DNA, our genetic blueprint, is made of repeating units called nucleotides (A, T, C, G). These letters can form specific patterns that repeat. One such pattern is the CTG repeat, a sequence of Cytosine, Thymine, and Guanine nucleotides. These repeats are a natural part of our DNA.
Understanding CTG Repeats
A CTG repeat is a trinucleotide sequence of Cytosine, Thymine, and Guanine arranged consecutively and repeated. Every individual has these CTG repeats in their genetic code, with the exact number varying. While a certain number is normal, problems arise when this sequence expands beyond a healthy range. These expanded repeats, located within specific genes, can interfere with gene function. An expanded number of CTG repeats is associated with certain genetic conditions.
CTG Repeats and Myotonic Dystrophy
Myotonic Dystrophy type 1 (DM1) is the primary genetic disorder linked to expanded CTG repeats. This multisystem disorder affects skeletal muscles, smooth muscles, eyes, heart, endocrine system, and central nervous system. The expansion of CTG repeats within the DMPK gene on chromosome 19q13.3 directly causes DM1.
The severity and onset of DM1 symptoms correlate with the length of the CTG repeat expansion. Mild DM1 (50-150 repeats) presents with mild cataracts and muscle weakness later in life, usually after age 50. Adult-onset DM1 (150-1000 repeats) shows early cataracts, weakness, and myotonia in teenage years or later. Childhood-onset DM1 (600-1200 repeats) involves intellectual impairment and gastrointestinal distress between ages 1 and 10. The most severe form, congenital DM1 (800 or more repeats), manifests with generalized weakness, breathing, and feeding difficulties at birth.
A characteristic of DM1 is anticipation. Here, the CTG repeat length tends to increase in successive generations within a family, leading to earlier onset and more severe symptoms in offspring.
How CTG Repeats Lead to Disease
Expanded CTG repeats cause Myotonic Dystrophy type 1 through “RNA gain-of-function” toxicity. When the DMPK gene, containing the expanded CTG repeats, is transcribed into an RNA molecule, this abnormal RNA forms a distinct hairpin structure. This expanded CUG RNA then sequesters specific RNA-binding proteins, such as Muscleblind-like splicing factor 1 (MBNL1).
The sequestration of MBNL1 and other RNA-binding proteins like CELF1 within these nuclear RNA foci disrupts their normal function in the cell. These proteins are responsible for regulating alternative splicing, a process where different protein versions are made from a single gene. The disruption of normal splicing leads to a wide range of mis-spliced transcripts, resulting in the diverse symptoms observed in DM1. This RNA toxicity mechanism underlies DM1 pathology.
Diagnosing and Managing CTG Repeat Disorders
Diagnosing CTG repeat expansion disorders, especially Myotonic Dystrophy type 1, relies on molecular genetic testing. This involves analyzing a DNA sample, usually from blood or saliva, to measure the CTG repeat expansion length in the DMPK gene. A repeat length of 50 or more CTG repeats in the DMPK gene is diagnostic for DM1.
Genetic counseling is an important part of the diagnostic process, providing individuals and families with information about inheritance patterns and implications. Currently, there is no cure for DM1, so management focuses on alleviating symptoms and providing supportive care. This often involves a multidisciplinary approach, including physical therapy for muscle weakness, medications to manage myotonia (prolonged muscle contraction), and regular monitoring for cardiac issues or cataracts.