Triplet Repeat Disease

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.