The discovery that trinucleotide repeats could expand during intergenerational transmission and could cause disease was the first evidence that not all disease-causing mutations are stably transmitted from parent to offspring.There are several known categories of trinucleotide repeat disorder. Category I includes Huntingtons disease (HD) and the spinocerebellar ataxias. These are caused by a CAG repeat expansion in protein-coding portions, or exons, of specific genes. Category II expansions are also found in exons, and tend to be more phenotypically diverse with heterogeneous expansions that are generally small in magnitude. Category III includes fragile X syndrome, myotonic dystrophy, two of the spinocerebellar ataxias, juvenile myoclonic epilepsy, and Friedreichs ataxia. These diseases are characterized by typically much larger repeat expansions than the first two groups, and the repeats are located in introns rather than exons. Types
Some of the problems in trinucleotide repeat syndromes result from causing alterations in the coding region of the gene, while others are caused by altered gene regulation. In over half of these disorders, the repeated trinucleotide, or codon, is CAG. In a coding region, CAG codes for glutamine (Q), so CAG repeats result in a polyglutamine tract. These diseases are commonly referred to as polyglutamine (or polyQ) diseases. The repeated codons in the remaining disorders do not code for glutamine, and these are classified as non-polyglutamine diseases. Polyglutamine (PolyQ) diseases
Non-polyglutamine diseases
Symptoms and signs
A common symptom of polyQ diseases is the progressive degeneration of nerve cells, usually affecting people later in life.
A parent with 35 repeats would be considered normal and would not exhibit any symptoms of the disease. However, that parents offspring would be at an increased risk of developing Huntingtons compared to the general population, as it would take only the addition of one more CAG codon to cause the production of mHTT (mutant HTT), the protein responsible for disease. Huntingtons very rarely occurs spontaneously; it is almost always the result of inheriting the defective gene from an affected parent. However, sporadic cases of Huntingtons in individuals who have no history of the disease in their families do occur. Among these sporadic cases, there is a higher frequency of individuals with a parent who already has a significant number of CAG repeats in their HTT gene, especially those whose repeats approach the number (36) required for the disease to manifest. Each successive generation in a Huntingtons-affected family may add additional CAG repeats, and the higher the number of repeats, the more severe the disease and the earlier its onset. As a result, families that have had Huntingtons for many generations show an earlier age of disease onset and faster disease progression. Non-trinucleotide expansions
The majority of diseases caused by expansions of simple DNA repeats involve trinucleotide repeats, but tetra-, penta- and dodecanucleotide repeat expansions are also known that cause disease. For any specific hereditary disorder, only one repeat expands in a particular gene. Mechanism
Triplet expansion is caused by slippage during DNA replication or during DNA repair synthesis.