Buchner David A, Trudeau Michelle, Meisler Miriam H
Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, MI 48109-0618, USA.
Science. 2003 Aug 15;301(5635):967-9. doi: 10.1126/science.1086187.
The severity of many inherited disorders is influenced by genetic background. We describe a modifier interaction in C57BL/6Jmice that converts a chronic movement disorder into a lethal neurological disease. The primary mutation (medJ) changes a splice donor site of the sodium channel gene Scn8a (Nav1.6). The modifier mutation is characteristic of strain C57BL/6Jand 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.
许多遗传性疾病的严重程度受遗传背景的影响。我们在C57BL/6J小鼠中描述了一种修饰基因相互作用，它将一种慢性运动障碍转化为一种致命的神经疾病。原发性突变（medJ）改变了钠通道基因Scn8a（Nav1.6）的一个剪接供体位点。修饰基因突变是C57BL/6J品系的特征，它在钠通道修饰因子1（SCNM1，一种锌指蛋白和假定的剪接因子）中引入了一个无义密码子。由于与共有外显子剪接增强子破坏相关的外显子跳跃，还预测会产生一种内部缺失的SCNM1蛋白。修饰基因突变的作用是将正确剪接的钠通道转录本丰度降低到生存阈值以下。我们发现假定的RNA剪接因子中的遗传变异会影响小鼠的疾病易感性，这增加了一种类似机制会改变人类遗传性疾病严重程度的可能性。
