Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia
Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia
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DOI：
10.1074/jbc.m702953200
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发表时间：
2007-08-17
影响因子：
4.8
通讯作者：
Law, Amanda J.
中科院分区：
文献类型：
--
作者：
Tan, Wei;Wang, Yanhong;Law, Amanda J.
神经调节蛋白1（NRG 1）对多器官系统的发育和功能至关重要，其失调与癌症和精神分裂症等疾病有关。最近，一种新的亚型（IV型）在大脑中的表达改变与精神分裂症相关的遗传变异有关，特别是rs6994992（SNP 8 NRG 243177）。在这里，我们已经分离和表征全长NRG 1 IV型cDNA从成人和胎儿的人脑，并确定了新的剪接变异体NRG 1。全长IV型跨越1.8 kb，编码590个氨基酸的推定蛋白质，预测分子量类似于66 kDa。该转录物由11个外显子组成，具有Ig样结构域、表皮生长因子样（EGF）结构域、β茎、跨膜结构域和胞质“a尾”，将其置于β 1a NRG 1亚类中。NRG 1 IV型在除脑外的任何组织中均未检测到，并且推定的66 kDa的IV型NRG 1蛋白具有类似的脑特异性。IV型转录本在胎儿脑中更丰富地表达，其中除了全长结构之外，还鉴定了两种新的IV型变体。体外内切酶-报告基因测定证明IV型上游的5'启动子区域是功能性的，具有与rs6994992处的遗传变异相关的差异活性，并且启动子竞争可能影响IV型表达。我们的数据表明，IV型是一种独特的脑特异性NRG 1，其在早期发育过程中差异表达和加工，被翻译，其表达受精神分裂症风险相关的功能启动子或单核苷酸多态性（SNP）调节。
Neuregulin 1 (NRG1) is essential for the development and function of multiple organ systems, and its dysregulation has been linked to diseases such as cancer and schizophrenia. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizophrenia-related genetic variants, especially rs6994992 (SNP8NRG243177). Here we have isolated and characterized full-length NRG1 type IV cDNAs from the adult and fetal human brain and identified novel splice variants of NRG1. Full-length type IV spans 1.8 kb and encodes a putative protein of 590 amino acids with a predicted molecular mass of similar to 66 kDa. The transcript consists of 11 exons with an Ig-like domain, an epidermal growth factor-like (EGF) domain, a beta-stalk, a transmembrane domain, and a cytoplasmic "a-tail," placing it in the beta 1a NRG1 subclass. NRG1 type IV was not detected in any tissues except brain and a putative type IV NRG1 protein of 66 kDa was similarly brain-specific. Type IV transcripts are more abundantly expressed in the fetal brain, where, in addition to the full-length structure, two novel type IV variants were identified. In vitro luciferase-reporter assays demonstrate that the 5' promoter region upstream of type IV is functional, with differential activity associated with genetic variation at rs6994992, and that promoter competition may impact on type IV expression. Our data suggest that type IV is a unique brain- specific NRG1 that is differentially expressed and processed during early development, is translated, and its expression regulated by a schizophrenia risk-associated functional promoter or single nucleotide polymorphism (SNP).