SCNM1, a putative RNA splicing factor that modifies disease severity in mice
SCNM1, a putative RNA splicing factor that modifies disease severity in mice
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DOI：
10.1126/science.1086187
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发表时间：
2003-08-15
期刊：
影响因子：
56.9
通讯作者：
Meisler, MH
中科院分区：
文献类型：
--
作者：
Buchner, DA;Trudeau, M;Meisler, MH
许多遗传性疾病的严重程度受遗传背景的影响。我们描述了一种在C57BL/6J小鼠中的修饰物相互作用，将慢性运动障碍转化为致命的神经疾病。原发突变(med(J))改变了钠通道基因Scn8a(Na(V)1.6)的剪接供体位置。该修饰突变是C57BL/6J株特有的，它在钠通道修饰因子1(SCNM1)中引入了一个无义密码子、一个锌指蛋白和一个可能的剪接因子。一个内部删除的SCNM1蛋白也被预测为与共识外显子剪接增强子的破坏相关的外显子跳过的结果。修饰突变的影响是将正确剪接的钠通道转录本的丰度降低到生存阈值以下。我们的发现是，一个假定的RNA剪接因子的基因变异影响了小鼠的疾病易感性，这增加了类似的机制改变人类遗传性疾病严重程度的可能性。
The severity of many inherited disorders is influenced by genetic background. We describe a modifier interaction in C57BL/6J mice that converts a chronic movement disorder into a lethal neurological disease. The primary mutation (med(J)) changes a splice donor site of the sodium channel gene Scn8a (Na(v) 1.6). The modifier mutation is characteristic of strain C57BL/6J and introduces a nonsense codon into sodium channel modifier 1 (SCNM1), a zinc finger protein and a putative splice factor. An internally deleted SCNM1 protein is also predicted as a result of exon skipping associated with disruption of a consensus exonic splicing enhancer. The effect of the modifier mutation is to reduce the abundance of correctly spliced sodium channel transcripts below the threshold for survival. Our finding that genetic variation in a putative RNA splicing factor influences disease susceptibility in mice raises the possibility that a similar mechanism modifies the severity of human inherited disorders.