Elucidation of molecular mechanisms of hereditary neurologic diseases by positional cloning

我们应用定位克隆的策略作为一种策略，以确定遗传性神经退行性疾病的基因。在各种形式的脊髓小脑变性中，我们已经集中精力在Machado-Joseph病（MJD），齿状核红核苍白球路易体萎缩（DRPLA）和早发性共济失调伴低白蛋白血症（EOAHA）。通过对90个微卫星标记的检测，发现MJD与D14 S55和D14 S48紧密连锁，最大lod值为9.719。在三核苷酸重复序列不稳定扩增是神经退行性疾病的常见机制的背景下，我们假设DRPLA是由类似的机制引起的，因为一个突出的预测是，DRPLA是由一个类似的机制引起的。在DRPLA中也观察到三重重复疾病的特征性特征（连续几代发病年龄加快）。通过寻找具有三核苷酸重复序列的基因，我们发现DRPLA是由位于12号染色体上的基因中的三核苷酸重复序列的不稳定扩增引起的。发病年龄与三核苷酸重复序列扩增程度密切相关，提示CAG重复序列扩增与DRPLA的发病密切相关。虽然EOAHA基因位于Friedreich共济失调基因位点附近，但对涉及Friedreich基因位点的多个重组事件的观察表明，从遗传学角度来看，EOAHA是一种独特的疾病。

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.