Triplet Repeat Disease

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Triplet Repeat Disease

Trinucleotide, or triplet repeats, consist of three consecutive nucleotides that are repeated within a region of DNA (for example, CCG CCG CCG CCG CCG). These are found in the genome of humans and many other species. All possible combinations of nucleotides are known to exist as triplet repeats, though some, including CGG and CAG, are more common than others. The repeats may be within genes or between genes. In genes, they may be in regions that specify proteins (coding regions called exons) or in noncoding regions (introns). If present within exons, they may be present in translated regions and hence encode a series of identical amino acids, or they may occur in regions not translated into protein. Triplet repeats are frequently found in genes that encode transcription factors and those involved in regulating development.

Implicated in Diseases

Triplet repeats were once thought to be apparently benign stretches of DNA. However, it is now known that these repeats can sometimes undergo dynamic or expansion mutation. In this type of mutation, through mechanisms during DNA replication that are only partly understood, the number of triplets in a repeat increases (expands) and can cause disease.

There are many diseases known to be caused by triplet repeats. They share certain common features. The mutant repeat length is unstable in both somatic and germ cells of the body, meaning it can change in length during DNA replication. Also, the triplet repeat often expands rather than contracts in successive generations. Increasing repeat size is correlated with decreasing age of onset or increasing disease severity in successive generations. This phenomenon is called anticipation, and is a characteristic of most triplet repeat diseases.

Classification of Triplet Repeat Disorders

Triplet repeat disorders fall into two subclasses, depending on the location of the trinucleotide repeat within the gene. The first subclass has triplet repeats occurring in noncoding sequences of DNA, either introns or regions at the start or end of the gene, called 5 ("five prime") or 3 ("three prime") untranslated regions. The second subclass is characterized by (CAG)n repeats that code for repeated stretches of the amino acid glutamine (polyglutamine) in coding regions of the affected gene.

Noncoding Triplet Repeat Disorders

The noncoding triplet repeat diseases typically have large and variable repeat expansions that result in multiple tissue dysfunction or degeneration. The triplet repeat sequences vary in this subclass (CGG, GCC, GAA, CTG, and CAG). It is clear that the particular triplet sequence and its location with respect to a gene are important defining factors in dictating the unique mechanism of pathogenesis for each disease. The pathogenic mechanism also varies from disease to disease depending on the consequences of the lost function of the respective proteins or in some cases acquired function of a toxic transcript.

Fragile X Syndrome.

This disorder is caused by the expansion of a (CGG)n repeat in the 5 untranslated region of the fragile X mental retardation (FMR1 ) gene. Normally there are about six to fifty-three repeats in this region. In the disease state there are more than 230 triplet repeats. This causes the transcriptional silencing of the gene, leading to loss of normal gene function. Some of the symptoms seen in this disorder include mental retardation, deformed features, and hyperactivity.

Myotonic Dystrophy (DM).

DM is a multisystem disorder with highly variable phenotypes and anticipation. Rigidity of muscles after contraction (tonic spasms), muscle weakness, and progressive muscle wasting characterize adult-onset DM. Developmental abnormalities, mental handicap, and respiratory distress are often evident in more severe forms. DM is caused by an expanded CTG triplet repeat in the 3 untranslated region of the protein kinase gene DMPK. The CTG expansion may disrupt DMPK transcription, causing loss of function. CTG expansions may also cause loss of function in two genes flanking DMPK : the DM locus-associated home-odomain protein (DMAHP) and gene 59 (also known as DMWD ). The CTG expanded transcript could also gain toxic function by interfering with normal processing of various RNAs. Congenital myotonic dystrophy occurs from birth in infants whose mothers have DM, often a case so mild it is never diagnosed. Due to anticipation, the child is much more severely affected than the mother.

Polyglutamine Diseases

In comparison with the noncoding disorders, polyglutamine diseases have triplet (CAG) repeat expansions in coding regions of genes. Although the mutant proteins do not share any homology (similar sequences) outside the polyglutamine tract, the polyglutamine diseases have several similar features and may share common mechanisms of pathogenesis.

A simple loss of normal function of the gene does not account for the phenotype seen in these diseases. Studies of animal models and tissue culture systems have demonstrated that the mutant protein is toxic. The mutant protein can aggregate and form inclusions in the cytoplasm and nucleus. Also, all the polyglutamine diseases known so far are characterized by progressive neuronal dysfunction that typically begins in midlife and results in severe neurodegeneration. Despite the ubiquitous expression of the mutant genes, only a specific subset of neurons is vulnerable to neurodegeneration in each disease. What makes these specific neurons more susceptible than other neurons and other cells of the body remains a mystery.

Huntington's disease is caused by a CAG expansion in the HD gene that codes for a protein called huntingtin. This protein has no known function. In the normal, nonmutant form of the gene there are about six to thirty-five CAG repeats. In the disease-causing allele there are usually more than thirty-seven CAG repeats. Patients typically show symptoms of dementia, involuntary movements, and abnormal posture.

Spinobulbar muscular atrophy (Kennedy's disease) is caused by CAG expansion in the AR gene that codes for the androgen receptor protein. The normal gene contains nine to thirty-six CAG repeats and the mutant gene usually contains thirty-eight to sixty-two repeats. This disease of motor neurons (nerve cells controlling muscle movement) is characterized by progressive muscle weakness and atrophy. Over 50 percent of the affected males may also have reduced fertility.

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.

see also Androgen Insensitivity Syndrome; Fragile X Syndrome; Gene; Genetic Testing; Inheritance Patterns; Pleiotrophy.

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. <>.

International Myotonic Dystrophy Organization. <>.

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