Three ENU-induced neurological mutations in the pore loop of sodium channel Scn8a (Nav1.6) and a genetically linked retinal mutation, rd13
Three ENU-induced neurological mutations in the pore loop of sodium channel Scn8a (Nav1.6) and a genetically linked retinal mutation, rd13
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DOI：
10.1007/s00335-004-2332-1
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发表时间：
2004-05-01
期刊：
影响因子：
2.5
通讯作者：
Meisler, MH
中科院分区：
文献类型：
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作者：
Buchner, DA;Seburn, KL;Meisler, MH
杰克逊实验室神经科学突变设施的目标是产生人类神经疾病的小鼠模型。我们描述了从三代隐性突变筛查中获得的三种新模型。品系nmf2和nmf5的纯合子突变小鼠表现出后肢瘫痪和幼年致死性。纯合子nmf58小鼠表现出不那么严重的运动障碍，包括持续的肌张力障碍姿势。这些突变被定位在小鼠染色体(Chr)15的远端区域。未能补充位置候选基因Scn8a的突变等位基因，表明这些突变是Scn8a的新等位基因。在这三个品系中发现了钠通道进化保守残基的错义突变，预测的氨基酸替换为N1370T、I1392F和L1404H。这些残基位于钠通道Na(V)1.6结构域3的孔环内。致命的表型表明，新的等位基因编码的蛋白质部分或完全丧失功能。人类的几种疾病是由类似的钠通道基因第三结构域的孔环突变引起的。Nmf5含有rd13基因的第二个独立突变，它会导致视网膜外核层的细胞数量减少。Rd13被定位在Chr 15的4Mb的末端，在Rd13的候选基因Pde1b上没有检测到编码或剪接位点突变。在1100个被测试的G3家系中产生了三个独立的Scn8a突变，表明Scn8a基因座对ENU突变高度敏感。Scn8a的新等位基因对钠通道生理和疾病的研究具有重要意义。
The goal of The Jackson Laboratory Neuroscience Mutagenesis Facility is to generate mouse models of human neurological disease. We describe three new models obtained from a three-generation screen for recessive mutations. Homozygous mutant mice from lines nmf2 and nmf5 exhibit hind limb paralysis and juvenile lethality. Homozygous nmf58 mice exhibit a less severe movement disorder that includes sustained dystonic postures. The mutations were mapped to the distal region of mouse Chromosome (Chr) 15. Failure to complement a mutant allele of a positional candidate gene, Scn8a, demonstrated that the mutations are new alleles of Scn8a. Missense mutations of evolutionarily conserved residues of the sodium channel were identified in the three lines, with the predicted amino acid substitutions N1370T, I1392F, and L1404H. These residues are located within the pore loop of domain 3 of sodium channel Na(v)1.6. The lethal phenotypes suggest that the new alleles encode proteins with partial or complete loss of function. Several human disorders are caused by mutation in the pore loop of domain 3 of paralogous sodium channel genes. Line nmf5 contains a second, independent mutation in the rd13 locus that causes a reduction in cell number in the outer nuclear layer of the retina. rd13 was mapped to the distal 4 Mb of Chr 15. No coding or splice site mutations were detected in Pde1b, a candidate gene for rd13. The generation of three independent Scn8a mutations among 1100 tested G3 families demonstrates that the Scn8a locus is highly susceptible to ENU mutagenesis. The new alleles of Scn8a will be valuable for analysis of sodium channel physiology and disease.