PDF(Pubmed)
Abstract：
The neurodevelopmental disorders Prader-Willi syndrome (PWS) and Schaaf-Yang syndrome (SYS) both arise from genomic alterations within human chromosome 15q11-q13. A deletion of the SNORD116 cluster, encoding small nucleolar RNAs, or frameshift mutations within MAGEL2 result in closely related phenotypes in individuals with PWS or SYS, respectively. By investigation of their subcellular localization, we observed that in contrast to a predominant cytoplasmic localization of wild-type (WT) MAGEL2, a truncated MAGEL2 mutant was evenly distributed between the cytoplasm and the nucleus. To elucidate regulatory pathways that may underlie both diseases, we identified protein interaction partners for WT or mutant MAGEL2, in particular the survival motor neuron protein (SMN), involved in spinal muscular atrophy, and the fragile-X-messenger ribonucleoprotein (FMRP), involved in autism spectrum disorders. The interactome of the non-coding RNA SNORD116 was also investigated by RNA-CoIP. We show that WT and truncated MAGEL2 were both involved in RNA metabolism, while regulation of transcription was mainly observed for WT MAGEL2. Hence, we investigated the influence of MAGEL2 mutations on the expression of genes from the PWS locus, including the SNORD116 cluster. Thereby, we provide evidence for MAGEL2 mutants decreasing the expression of SNORD116, SNORD115, and SNORD109A, as well as protein-coding genes MKRN3 and SNRPN, thus bridging the gap between PWS and SYS.
摘要：
神经发育障碍Prader-Willi综合征（PWS）和Schaaf-Yang综合征（SYS）均源于人类染色体15q11-q13内的基因组改变。删除SNORD116簇，编码小核仁RNA，MAGEL2内的或移码突变导致PWS或SYS个体中密切相关的表型，分别。通过研究它们的亚细胞定位，我们观察到,与野生型(WT)MAGEL2的主要细胞质定位相反,一个截短的MAGEL2突变体在细胞质和细胞核之间均匀分布.为了阐明这两种疾病的调节途径，我们确定了WT或突变MAGEL2的蛋白质相互作用伴侣，特别是存活运动神经元蛋白（SMN），与脊髓性肌萎缩有关，和脆性X信使核糖核蛋白（FMRP），涉及自闭症谱系障碍。还通过RNA-CoIP研究了非编码RNASNORD116的相互作用组。我们表明WT和截短的MAGEL2都参与RNA代谢，而转录调控主要是观察到的WTMAGEL2。因此，我们研究了MAGEL2突变对PWS基因座基因表达的影响，包括SNORD116集群。因此，我们提供了MAGEL2突变体降低SNORD116，SNORD115和SNORD109A表达的证据，以及蛋白质编码基因MKRN3和SNRPN，从而桥接PWS和SYS之间的间隙。
