR1 (fragile X mental retardation 1) gene. The CGG repeats are not in a section of the gene that gets edited out (an intron), but rather in a section that is copied and remains after the editing is finished (an exon). Even though the repeat section is part of the finished messenger RNA (mRNA), it doesn't actually get translated into protein.

As a result of an expansion in the CGG repeats, there is methylation of part of the DNA which blocks its ability to be used. This blocks the cell from making FMRP (fragile X mental retardation protein) and the lack of FMRP causes fragile X syndrome.

Within the intermediate range of repeats, an increase in size correlates somewhat with increased effect of fragile X. For persons with the full mutation (>200 repeats), the number of repeats does not appear to affect the severity of the symptoms.