Chwalisz Wojciech T, Koelsch Bernd U, Kindler-Röhrborn Andrea, Hedrich Hans J, Wedekind Dirk
Institute for Laboratory Animal Science, Hannover Medical School, Carl-Neuberg-Strasse 1, D-30625 Hannover, Germany.
Mamm Genome. 2003 Sep;14(9):620-7. doi: 10.1007/s00335-003-3009-x.
The LEW/Ztm-ci2 rat is an autosomal recessive mutant that displays circling behavior, deafness, progressive retinopathy, locomotor hyperactivity, ataxia, and opisthotonus. We performed a genome-wide scan of a (LEW/Ztm-ci2 x BN/Ztm) F1 x LEW/Ztm-ci2 backcross population with anonymous microsatellite markers to analyze the genetics of this mutant rat. This linkage analysis demonstrated a very strong association of RNO10 SSLP markers to the phenotype with a core region in the central part of the chromosome. The knowledge of genes mapping to this part of the rat genome and their linkage to SSLP markers is still poor. We developed SSLP markers closely linked to genes, which might be responsible for the mutant phenotype by using the growing amount of rat-specific DNA sequences available at World Wide Web databases. Application of this method facilitated the search for candidate genes for the phenotype of the LEW-ci2 rat. We were able to map Myo15 and its neighboring genes, Znf179 and Aldh3a1, to the region of interest and Myo1c to a more distal location on RNO10. Further rat BAC clones were used to create a physical map of the region of interest. This map revealed the position of further genes. Among those is Kcnj12. Owing to their localization on RNO10 and their involvement in a similar pathology in human and mouse, Myo15 and Kcnj12 can be regarded as candidate genes for the deafblind phenotype of the LEW-ci2 rat.
LEW/Ztm-ci2大鼠是一种常染色体隐性突变体，表现出转圈行为、耳聋、进行性视网膜病变、运动亢进、共济失调和角弓反张。我们用匿名微卫星标记对（LEW/Ztm-ci2×BN/Ztm）F1×LEW/Ztm-ci2回交群体进行了全基因组扫描，以分析这种突变大鼠的遗传学。这种连锁分析表明，RNO10的简单序列长度多态性（SSLP）标记与位于染色体中部核心区域的表型有很强的关联。关于定位到大鼠基因组这一部分的基因及其与SSLP标记的连锁关系，目前了解还很少。我们利用万维网数据库中不断增加的大鼠特异性DNA序列，开发了与可能导致突变表型的基因紧密连锁的SSLP标记。应用这种方法有助于寻找LEW-ci2大鼠表型的候选基因。我们能够将肌球蛋白15（Myo15）及其邻近基因锌指蛋白179（Znf179）和醛脱氢酶3A1（Aldh3a1）定位到感兴趣的区域，而肌球蛋白1C（Myo1c）则定位到RNO10上更远的位置。进一步利用大鼠细菌人工染色体（BAC）克隆构建了感兴趣区域的物理图谱。该图谱揭示了其他基因的位置。其中包括内向整流钾通道12（Kcnj12）。由于Myo15和Kcnj12定位于RNO10且与人及小鼠的类似病理有关，它们可被视为LEW-ci2大鼠致聋致盲表型的候选基因。
