美国西奈山伊坎医学院Kristen J. Brennand、Gang Fang等研究人员，合作揭示了患者特异性异常NRXN1α剪接对神经元的影响。相关论文11月29日发表在《自然—遗传学》上。

研究人员建立了人类诱导的多能干细胞（hiPSC）来源的神经元，其很好地代表了在人类大脑中观察到的NRXN1α选择性剪接的多样性，并能够分类为123种高信度框内人类NRXN1α亚型。患者来源的NRXN1+/-hiPSC神经元在一半的野生型NRXN1α亚型中表现出两倍以上的减少，并从突变等位基因表达了数十种新亚型。

患者个体产生的NRXN1+/-hiPSC-神经元中神经元活性的降低可通过以基因型依赖的方式过度表达单个对照亚型而得到缓解，而单个突变体亚型降低对照hiPSC-神经元中的神经元活性水平。以基因型依赖的方式，患者特异性NRXN1+/-突变表型影响可以通过降低野生型NRXN1α亚型水平以及突变NRXN1α亚型的存在而发生。

据悉，NRXN1基因经历了广泛的可变剪接，并且NRXN1中的非复发性杂合缺失与神经精神疾病密切相关。

附：英文原文

Title: Neuronal impact of patient-specific aberrant NRXN1α splicing

Author: Erin Flaherty, Shijia Zhu, Natalie Barretto, Esther Cheng, P. J. Michael Deans, Michael B. Fernando, Nadine Schrode, Nancy Francoeur, Alesia Antoine, Khaled Alganem, Madeline Halpern, Gintaras Deikus, Hardik Shah, Megan Fitzgerald, Ian Ladran, Peter Gochman, Judith Rapoport, Nadejda M. Tsankova, Robert McCullumsmith, Gabriel E. Hoffman, Robert Sebra, Gang Fang, Kristen J. Brennand

Issue&Volume: 2019-11-29

Abstract: NRXN1 undergoes extensive alternative splicing, and non-recurrent heterozygous deletions in NRXN1 are strongly associated with neuropsychiatric disorders. We establish that human induced pluripotent stem cell (hiPSC)-derived neurons well represent the diversity of NRXN1α alternative splicing observed in the human brain, cataloguing 123 high-confidence in-frame human NRXN1α isoforms. Patient-derived NRXN1+/ hiPSC-neurons show a greater than twofold reduction in half of the wild-type NRXN1α isoforms and express dozens of novel isoforms from the mutant allele. Reduced neuronal activity in patient-derived NRXN1+/ hiPSC-neurons is ameliorated by overexpression of individual control isoforms in a genotype-dependent manner, whereas individual mutant isoforms decrease neuronal activity levels in control hiPSC-neurons. In a genotype-dependent manner, the phenotypic impact of patient-specific NRXN1+/ mutations can occur through a reduction in wild-type NRXN1α isoform levels as well as the presence of mutant NRXN1α isoforms.

DOI: 10.1038/s41588-019-0539-z

Source: https://www.nature.com/articles/s41588-019-0539-z