Disruption of the mouse necdin gene results in early post-natal lethality
Disruption of the mouse necdin gene results in early post-natal lethality
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DOI：
10.1038/13828
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发表时间：
1999-10-01
期刊：
影响因子：
30.8
通讯作者：
Stewart, CL
中科院分区：
文献类型：
--
作者：
Gérard, M;Hernandez, L;Stewart, CL
Prader-Willi综合征（PWS）是一种神经行为障碍，其特征为新生儿呼吸抑制、张力减退和婴儿期发育不良，随后出现摄食过多和肥胖等症状（1，2）。PWS是由染色体15 q11-q13上一个或多个父系表达基因的丢失引起的，这可能是由于基因缺失、母系单亲二体或突变破坏了印记机制。定位于该区域的印记基因包括SNRPN（参考文献3，4）、ZNF 127（参考文献5）、IPW（参考文献6）和NDN（其编码DNA结合蛋白necdin;参考文献7-10）。这些基因的小鼠同源物定位于小鼠7号染色体与人染色体15 q11-q13同线的区域（参考文献7，11）。人类基因的印记受印记中心（IC）的控制，印记中心是位于SNRPN 5 '区的长程顺式作用元件（参考文献12）。在小鼠Snrpn基因组区域中分离出一种相关的控制元件，当在父系遗传染色体上缺失时，导致所有四种基因表达的丧失和出生后早期致死（13）。为了确定Ndn对PWS表型的可能贡献，我们产生了Ndn突变小鼠。遗传突变的母体等位基因的杂合子小鼠与它们的野生型同窝出生的小鼠没有区别。携带父系遗传的Ndn缺失等位基因的小鼠表现出出生后早期致死性。这是第一个单一基因负责PWS相关表型的例子。
Prader-Willi syndrome (PWS) is a neurobehavioural disorder characterized by neonatal respiratory depression, hypotonia and failure to thrive in infancy, followed by hyperphagia and obesity among other symptoms(1,2). PWS is caused by the loss of one or more paternally expressed genes on chromosome 15q11-q13, which can be due to gene deletions, maternal uniparental disomy or mutations disrupting the imprinting mechanism. Imprinted genes mapped to this region include SNRPN (refs 3,4), ZNF127 (ref. 5), IPW (ref. 6) and NDN (which encodes the DNA-binding protein necdin; refs 7-10). The mouse homologues of these genes map to mouse chromosome 7 in a region syntenic with human chromosome 15q11-q13 (refs 7,11). Imprinting of the human genes is under the control of an imprinting center (IC), a long-range, cis-acting element located in the 5 ' region of SNRPN (ref. 12). A related control element was isolated in the mouse Snrpn genomic region which, when deleted on the paternally inherited chromosome, resulted in the loss of expression of all four genes and early post-natal lethality(13). To determine the possible contribution of Ndn to the PWS phenotype, we generated Ndn mutant mice. Heterozygous mice inheriting the mutated maternal allele were indistinguishable from their wild-type littermates. Mice carrying a paternally inherited Ndn deletion allele demonstrated early post-natal lethality. This is the first example of a single gene being responsible for phenotypes associated with PWS.