Molecular features of the CAG repeats and clinical manifestation of Machado--Joseph disease

Abstract

Machado--Joseph disease (MJD) is an autosomal dominant spinocerebellar degeneration mapped to chromosome 14q32.1. The CAG expansions of the MJD1 gene was identified as the cause of the disease. We have analyzed 90 MJD individuals from 62 independent MJD families and found that the MJD1 repeat length is inversely correlated with the age of onset (r = -0.87). The MJD chromosomes contained 61-84 repeat units, whereas normal chromosomes displayed 14-34 repeats. In the normal chromosomes, 14 repeat units were the most common and the shortest. In association with the clinical anticipation of the disease, a parent--child analysis showed the unidirectional expansion of CAG repeats and no case of diminution in the affected family. The differences in CAG repeat length between parent and child and between siblings are greater in paternal transmission than in maternal transmission. Detailed analysis revealed that a large degree of expansion was associated with a shorter length of MJD1 gene in paternal transmission. On the other hand, the increments of increase were similar for shorter and longer expansion in maternal transmission. Among the three clinical subtypes, type I of MJD, with dystonia, showed a larger degree of expansion in CAG repeats of the gene and younger ages of onset than the other types.

Autosomal dominant cerebellar ataxias in the Kinki area of Japan

“…Distributions of CAG repeat length in expanded alleles from MJD and DRPLA patients in the Kinki area were similar to those previously repoi'ted (lkeuchi et al, 1995;Komure et al, 1995;Maciel et al, 1995;Maruyama et al, 1995;Takiyama et al, 1995). We also found a significant inverse correlation between the age of onset and the repeat length in both MJD and DRPLA.…”

Comparison of expanded CAG repeat tracts in sperm and lymphocyte DNA from Machado Joseph disease and spinocerebellar ataxia type I patients

“…These results confirm the earlier result from the single MJD patient that the distribution of alleles in sperm is broadened but not offset by more than one repeat unit from the lymphocyte distribution (Cancel et al, 1995). The results do not correlate with the observed parent-to-child increase of three repeat units reported in two studies of MJD (Maruyama et al, 1995;Takiyama et al, 1995). Although repeat tract changes occur often in MJD, the variation in sperm allele sizes do not suggest a large paternal anticipation bias.…”

“…Although MJD children often differ from their affected parent in their repeat lengths (Cancel et al, 1995;Giuniti et al, 1995;Maruyama et al, 1995;Takiyama et al, 1995), the phenomenon of anticipation has not been firmly established (Takiyama et al, 1995). A recent study showed that the distribution of expanded repeat tracts from the sperm of an MJD patient differed from the distribution from his lymphocyte DNA only by its breadth but not by a skew toward longer tracts (Cancel et al, 1995).…”

Machado-Joseph Disease / Spinocerebellar Ataxia Type 3

“…This high threshold of pathogenicity is a special characteristic of this disorder, since in most other polyglutamine disorders trinucleotide repeats over 36 to 40 become pathogenic. There is an inverse correlation between the age of onset and the number of CAG repeats, as is the case for other polyglutamine disorders (Maciel et al, 1995;Maruyama et al, 1995;Globas et al, 2008).…”