Elucidation of molecular mechanisms of hereditary neurologic diseases by positional cloning

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We have applied the strategy of positional cloning as a strategy to identify genes for hereditary neurodegenerative disorder. Among various forms of spinocerebellar degeneration, we have focused out effort on Machado-Joseph disease (MJD), dentatorubral-pallidoluysian atrophy (DRPLA), and early onset ataxia associated with hypoalbuminemia (EOAHA).We have initiated systematic linkage analyzes of MJD using microsatellite polymorphisms. After checking 90 microsatellite markers, we have found that the MJD is tightly linked to D14S55 and D14S48 with a maximum lod score of 9.719. To further narrow down the candidate region, further detailed linkage as well as linkage disequilibrium analysis will be required.With the background that unstable expansion of trinucleotide repeat is a common mechanism for neurodegenerative disorder, we have hypothesized that DRPLA is caused by the similar mechanism, because a prominent anticipation (accelerated ages of onset in successive generations), a characteristic feature for triplet repeat diseases, is observed in DRPLA as well. By searching for genes with trinucleotide repeat, we have discovered that DRPLA is caused by unstable expansion of trinucleotide repeat in the gene located on chromosome 12. Close correlation between ages of onset and the degree of expanded trinucleotide repeat suggests that the expansion of the CAG repeat is intimately involved in the pathogenesis of DRPLA.With detailed linkage analysis we have doscpvered that the gene is lcoated on chromosome 9. Although the gene for EOAHA is located near the locus for Friedreich's ataxia, observation of multiple recombination events involving the Friedreich's locussuggests that EOAHA is a distinct disease from a genetic point of view.