- Repeat expansion disorders are a group of genetic conditions caused by an abnormal increase in the number of short DNA sequence repeats within certain genes. These expansions often occur in trinucleotide (three-base), tetranucleotide (four-base), or pentanucleotide (five-base) sequences.
- While small variations in repeat length are typically harmless, once the repeat number crosses a disease-specific threshold, it can disrupt normal gene function and lead to disease. Importantly, these expansions tend to be unstable during cell division and across generations, leading to a phenomenon called anticipation, in which disease severity increases and age of onset decreases in successive generations.
- A classic example is Huntington’s disease (HD), caused by expansion of a CAG trinucleotide repeat in the HTT gene on chromosome 4. Normal alleles typically contain fewer than 36 repeats, whereas disease-causing alleles harbor 36 or more. The CAG codon encodes glutamine, so this expansion results in an abnormally long polyglutamine tract within the huntingtin protein. The mutant protein becomes toxic, leading to progressive neurodegeneration, particularly in the striatum and cortex. Clinically, HD is characterized by involuntary movements (chorea), cognitive decline, and psychiatric disturbances. The number of repeats strongly correlates with disease onset: larger expansions usually cause earlier and more severe disease.
- Other polyglutamine (polyQ) disorders are also caused by CAG expansions. Examples include spinocerebellar ataxias (SCAs), such as SCA1, SCA2, SCA3 (Machado-Joseph disease), and SCA6, which primarily affect the cerebellum and brainstem, leading to progressive incoordination and motor dysfunction. Another is spinal and bulbar muscular atrophy (SBMA, Kennedy’s disease), where CAG expansion occurs in the AR (androgen receptor) gene, leading to muscle weakness and androgen insensitivity.
- Beyond CAG/polyQ disorders, repeat expansions in non-coding regions can also cause disease, typically through RNA toxicity, gene silencing, or disruption of splicing. For instance, fragile X syndrome, the most common inherited form of intellectual disability, results from CGG repeat expansion in the 5′ untranslated region (UTR) of the FMR1 gene, leading to gene silencing via hypermethylation. Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion in the 3′ UTR of the DMPK gene, while myotonic dystrophy type 2 (DM2) involves a CCTG expansion in the CNBP gene. In both cases, expanded RNA transcripts sequester RNA-binding proteins, disrupting splicing of multiple cellular transcripts and causing multisystem disease.
- Another important group is non-ATG (RAN) translation–related diseases, where repeat expansions can drive the production of toxic proteins even without a conventional start codon. A prominent example is C9orf72-related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), where a GGGGCC (G4C2) hexanucleotide expansion in the C9orf72 gene leads to both RNA foci and dipeptide repeat protein accumulation, driving neurodegeneration.
- In summary, repeat expansion diseases represent a unique class of genetic disorders in which the instability and abnormal length of repetitive DNA sequences drive pathology. They encompass both coding expansions (leading to toxic proteins, as in Huntington’s disease and SCAs) and non-coding expansions (leading to RNA toxicity or epigenetic silencing, as in fragile X syndrome, myotonic dystrophies, and C9orf72-ALS/FTD). Their shared features include genetic anticipation, repeat instability, and progressive neurodegenerative or neuromuscular symptoms, but the underlying mechanisms vary depending on repeat type and gene context.
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