Polyglutamineexpanded

Polyglutamine expansion, often referred to as polyQ expansion, is a genetic mutation in which cytosine-adenine-guanine (CAG) trinucleotide repeats in the coding region of specific genes increase in number. Because each CAG encodes a glutamine residue, expansions produce proteins with abnormally long polyglutamine tracts. When the tract becomes sufficiently long, it promotes misfolding and aggregation of the protein.

PolyQ expansions underlie a group of inherited neurodegenerative disorders known as polyglutamine diseases. The best-known example is Huntington disease, caused by expansions in the HTT gene. Other diseases include several spinocerebellar ataxias (such as SCA1, SCA2, SCA3/Machado-Joseph disease), DRPLA, and others. These conditions are typically autosomal dominant and show anticipation, with earlier onset associated with longer repeats.

Pathogenesis involves toxic effects of the expanded polyQ-containing proteins, including misfolding, accumulation of aggregates, disruption of transcription, and impairment of cellular proteostasis. Nuclear localization of mutant proteins and intranuclear inclusions are common histological features in affected neurons. The regional pattern of neurodegeneration varies by gene, contributing to disease-specific clinical manifestations.

Diagnosis relies on genetic testing to determine CAG repeat length in the relevant gene. There is currently no cure for polyQ diseases; management focuses on symptom relief, multidisciplinary care, and genetic counseling. Prenatal and preimplantation testing may be offered in families with known expansions.

Research efforts include developing antisense oligonucleotides and other gene-silencing approaches to lower mutant transcript levels, as well as strategies to enhance proteostasis and clearance of toxic proteins. Model organisms and patient-derived cells are used to study mechanisms and test therapies.