SMARCA2 and THAP11: potential candidates for polyglutamine disorders as evidenced from polymorphism and protein-folding simulation studies
SMARCA2 and THAP11: potential candidates for polyglutamine disorders as evidenced from polymorphism and protein-folding simulation studies
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DOI：
10.1007/s10038-004-0194-8
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发表时间：
2004-11-01
影响因子：
3.5
通讯作者：
Mukerji, M
中科院分区：
文献类型：
--
作者：
Pandey, N;Mittal, U;Mukerji, M
CAG重复扩增是越来越多的神经退行性疾病，尤其是遗传性共济失调的原因。然而，在不同的人群中，10-50%的临床诊断共济失调的基因仍然是未知的。传统的基于连锁和重复扩增检测的方法与人类基因组序列和表达信息相辅相成，现在可以加快识别假定的候选疾病的步伐。我们使用计算和多态性扫描方法分析了两个CAG重复包含位点，人类SMARCA2和THAP 11，它们在大脑中作为sca的假定候选者表达。这两个基因座都表现出与重复疾病相关的基因特征。在印度人群中，这些基因座在大小和中断模式方面是多态的。此外，对各自蛋白质中谷氨酰胺延伸嵌入结构域的计算分析预测，这些区域在超过40个谷氨酰胺的阈值时将“天然展开”。比较基因组分析表明，CAA穿插在THAP11重复束中具有稳定作用，但在SMARCA2中没有。尽管在印度报道的未识别的共济失调患者中，这些基因中未检测到重复扩增，但我们建议在其他人群中筛查这些基因座，因为这些疾病在不同人群中的患病率存在广泛的异质性。
CAG repeat expansion is the cause of an ever-increasing list of neurodegenerative disorders, especially hereditary ataxias. However, genes responsible for 10-50% of the clinically diagnosed ataxias are still unidentified in different populations. Traditional linkage and repeat expansion-detection based methods complemented with human genome sequence and expression information can now accelerate the pace of identification of putative disease candidates. We have analyzed two CAG repeat containing loci, human SMARCA2 and THAP 11, which are expressed in the brain as putative candidates for SCAs, using computational as well as polymorphism scanning approaches. Both loci exhibited features characteristic of genes associated with repeat disorders. These loci are polymorphic with respect to size and interruption pattern in the Indian population. Furthermore, computational analysis of glutamine-stretch embedded domains in the respective proteins predicted these regions to be "natively unfolded" beyond a threshold of 40 glutamines. Comparative genome analysis suggested a stabilizing influence of CAA interspersions in repeat tract in THAP11 but not in SMARCA2. Although repeat expansion could not be detected within these genes in unidentified ataxia patients reported in India, we suggest that these loci be screened in other populations, as there is a wide heterogeneity in the prevalence of these disorders in different populations.