- A trinucleotide repeat disorder is a type of genetic condition caused by an abnormal expansion of a sequence of three nucleotides—most often CAG, CGG, CTG, or GAA—within a gene.
- Normally, short tandem repeats of these triplets are found in many genes and are stable across generations. However, in trinucleotide repeat disorders, the number of repeats becomes unstable and expands beyond a normal threshold. This expansion alters the gene’s function, either by producing a dysfunctional protein, causing gene silencing, or interfering with RNA processing, ultimately leading to disease.
- The location of the repeat expansion within the gene plays a critical role in determining the mechanism of pathogenesis. When expansions occur in coding regions, such as CAG repeats, they typically lead to proteins with elongated polyglutamine tracts that misfold and aggregate, as seen in Huntington’s disease and certain spinocerebellar ataxias.
- Expansions in noncoding regions can disrupt gene regulation or RNA processing. For example, CGG repeat expansions in the 5′ untranslated region of the FMR1 gene cause Fragile X syndrome by leading to hypermethylation and gene silencing, while CTG repeats in the 3′ untranslated region of the DMPK gene result in myotonic dystrophy through toxic RNA accumulation.
- These disorders often show a phenomenon known as anticipation, in which the severity of disease increases and the age of onset decreases in successive generations. This occurs because the unstable repeats tend to expand further when transmitted, especially during gametogenesis. The degree of expansion is influenced by whether the repeat is inherited from the mother or father, depending on the specific disorder. For instance, Huntington’s disease expansions are typically more unstable through paternal transmission, while myotonic dystrophy shows greater instability through maternal transmission.
- Clinically, trinucleotide repeat disorders manifest with a wide range of neurological, muscular, and developmental symptoms. Huntington’s disease presents with progressive motor dysfunction, psychiatric disturbances, and cognitive decline. Fragile X syndrome is a leading inherited cause of intellectual disability and autism spectrum features. Myotonic dystrophy affects both skeletal and smooth muscle, causing weakness, myotonia, and multi-systemic involvement. Friedreich’s ataxia, caused by GAA expansions in the FXN gene, leads to neurodegeneration and cardiomyopathy.
- Diagnosis typically involves genetic testing to measure the size of the repeat expansion using techniques such as PCR and Southern blotting. There are currently no curative therapies, and treatment is generally supportive and symptomatic, although research into gene editing, antisense oligonucleotides, and RNA-targeted therapies holds promise for future interventions.
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