Mouse imprinting defect mutations that model Angelman syndrome
Mouse imprinting defect mutations that model Angelman syndrome
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DOI：
10.1002/gene.20179
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发表时间：
2006-01
期刊：
影响因子：
1.5
通讯作者：
Mei-Yi Wu;Ken-Shiung Chen;J. Bressler;A. Hou;T. Tsai;A. Beaudet
中科院分区：
文献类型：
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作者：
Mei-Yi Wu;Ken-Shiung Chen;J. Bressler;A. Hou;T. Tsai;A. Beaudet
Prader-Willi综合征(PWS)和Angelman综合征(AS)分别是由于父亲或母亲染色体15q11-15q13印记基因表达不足引起的神经行为障碍。在人类中，印记基因的表达受两部分顺式作用印记中心(IC)的控制。缺失导致PWS印迹缺陷的家族将PWS-IC定位于4.3kb，与Snrpn外显子1重叠。具有AS印迹缺陷的缺失家族将AS-IC定位于PWS-IC上游的880bp35kb。我们报告了两个导致AS患者AS-IC缺失的缺陷的小鼠突变。Snrpn外显子1上游13kb的插入/复制突变导致母体Snrpn启动子甲基化缺失，母系抑制基因激活，父系抑制基因表达降低。在PWS印记缺陷的小鼠模型中，通过挽救致死性和生长迟缓的能力，证明了突变小鼠在母体染色体上获得了父系表观遗传类型。第二个突变是一个80kb的缺失，延伸到第一个突变的上游，导致了类似的外显性不同的印记缺陷。这些结果表明，小鼠的功能等同于人类的AS-IC。创世纪44：12-22,2006。©2006 Wiley-Liss，Inc.
Prader‐Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders resulting from deficiency of imprinted gene expression from paternal or maternal chromosome 15q11‐15q13, respectively. In humans, expression of the imprinted genes is under control of a bipartite cis‐acting imprinting center (IC). Families with deletions causing PWS imprinting defects localize the PWS‐IC to 4.3 kb overlapping with SNRPN exon 1. Families with deletions causing AS imprinting defects localize the AS‐IC to 880 bp 35 kb upstream of the PWS‐IC. We report two mouse mutations resulting in defects similar to that seen in AS patients with deletion of the AS‐IC. An insertion/duplication mutation 13 kb upstream of Snrpn exon 1 resulted in lack of methylation at the maternal Snrpn promoter, activation of maternally repressed genes, and decreased expression of paternally repressed genes. The acquisition of a paternal epigenotype on the maternal chromosome in the mutant mice was demonstrated by the ability to rescue the lethality and growth retardation in a mouse model of a PWS imprinting defect. A second mutation, an 80‐kb deletion extending upstream of the first mutation, caused a similar imprinting defect with variable penetrance. These results suggest that there is a mouse functional equivalent to the human AS‐IC. genesis 44:12–22, 2006. © 2006 Wiley‐Liss, Inc.