D90A-SOD1 Mediated Amyotrophic Lateral Sclerosis: A Single Founder for All Cases With Evidence for a Cis-acting Disease Modifier in the Recessive Haplotype
D90A-SOD1 Mediated Amyotrophic Lateral Sclerosis: A Single Founder for All Cases With Evidence for a Cis-acting Disease Modifier in the Recessive Haplotype
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DOI：
10.1002/humu.9081
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发表时间：
2002-12-01
期刊：
影响因子：
3.9
通讯作者：
Shaw, Christopher E.
中科院分区：
文献类型：
--
作者：
Parton, Matthew J.;Broom, Wendy;Shaw, Christopher E.
在肌萎缩性侧索硬化症（ALS）患者中发现了100多种不同的铜/锌超氧化物歧化酶（SOD1）杂合突变。独特的是，D90A-SOD1在隐性、显性和明显散发的家系中被发现。纯合子的表型是刻板的，具有较长的生存期，而受影响的杂合子的表型则各不相同。在斯堪的纳维亚半岛，D90A-SOD1的频率是其他地区的50倍（2.5%），尽管那里的ALS患病率并没有升高。我们早期的研究表明，隐性和显性/散发性ALS的创始人是不同的，我们提出了一种与隐性突变相关的疾病修饰因子。在这里，我们加倍了我们的样本集，并采用新的标记来表征突变的起源和定位任何修饰因素。连锁不平衡分析表明，D90A纯合子和杂合子共享一个罕见的单倍型，并且都是大约895代以前的一个古代创始人（α 0.974）的后代。纯合子仅在约63代前出现（α 0.878）。重组将隐性类群在SOD1周围共有的区域减少到97-265 kb，不包括所有邻近基因。我们提出，在隐性奠基者D90A-SOD1附近出现了顺式作用的调控多态性，该多态性降低了杂合子的ALS易感性并减缓了疾病进展。(C) 2002 Wiley-Liss, Inc。
More than 100 different heterozygous mutations in copper/zinc superoxide dismutase (SOD1) have been found in patients with amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. Uniquely, D90A-SOD1 has been identified in recessive, dominant and apparently sporadic pedigrees. The phenotype of homozygotes is stereotyped with an extended survival, whereas that of affected heterozygotes varies. The frequency of D90A-SOD1 is 50 times higher in Scandinavia (2.5%) than elsewhere, though ALS prevalence is not raised there. Our earlier study indicated separate founders for recessive and dominant/sporadic ALS and we proposed a disease-modifying factor linked to the recessive mutation. Here we have doubled our sample set and employed novel markers to characterise the mutation's origin and localise any modifying factor. Linkage disequilibrium analysis indicates that D90A homozygotes and heterozygotes share a rare haplotype and are all descended from a single ancient founder (alpha 0.974) c. 895 generations ago. Homozygotes arose subsequently only c. 63 generations ago (alpha 0.878). Recombination has reduced the region shared by recessive kindreds to 97-265 kb around SOD1, excluding all neighbouring genes. We propose that a cis-acting regulatory polymorphism has arisen close to D90A-SOD1 in the recessive founder, which decreases ALS susceptibility in heterozygotes and slows disease progression. (C) 2002 Wiley-Liss, Inc.