The CAG/polyglutamine tract diseases: gene products and molecular pathogenesis

In the past few years, a new type of genetic mutation, expansion of trinucleotide repeats, has been shown to cause neurologic disease. This new class of mutations was first identified in 1991 as the underlying genetic defect in spinal and bulbar muscular atrophy and the fragile X syndrome, and in recent years, trinucleotide repeat expansions have been found to be the causative mechanism in 10 other neurologic diseases. These mutations are produced by heritable unstable DNA and are termed "dynamic mutations" because of changes in the number of repeat units inherited from generation to generation. In the normal population, these repeat units, although polymorphic, are stably inherited. To date four types of trinucleotide repeat expansions have been identified: (1) long cytosine-guanine-guanine (CGG) repeats in the two fragile X syndromes (FRAXA and FRAXE), (2) long cytosine-thymine-guanine (CTG) repeat expansions in myotonic dystrophy, (3) long guanine-adenine-adenine repeat expansions in Friedreich's ataxia and (4) short cytosine-adenine-guanine repeat expansions (CAG) which are implicated in eight neurodegenerative disorders and are the focus of this review. Diseases that are caused by trinucleotide repeat expansions exhibit a phenomenon called anticipation that can not be explained by conventional Mendelian genetics. Anticipation is defined as increase in the severity of disease with an earlier age of onset of symptoms in successive generations. Anticipation is often influenced by the sex of the transmitting parent, and for most CAG repeat disorders, the disease is more severe when paternally transmitted. The severity and the age of onset of the disease have been correlated with the size of the repeats on mutant alleles, with the age of onset being inversely correlated with the size of the expansion. In all eight disorders caused by CAG repeat expansion, the repeat is located within the coding region of the gene involved and in all cases it is translated into a stretch of polyglutamines in the respective proteins. All the proteins are unrelated outside of the polyglutamine stretch and most are novel with exception of the androgen receptor and the voltage gated alpha 1A calcium channel, which are mutated in spinal and bulbar muscular atrophy and spinocerebellar ataxia type 6. It is intriguing that the proteins are ubiquitously expressed in both peripheral and nervous tissue but in each disorder only a select population of nerve cells are targeted for degeneration as a consequence of the expanded CAG repeat. Current thinking among scientists working on the molecular mechanisms of neurodegeneration in these diseases is that the presence of an expanded polyglutamine confers a gain of function onto the involved protein. To understand the mechanisms underlying the pathogenesis of these diseases, investigators have turned to generating transgenic mice which recapitulate some of the features of the human disease and hence are excellent model systems to study the progression of the disease in vivo.