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Triplet Repeat Disease

Why Are Polyglutamines Toxic?

Several hypotheses have been offered to explain the toxic nature of polyglutamine repeats, though none has yet been conclusively proven, and may yet be wrong in either details or central concept. The Nobel Prize recipient Max Perutz suggested that the expanded polyglutamine repeats promote the formation of protein aggregates. These aggregates often contain ubiquitin, a marker for protein degradation. Expanded polyglutamine proteins may adopt energetically stable structures that resist unfolding and therefore impede clearance by the cell's protein-degrading machinery, called the proteasome. This concept is supported by the observation that addition of proteasome inhibitors promotes aggregation of mutant huntingtin, ataxin-1, and ataxin-3 in cell culture.

Most polyglutamine aggregates are found in the nucleus. Is nuclear localization of the mutant proteins a critical event in polyglutamine disease, and if so, how do the mutant proteins affect nuclear function? Aggregates may interfere with such important events occurring in the nucleus as gene transcription, RNA processing, and nuclear protein turnover. The aggregates formed may sequester and deplete critical nuclear factors required for transcription. Recent evidence suggests that mutant huntingtin does interfere with transcription factors.

Scientists have only begun to understand the role of triplet repeats in disease. The cloning of the disease gene and the identification of expanding repeats represent preliminary steps to the understanding of the full disease process. Genetic testing provides at least an immediate diagnostic tool, but much still remains to be determined for effective therapies to be developed for tomorrow's patients. Many questions, including the biological role of these triplet expansions in evolution, remain unanswered.

Nandita Jha


Cummings, Christopher J. "Fourteen and Counting: Unraveling Trinucleotide Repeat Diseases." Human Molecular Genetics 9, no. 6 (2000): 909-916.

Green, Howard. "Human Genetic Diseases Due to Codon Reiteration: Relationship to an Evolutionary Mechanism." Cell 74 (1993): 955-956.

Moxon, E. Richard, and Christopher Wills. "DNA Microsatellites: Agents of Evolution?" Scientific American (January 1999): 94-99.

Perutz, Max F., and A. H. Windle. "Cause of Neural Death in Neurodegenerative Diseases Attributable to Expansion of Glutamine Repeats." Nature 412 (2001): 142-144.

Tobin, Allan J., and Ethan R. Signer. "Huntington's Disease: The Challenge for Cell Biologists." Trends in Cell Biology 10, no. 12 (2000): 531-536.

Internet Resources

Huntington's Disease Society of America. <www.hdsa.org/>.

International Myotonic Dystrophy Organization. <http://www.myotonicdystrophy.org/>.

Diseases with Triplet Repeats in Noncoding Regions

Fragile X syndrome (CGG repeat) Fragile XE syndrome (GCC repeat) Friedreich ataxia (GAA repeat) Myotonic dystrophy (CTG repeat) Spinocerebellar ataxia type 8 (CTG repeat) Spinocerebellar ataxia type 12 (CAG repeat)

Diseases with (CAG)n Repeats in Coding Regions

Spinobulbar muscular atrophy (Kennedy's disease)
Huntington's disease
Dentatorubral-pallidoluysian atrophy
Spinocerebellar ataxia types 1, 2, 3, 6 and 7

Additional topics

Medicine EncyclopediaGenetics in Medicine - Part 4Triplet Repeat Disease - Implicated In Diseases, Classification Of Triplet Repeat Disorders, Noncoding Triplet Repeat Disorders, Polyglutamine Diseases