Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA)

Abstract

Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified unstable expansion of a CAG in a gene on chromosome 12 in all the 22 DRPLA patients examined. A good correlation between the size of the CAG repeat expansion and the ages of disease onset is found in this group. Patients with earlier onset tended to have a phenotype of progressive myoclonus epilepsy and larger expansions. We propose that the wide variety of clinical manifestations of DRPLA can now be explained by the variable unstable expansion of the CAG repeat.

Unstable expansion of triplet repeats as a new disease mechanism for neurodegenerative diseases

“…There are statistically significant Table 1. Genetic anticipation in DRPLA (Koide et al, 1994;Ikeuchi et al, 1995a, b, c) Paternal Maternal Our cohort -25.6+2.4 (n=27) -14.0+4.0 (n=9) p<0.05 Literature --28.8--+-1.9 (n=27) -14.8--+4.0 (n= 11) p<0.05 differences in the magnitude of decrease in age at onset between paternal and maternal transmissions. The parental bias in the genetic anticipation implies that the genetic anticipation is intimately associated with the differences in meiotic instability of the CAG repeats between paternal and maternal transmissions.…”

“…Expansion of CAG repeats in protein coding regions was first identified as the causative gene for spinal and bulbar muscular atrophy (SBMA) (La Spada et al, 1991). Since then expansion of CAG repeats in protein coding regions has been identified in Huntington's disease (HD) (The Huntington's Disease Collaborative Research Group, 1993), spinocerebellar ataxia type 1 (SCA1) (Orr et al, 1993), dentatorubral-pallidoluysian atrophy (DRPLA) (Koide et al, 1994;Nagafuchi et al, 1994a) and Machado-Joseph disease (MJD) (Kawaguchi et al, 1994) (Fig. 1).…”

“…As mentioned above, to date five diseases have been identified to be caused by unstable expansion of CAG repeats including SBMA, HD, SCA1, DRPLA and MJD (La Spada et al, 1991;The Huntington's Disease Collaborative Research Group, 1993;Orr et al, 1993;Koide et al, 1994;Nagafuchi et al, 1994a;Kawaguchi et al, 1994). The mode of inheritance of these diseases is autosomal dominant one except for SBMA which is inherited as an X-linked recessive trait.…”

“…Since the conventional approach to identification of causative genes by positional cloning requires large pedigrees for linkage studies, development of novel strategies for direct identification of expanded triplet repeats will be required. Figure 2 shows the correlation of the size of expanded CAG repeat of the DRPLA gene and the age of onset of DRPLA (Koide et al, 1994;Ikeuchi et al, 1995a, b, c). As has been demonstrated in diseases caused by expansion of CAG repeats, a strong inverse correlation between the size of expanded CAG repeats and the age at onset was demonstrated in DRPLA.…”

C‐terminal deletion of the atrophin‐1 protein results in growth retardation but not neurodegeneration in mice

“…This disease is caused by a mutant Atrophin-1 protein carrying an expanded poly-glutamine (poly-Q) repeat. The wild-type Atrophin-1 protein has a poly-Q stretch that typically contains 6 to 35 glutamine residues, while the number of repeated glutamine varies from 48 to 88 in DRPLA patients (Koide et al, 1994;Nagafuchi et al, 1994;Onodera et al, 1995). The causative link between poly-Q expanded Atrophin-1 and DR-PLA disease was also proved in transgenic mice, where ectopic expression of the mutant protein is sufficient to cause DRPLA like neurodegenerative phenotypes (Sato et al, 1999;Schilling et al, 1999;Ying et al, 2006).…”