Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by combined systemic degeneration of the dentatofugal and pallidofugal pathways. We investigated a candidate gene and found that DRPLA patients had an expanded CAG trinucleotide repeat in a gene on the short arm of chromosome 12. The repeat size varied from 7-23 in normal individuals. In patients one allele was expanded to between 49-75 repeats or occasionally even more. Expansion was usually associated with paternal transmission and only occasionally with maternal transmission. Repeat size showed a close correlation with age of onset of symptoms and disease severity. We conclude that DRPLA is the seventh genetic disorder known to be associated with expansion of an unstable trinucleotide repeat.

SUMMARYWe examined whether or not dietary fructooligosaccharides (FOS) in infancy can have a beneficial effect on the mucosal immune system. Newborn BALB/c mice, accompanied by their dams until 21 days of age, were fed either a control diet based on casein [FOS(-) diet group] or a FOS(-) diet supplemented with 5% (w/w) FOS [FOS(+) diet group]. Total IgA levels in tissue extracts from the intestines of mice in the FOS(+) diet group at 38 days of age were about twofold higher ( P < 0·05) than those in the FOS(-) diet group in the jejunum, ileum and colon. Ileal and colonic polymeric immunoglobulin receptor (pIgR) expression in the FOS(+) diet group at 36 days of age was 1·5-fold higher than in the FOS(-) diet group ( P < 0·05). Consistent with these results, the ileal IgA secretion rate of the FOS(+) diet group at 37 days of age was twofold higher than that of the FOS(-) diet group ( P < 0·05). Moreover, the percentage of B220 + IgA + cells in Peyer's patches (PP) was significantly higher in the FOS(+) diet group than in the FOS(-) diet group (6·2% versus 4·3%, P < 0·05), suggesting that isotype switching from IgM to IgA in PP B cells might be enhanced in vivo . Taken together, our findings suggest that dietary FOS increases the intestinal IgA response and pIgR expression in the small intestine as well as the colon in infant mice.

Dentatorubral and pallidoluysian atrophy is associated with expansion of an unstable CAG repeat on chromosome 12p. We have determined the nucleotide sequences of overlapping cDNA clones and deduced the gene structure. The gene is ubiquitously expressed to form a single 4.5 kb transcript and encoded by an open reading frame of 1184 amino acids (aa), in which a polyglutamine track with variable length starts at aa 484. Although the predicted amino acid sequence does not reveal any function, it does contain several interesting motifs consisting of a simple repeated amino acid sequence, a homo-proline track, two stretches of arginine-glutamic acid dipeptides and a stretch of alternative histidine residues. These results provide clues toward understanding neurodegenerative diseases associated with triplet repeat expansion.

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Dentatorubral pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder. It is associated with an abnormal CAG repeat expansion resulting in formation of a protein with an elongated polyglutamine stretch. However, neither the physiological roles of the DRPLA gene product nor molecular mechanisms of its pathogenesis have yet been elucidated. Here we report that the DRPLA protein is cleaved at a site near the N terminus during apoptosis induced by VP-16, staurosporine, or glucocorticoid. Moreover, the in vitro translated DRPLA protein is cleaved by recombinant caspase-3, a member of the cysteine protease family, which is thought to be a main executioner of apoptosis. Using mutant DRPLA proteins, the cleavage site was identified as 106 DSLDG 110 . The cleavage, however, was not modulated by the length of the polyglutamine stretch. These findings suggest that the DRPLA protein is one of the physiological substrates of caspase-3, and its cleavage may result in structural and biochemical alterations associated with apoptosis.

We analyzed deoxyribonucleic acid from 50 Japanese men with azoospermia whose Y chromosomes were cytogenetically normal. A total of 26 loci was examined in each patient. Of these patients 6 had small interstitial deletions, each of which was located within the distal part of Yq11. Five of these 6 patients lacked the same 2 loci, DYS7C and DYS1, while 1 patient had a larger deletion including DYS7C but not DYS1. More than 10% of all men with azoospermia of unknown origin may have minute interstitial deletions of the Y chromosome surrounding the DYS7C locus. The proximal part of this zone presumably encompasses the gene deletion that causes azoospermia.

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Our findings suggest that prebiotics affect the intestinal microbiota and might maintain the antibody titers in elderly individuals.