Nucleotide Repeat Disorders
Numerous Diseases Occur Because Small DNA Segments are Duplicated
There are a growing number of genetic diseases that would seem to have very little in common, yet they share in some unusual molecular changes.
Huntington’s disease, Friedrich’s Ataxia, the Spinocerebellar Ataxias, Fragile X syndrome, and Myotonic Dystrophy all arise from mutations in different genes but what do they have in common? They are all characterized by unstable genetic mutations where the DNA for the specific disease-related genes has had a 3 or 4 nucleotide sequence that they contain duplicated over and over and over again.
First, some basic DNA biochemistry. DNA encodes the information to synthesize all of the proteins needed by a cell. This information is encoded in the DNA molecule through the use of only 4 “letters”, the chemical shorthand being A, C, T, and G. Each of these letters represents a specific compound known as a nucleotide. The genetic code specifies the order of amino acids needed to make proteins based on triplet combinations of these nucleotides. For instance, the code ‘TGG’ in DNA instructs the cell’s machinery to use the amino acid tryptophan at that specific point in synthesizing a protein.
Huntington’s Disease (HD) as an example. For patients with HD, the telling mutation is the repetitive duplication, or expansion, of the three nucleotide sequence in DNA that specifies the molecular code for the amino acid glutamine, the letters CAG. This so-called ‘triplet’ is duplicated contiguously anywhere from 6 to over 100 times in a specific location in the information encoding the protein known as ‘huntingtin’. Because of this, Huntington’s disease is referred to as either a ‘polyglutamine disorder’ or as a ‘trinucleotide repeat disorder’. Interestingly, the severity and time of onset of HD is governed by how many times the CAG triplet is duplicated. When there are greater than 60 duplications of the CAG triplet the disease usually has an onset when the patient is in his or her 20s.
Are proteins always affected in these disorders? When RNA copies of the information encoded by DNA are synthesized, or transcribed, they are longer than just the sequence of nucleotides necessary to convey the information about the synthesis of a specific protein. The process of synthesizing protein from the information transcribed into RNA is known as translation. The start and stop signs for translation are not at the absolute ends of the RNA molecules that are made. There are additional sequences both before the start sign and after the stop sign for protein information. These sequences are referred to as ‘untranslated sequences’ and they can influence the stability and efficiency of use of the RNA molecules. For several of the nucleotide expansion disorders it is the sequence of the RNA in these untranslated regions that can be altered. For this particular case, both Friedrich’s Ataxia and Myotonic Dystrophy Type 1 are examples of expansion disorders where the duplication occurs in a region that does not encode the actual protein.
The Case of Genetic Anticipation. For many nucleotide expansion disorders an effect referred to as genetic anticipation can be identified. A parent may carry a copy of the gene with an unstable, moderate number of repeats and not show any, or perhaps only minor, symptoms of the disease. Yet, when the gene is inherited by one of their children it will have expanded the number of repeats dramatically, leading to disease that occurs at a relatively young age.
Other Commonalities in Nucleotide Expansion Disorders. In the case of the spinocerebellar degeneration disorders for example, a number of different genes have been linked to the disease. However, while the various genes do not encode proteins with even vaguely related functions, they are all characterized by expansions of a specific trinucleotide sequence. And surprisingly perhaps, the majority of patients present with quite similar symptoms. While many of the genes that have been linked to these various disorders encode proteins that are synthesized widely throughout the body, the central nervous system seems to be the major target of damage if not, in many cases, the exclusive target. The brain and spinal cord obviously contain groups of cells that are uniquely susceptible to many negative effects that cells from outside of the nervous system simply are not.
