Exome Sequencing Identifies TENM4 as a Novel Candidate Gene for Schizophrenia in the SCZD2 Locus at 11q14-21
Exome Sequencing Identifies TENM4 as a Novel Candidate Gene for Schizophrenia in the SCZD2 Locus at 11q14-21
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外显子组测序将 TENM4 确定为 11q14-21 SCZD2 基因座中精神分裂症的新候选基因
DOI：
10.3389/fgene.2018.00725
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发表时间：
2019-01-28
影响因子：
3.7
通讯作者：
Chen, Jian-Huan
中科院分区：
文献类型：
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作者：
Xue, Chao-Biao;Xu, Zhou-Heng;Chen, Jian-Huan
精神分裂症是一种具有高度遗传异质性的复杂精神疾病，然而，罕见突变对疾病病因的贡献仍有待进一步阐明。我们在此对一个中国汉族精神分裂症家系进行了外显子组测序，并在SCZD 2基因座的TENM 4基因中发现了一个错义突变（c.6724C>T，p.R2242C），该基因座是先前与精神分裂症连锁的11 q14 -21区域。该突变被证实与家族中的精神分裂症表型共分离。随后对TENM 4外显子31、32和33邻近p.R2242C突变的研究显示，在120例散发性精神分裂症患者中有两个额外的错义突变。在这些突变中突变的残基被预测为对蛋白质功能有害，在脊椎动物中高度保守。在1000个基因组、NHLBI外显子组测序项目数据库或我们内部的1136个非精神分裂症对照外显子组中未检测到这些罕见突变。RNA-Seq数据分析显示，TENM 4在脑中以高丰度和特异性表达。与TENM 4在中枢神经系统发育中的重要作用一致，我们的研究结果表明TENM 4中罕见变异的增加可能与精神分裂症相关，因此TENM 4可能是SCZD 2位点中精神分裂症的新候选基因。
Schizophrenia is a complex psychiatric disorder with high genetic heterogeneity, however, the contribution of rare mutations to the disease etiology remains to be further elucidated. We herein performed exome sequencing in a Han Chinese schizophrenia family and identified a missense mutation (c.6724C>T, p.R2242C) in the teneurin transmembrane protein 4 (TENM4) gene in the SCZD2 locus, a region previously linked to schizophrenia at 11q14-21. The mutation was confirmed to co-segregate with the schizophrenia phenotype in the family. Subsequent investigation of TENM4 exons 31, 32, and 33 adjacent to the p.R2242C mutation revealed two additional missense mutations in 120 sporadic schizophrenic patients. Residues mutated in these mutations, which are predicted to be deleterious to protein function, were highly conserved among vertebrates. These rare mutations were not detected in 1000 Genomes, NHLBI Exome Sequencing Project databases, or our in-house 1136 non-schizophrenic control exomes. Analysis of RNA-Seq data showed that TENM4 is expressed in the brain with high abundance and specificity. In line with the important role of TENM4 in central nervous system development, our findings suggested that increased rare variants in TENM4 could be associated with schizophrenia, and thus TENM4 could be a novel candidate gene for schizophrenia in the SCZD2 locus.