A trinucleotide is a sequence of three DNA building blocks, or nucleotides, strung together. These three-letter sequences form the fundamental words of the genetic code, directing the cell’s machinery to build proteins. Located within genes, trinucleotides encode information for various cellular functions.
Understanding Trinucleotide Repeats
Within the human genome, trinucleotides can appear multiple times in a row, forming trinucleotide repeats. These repetitive sequences are a common feature of our DNA, found in various genes. Examples include CAG, CGG, and GAA.
These repeats are present in varying numbers and do not cause health issues under normal circumstances. They contribute to the normal functioning of genes. The specific number of repeats can differ from person to person without leading to disease, unless they exceed a certain threshold for a particular condition.
How Repeat Expansion Causes Problems
The issue arises when trinucleotide repeats abnormally increase in length, a phenomenon called trinucleotide repeat expansion. This expansion occurs when the number of repeats goes beyond the normal range, making the DNA segment unstable. Errors during DNA replication or repair processes can cause this increase in repeat numbers.
This abnormal expansion can disrupt gene function in several ways, leading to genetic conditions. It might result in the production of faulty proteins, prevent proteins from being made altogether, or alter how genes are regulated. An expanded repeat can lead to the creation of an abnormally long protein or a toxic RNA molecule that interferes with cellular processes. A larger expansion in repeat length correlates with an earlier onset and increased severity of the disease.
Common Trinucleotide Repeat Disorders
Over 30 genetic disorders are linked to trinucleotide repeat expansion, primarily affecting the nervous system. These conditions manifest differently based on the specific gene affected and the type of repeat involved. Many of these disorders involve CAG repeats, which code for the amino acid glutamine, leading to polyglutamine diseases.
Huntington’s Disease
Huntington’s disease is caused by an expansion of CAG repeats in the HTT gene on chromosome 4. While a normal HTT gene has 10 to 35 CAG repeats, individuals with Huntington’s disease have 36 to over 120 repeats. This expansion leads to an abnormally long huntingtin protein, which forms toxic fragments that accumulate and cause the death of neurons. Symptoms include uncontrolled movements, cognitive decline, and psychiatric changes.
Fragile X Syndrome
Fragile X syndrome results from an expansion of CGG repeats in the FMR1 gene located on the X chromosome. Unaffected individuals have fewer than 44 CGG repeats, while those with the full mutation have over 200 repeats. This expansion leads to reduced or absent production of the FMRP protein, which is important for brain development, causing intellectual disability and behavioral issues, with males being more severely affected than females.
Myotonic Dystrophy Type 1 (DM1)
Myotonic Dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an expansion of CTG repeats in the DMPK gene. Normal individuals have fewer than 35 CTG repeats, but those with DM1 can have hundreds or thousands. This expansion can suppress the expression of local genes and affects many cellular processes, leading to symptoms like muscle weakness, myotonia (difficulty relaxing muscles), and cataracts.
Genetic Inheritance and Anticipation
Trinucleotide repeat disorders exhibit distinct patterns of inheritance. Huntington’s disease and Myotonic Dystrophy are inherited in an autosomal dominant pattern, meaning only one copy of the altered gene is sufficient to cause the disorder. Fragile X syndrome, however, is X-linked dominant, with the affected gene on the X chromosome.
A notable characteristic of these disorders is “genetic anticipation,” where the disease appears earlier and with greater severity in successive generations. This occurs because the trinucleotide repeat length increases as the gene is passed from parent to child. A parent with a repeat length at the higher end of the normal range might not show symptoms, but their child could inherit an even longer repeat, leading to earlier disease onset. This progressive expansion across generations contributes to the familial patterns of these conditions.