The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons.
The role of UBE3A in the autism and epilepsy-related Dup15q syndrome using patient-derived, CRISPR-corrected neurons.
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DOI：
10.1016/j.stemcr.2023.02.002
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发表时间：
2023-04-11
影响因子：
5.9
通讯作者：
Levine, Eric S.
中科院分区：
文献类型：
--
作者：
Elamin, Marwa;Dumarchey, Aurelie;Stoddard, Christopher;Robinson, Tiwanna M.;Cowie, Christopher;Gorka, Dea;Chamberlain, Stormy J.;Levine, Eric S.
染色体15 q11-q13重复综合征（Dup 15 q）是由母体重复该区域引起的神经发育障碍。自闭症和癫痫是Dup 15 q的关键特征。编码E3泛素连接酶的UBE 3A可能是Dup 15 q的主要驱动因子，因为UBE 3A是唯一一个仅从母体等位基因表达的印记基因。然而，UBE 3A的确切作用尚未确定。为了确定UBE 3A过表达是否是Dup 15 q神经元缺陷所必需的，我们产生了Dup 15 q患者衍生的诱导多能干细胞系的同基因对照系。与对照神经元相比，Dup 15 q神经元表现出超兴奋性，并且通常可以通过使用反义寡核苷酸使UBE 3A水平正常化来防止这种表型。UBE 3A的过表达导致了类似于Dup 15 q神经元的轮廓，除了突触表型。这些结果表明，UBE 3A过表达是大多数Dup 15 q细胞表型所必需的，但也表明了重复区域中其他基因的作用。UBE 3A在Dup 15 q中的作用通过产生iPSC系的同基因对来研究。使人Dup 15 q神经元中的UBE 3A表达正常化防止了大多数细胞缺陷，UBE 3A过表达未能再现Dup 15 q突触表型UBE 3A过表达是必要的，但不是足够的，Levine及其同事研究了UBE 3A在染色体15 q11-q13重复（Dup 15 q）综合征中的作用。正常化的UBE 3A水平在人类Dup 15 q神经元揭示，过度表达是必要的发展大多数细胞表型。然而，UBE 3A过表达不足以复制Dup 15 q突触表型。这些发现表明，重复区域中的其他基因导致了Dup 15 q综合征。
Chromosome 15q11-q13 duplication syndrome (Dup15q) is a neurodevelopmental disorder caused by maternal duplications of this region. Autism and epilepsy are key features of Dup15q. UBE3A, which encodes an E3 ubiquitin ligase, is likely a major driver of Dup15q because UBE3A is the only imprinted gene expressed solely from the maternal allele. Nevertheless, the exact role of UBE3A has not been determined. To establish whether UBE3A overexpression is required for Dup15q neuronal deficits, we generated an isogenic control line for a Dup15q patient-derived induced pluripotent stem cell line. Dup15q neurons exhibited hyperexcitability compared with control neurons, and this phenotype was generally prevented by normalizing UBE3A levels using antisense oligonucleotides. Overexpression of UBE3A resulted in a profile similar to that of Dup15q neurons except for synaptic phenotypes. These results indicate that UBE3A overexpression is necessary for most Dup15q cellular phenotypes but also suggest a role for other genes in the duplicated region. The role of UBE3A in Dup15q was studied by generating an isogenic pair of iPSC lines Normalizing UBE3A expression in human Dup15q neurons prevented most cellular deficits UBE3A overexpression failed to reproduce Dup15q synaptic phenotypes UBE3A overexpression is necessary, but not sufficient, for Dup15q cellular phenotypes Levine and colleagues examined the role of UBE3A in chromosome 15q11-q13 duplication (Dup15q) syndrome. Normalizing UBE3A levels in human Dup15q neurons revealed that overexpression is necessary for the development of most cellular phenotypes. UBE3A overexpression, however, was not sufficient to reproduce Dup15q synaptic phenotypes. These findings suggest that other genes in the duplicated region contribute to Dup15q syndrome.
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