Trinucleotide repeats are specific DNA sequences that are repeated numerous times in our genetic blueprint. While a natural part of human genetics, these repetitive segments can sometimes expand beyond their normal range. When such expansions occur, they are linked to the development of a diverse group of inherited neurological and neuromuscular conditions.
Understanding Trinucleotide Repeats
Trinucleotide repeats are specific DNA sequences where a set of three nucleotides is repeated consecutively. Common examples include CAG, CTG, and CGG. These repetitive segments are found throughout the human genome, often located within or near genes, and their length typically remains stable across generations. A normal individual carries a specific number of these repeats, which does not cause disease.
The number of repeats varies, generally falling within a non-pathogenic range. For instance, the CAG repeat in the HTT gene is normally present in fewer than 26 copies. Some normal repeat stretches are thought to play roles in gene regulation or protein stability.
Mechanisms of Disease Development
The expansion of trinucleotide repeats beyond a certain threshold can lead to disease through various molecular mechanisms. This dynamic mutation means the repeat length is unstable and can increase as it is passed down through generations. Such expansions often lead to anticipation, where the disease manifests with earlier onset and greater severity in successive generations within a family.
One primary mechanism is a “gain of function,” often seen in polyglutamine (polyQ) disorders like Huntington’s disease. Here, an expanded CAG repeat within a gene leads to the production of a protein with an abnormally long stretch of glutamine amino acids. This altered protein misfolds and aggregates, becoming toxic to cells, particularly neurons.
Conversely, some disorders arise from a “loss of function” mechanism. In this scenario, an expanded repeat interferes with the normal expression of a gene. For example, in Fragile X syndrome, an expanded CGG repeat in the FMR1 gene causes increased methylation, which silences the gene and prevents the production of the FMR1 protein. The absence of this protein leads to the characteristic symptoms of the disorder.
Another mechanism involves RNA-mediated toxicity, where the expanded repeat, when transcribed into RNA, directly becomes harmful. The expanded RNA itself forms abnormal structures that sequester important cellular proteins. This disrupts normal cellular processes, leading to dysfunction and cell death, as observed in Myotonic Dystrophy types 1 and 2.
Common Trinucleotide Repeat Disorders
Huntington’s disease is a neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the HTT gene. Individuals with 36 or more CAG repeats develop the disease. This expansion leads to a misfolded huntingtin protein that forms toxic aggregates within brain cells, resulting in progressive loss of motor control, cognitive decline, and psychiatric problems.
Fragile X syndrome, the most common inherited cause of intellectual disability, stems from an expansion of the CGG repeat in the FMR1 gene on the X chromosome. A full mutation involves over 200 CGG repeats, which hypermethylates the gene, effectively silencing it. This prevents the production of the fragile X mental retardation protein (FMRP), which is important for synaptic development and function, leading to developmental delays, intellectual disability, and behavioral challenges.
Myotonic Dystrophy type 1 (DM1) is caused by an expanded CTG repeat in the DMPK gene. Normal individuals have fewer than 37 repeats, while those with DM1 can have hundreds or thousands. The expanded CTG repeat, when transcribed into RNA, forms abnormal structures that trap specific RNA-binding proteins, preventing them from performing their normal functions in other genes. This leads to a wide range of symptoms, including muscle weakness, myotonia (difficulty relaxing muscles), cataracts, and cardiac abnormalities.
Inheritance and Diagnosis
Trinucleotide repeat disorders follow distinct inheritance patterns, depending on the specific gene involved. Huntington’s disease, for example, is inherited in an autosomal dominant manner, meaning only one copy of the expanded gene is sufficient to cause the disorder. Fragile X syndrome, being X-linked, affects males more severely than females, as males have only one X chromosome. Myotonic Dystrophy is also autosomal dominant, with repeat expansion size often correlating with symptom severity.
A significant aspect of inheritance is the distinction between a “premutation” and a “full mutation.” A premutation involves an intermediate number of repeats that does not cause the full-blown disease but is unstable and can expand into a full mutation in subsequent generations. For instance, in Fragile X, a premutation range of 55-200 CGG repeats can expand to over 200 in offspring, leading to the syndrome.
Genetic testing is the primary method for diagnosing these disorders and involves analyzing DNA to determine the exact number of trinucleotide repeats. Polymerase chain reaction (PCR)-based methods, along with Southern blotting, are used to accurately measure repeat lengths. Such testing can confirm a diagnosis, identify carriers, and provide information for family planning and genetic counseling.