Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome
Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome
复制标题
DOI：
10.1038/sj.ejhg.5201429
复制
发表时间：
2005-08-01
影响因子：
5.2
通讯作者：
Kalscheuer, VM
中科院分区：
文献类型：
--
作者：
Borg, I;Freude, K;Kalscheuer, VM
我们已经鉴定出一名具有 Rett 综合征 (RTT) 特征的女孩，她携带涉及 1 号和 7 号染色体的从头平衡易位。通过与来自感兴趣区域的选定基因组克隆进行荧光原位杂交，绘制了两个断点。 Southern 印迹杂交利用来自跨越 BAC 断点的探针，检测到了患者特有的几个异常片段。克隆连接片段的序列分析表明，在 1 号染色体上，主要在大脑中表达的 Netrin G1 (NTNG1) 基因被破坏，而在 7 号染色体上，没有迹象表明基因被截断。 1 号染色体断点位于 NTNG1 的 30 部分内，影响选择性剪接转录本，表明该患者的表型是 NTNG1 表达紊乱的结果。 NTNG1 剪接变体的计算机翻译预测了具有不同 C 末端的蛋白质亚型：一个膜通过糖基磷脂酰肌醇锚结合，另一个可溶。膜结合蛋白亚型将受到断点的影响，而可溶形式将保持完整。我们的结果表明中枢神经系统对 NTNG1 表达水平敏感，并且 NTNG1 是 RTT 的新候选疾病基因。
We have identified a girl with characteristic features of Rett syndrome ( RTT) who carries a de novo balanced translocation involving chromosomes 1 and 7. Both breakpoints were mapped by fluorescence in situ hybridization with selected genomic clones from the regions of interest. Southern blot hybridisations, utilizing probes derived from breakpoint spanning BACs, detected several aberrant fragments specific for the patient. Sequence analysis of the cloned junction fragment indicated that on chromosome 1 the predominantly brain-expressed Netrin G1 ( NTNG1) gene is disrupted, whereas on chromosome 7 there was no indication for a truncated gene. The chromosome 1 breakpoint lies within the 30 part of NTNG1 and affects alternatively spliced transcripts, suggesting that the phenotype in this patient is the result of disturbed NTNG1 expression. In silico translation of the NTNG1 splice variants predicted protein isoforms with different C-termini: one membrane bound through a glycosylphosphatidylinositol anchor and the other soluble. The membrane-bound protein isoform would be affected by the breakpoint, whereas the soluble form would remain intact. Our results suggest that the central nervous system is sensitive to NTNG1 expression levels and that NTNG1 is a novel candidate disease gene for RTT.