Evidence for inter-generational instability in the CAG repeat in the MJD1 gene and for conserved haplotypes at flanking markers amongst Japanese and Caucasian subjects with Machado-Joseph disease

Abstract

The size of the (CAG)n repeat array in the 3' end of the MJD1 gene and the haplotype at a series of microsatellite markers surrounding the MJD1 gene were examined in a large cohort of Japanese and Caucasian subjects affected with Machado-Joseph disease (MJD). Our data provide five novel observations. First, MJD is associated with expansion fo the array from the normal range of 14-37 repeats to 68-84 repeats in most Japanese and Caucasian subjects, but no subjects were observed with expansions intermediate in size between those of the normal and MJD affected groups. Second, the expanded allele associated with MJD displays inter-generational instability, particularly in male meioses, and this instability was associated with the clinical phenomenon of anticipation. Third, the size of the expanded allele is not only inversely correlated with the age-of-onset of MJD (r = -0.738, p < 0.001), but is also correlated with the frequency of other clinical features [e.g. pseudoexophthalmos and pyramidal signs were more frequent in subjects with large repeats (p < 0.001 and p < 0.05 respectively)]. Fourth, the disease phenotype is significantly more severe and had an early age of onset (16 years) in a subject homozygous for the expanded allele, which contrasts with Huntington disease and suggests that the expanded allele in the MJD1 gene could exert its effect either by a dominant negative effect (putatively excluded in HD) or by a gain of function effect as proposed for HD. Finally, Japanese and Caucasian subjects affected with MJD share haplotypes at several markers surrounding the MJD1 gene, which are uncommon in the normal Japanese and Caucasian population, and which suggests the existence either of common founders in these populations or of chromosomes susceptible to pathologic expansion of the CAG repeat in the MJD1 gene.

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).…”

SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6

“…16 Unfortunately, we could not investigate if the (Glu) 47 allele detected in the patient presented here is associated with reduced penetrance as shown for a (Glu) 48 allele in one of our families. 10 More severe disease phenotypes in patients homozygous for expanded alleles were found also in SCA3 17,18 in contrast to Huntington's disease (HD). Homozygotes for the HD mutation do not differ in clinical expression from typical heterozygotes.…”

Linkage Disequilibrium between the Spinocerebellar Ataxia 3/Machado‐Joseph Disease Mutation and Two Intragenic Polymorphisms, One of Which, X359Y, Affects the Stop Codon

“…Until recently, the SCA3/MJD mutation was thought to originate in the Azores Islands. We now know that the disease is not restricted to patients of Portuguese descent and that several different mutations probably are involved, even in Portuguese pedigrees (Stevanin et al 1995a;Takiyama et al 1995;Gaspar et al 1996;lughetti et al 1996). We report here a new intragenic polymorphism at the stop codon (1118A--C) of the MJD1 cDNA, resulting in the addition of 16 amino acid residues to the C-terminal domain of the gene product, that does not affect the phenotype.…”