Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder:: evidence for a linked protective factor
Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder:: evidence for a linked protective factor
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DOI：
10.1093/hmg/7.13.2045
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发表时间：
1998-12-01
影响因子：
3.5
通讯作者：
Powell, JF
中科院分区：
文献类型：
--
作者：
Al-Chalabi, A;Andersen, PM;Powell, JF
肌萎缩性侧索硬化症（ALS）是一种进行性运动神经退行性疾病，可在3-5年内导致瘫痪和呼吸衰竭死亡。大约20%的家族性病例与铜/锌超氧化物歧化酶（SOD1）基因突变有关，该基因催化超氧化物自由基向过氧化氢和氧的歧化酶。实验证据表明，突变的作用是毒性的功能增益，但机制尚不清楚。已知与ALS相关的SOD1突变有60个，除外显子4中的一个突变外，所有突变都是显性的，这是一个隐性的D90A替代。现在已经报道了具有显性遗传的D90A谱系，这种明显的矛盾需要解释。我们利用6个高度多态性的微卫星标记对28个D90A家系进行了全球单倍型研究。我们现在表明，无论地理位置如何，所有20个隐性家族都有相同的创始人（alpha = 0.999），而8个显性家族有几个创始人（alpha = 0.385）。这一发现证实了D90A可以在与所有其他SOD1突变保持一致的主导方式中起作用，但是在一个场合，这种突变的新实例是隐性的。我们提出了一种紧密相关的保护因子，它可以改变隐性家族中突变SOD1的毒性作用。
Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegeneration resulting in paralysis and death from respiratory failure within 3-5 years. About 20% of familial cases are associated with mutations in the gene for copper/zinc superoxide dismutase (SOD1), which catalyses the dismutation of the superoxide radical to hydrogen peroxide and oxygen. Experimental evidence suggests mutations act by a toxic gain of function but the mechanism is unknown. There are >60 known SOD1 mutations associated with ALS and all am dominant except for one in exon 4, a D90A substitution which is recessive. D90A pedigrees with dominant inheritance have now been reported and this apparent contradiction needs to be explained. We performed a worldwide haplotype study on 28 D90A pedigrees using six highly polymorphic microsatellite markers. We now show that all 20 recessive families share the same founder (alpha = 0.999), regardless of geographical location, whereas several founders exist for the eight dominant families (alpha = 0.385). This finding confirms that D90A can act in a dominant fashion in keeping with all other SOD1 mutations, but that on one occasion, a new instance of this mutation has been recessive. We propose a tightly linked protective factor which modifies the toxic effect of mutant SOD1 in recessive families.