Human CRMP4 mutation and disrupted Crmp4 expression in mice are associated with ASD characteristics and sexual dimorphism.
Human CRMP4 mutation and disrupted Crmp4 expression in mice are associated with ASD characteristics and sexual dimorphism.
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DOI：
10.1038/s41598-017-16782-8
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发表时间：
2017-12-01
影响因子：
4.6
通讯作者：
Ohtani-Kaneko R
中科院分区：
文献类型：
--
作者：
Tsutiya A;Nakano Y;Hansen-Kiss E;Kelly B;Nishihara M;Goshima Y;Corsmeier D;White P;Herman GE;Ohtani-Kaneko R
自闭症谱系障碍 (ASD) 在男孩中比女孩更常见。自闭症谱系障碍症状及其性别差异的机制仍不清楚。我们之前发现崩溃蛋白反应介导蛋白 4 (CRMP4) 是一种在下丘脑性二态性核的性别分化过程中表现出性别差异表达的蛋白质。本研究调查了自闭症特征的性别差异发展与 CRMP4 缺陷之间的关系。全外显子组测序在一名男性 ASD 患者中检测到了 CRMP4 的从头变异 (S541Y)。与转染野生型 (WT) Crmp4 的小鼠相比，在 Crmp4 敲除 (KO) 小鼠培养的海马神经元中，与人类 CRMP4 S541Y 同源的突变小鼠 CRMP4 S540Y 的表达增加了树突分支，表明这种突变导致神经元中 CRMP4 功能的改变。 Crmp4-KO 小鼠表现出社交互动减少和感觉反应的一些改变。大多数这些变化在雄性 Crmp4-KO 小鼠中比在雌性小鼠中更为严重。 Crmp4-KO 小鼠大脑中一些与神经传递和细胞粘附相关的基因 mRNA 表达水平发生改变，主要以性别依赖性方式发生改变。这些结果表明，Crmp4 基因的一种特定病例的罕见变异与 ASD 的几个特征（包括性别差异）之间存在功能联系。
Autism spectrum disorders (ASD) are more common among boys than girls. The mechanisms responsible for ASD symptoms and their sex differences remain mostly unclear. We previously identified collapsin response mediator protein 4 (CRMP4) as a protein exhibiting sex-different expression during sexual differentiation of the hypothalamic sexually dimorphic nucleus. This study investigated the relationship between the sex-different development of autistic features and CRMP4 deficiency. Whole-exome sequencing detected a de novo variant (S541Y) of CRMP4 in a male ASD patient. The expression of mutated mouse CRMP4 S540Y, which is homologous to human CRMP4 S541Y, in cultured hippocampal neurons derived from Crmp4-knockout (KO) mice had increased dendritic branching, compared to those transfected with wild-type (WT) Crmp4, indicating that this mutation results in altered CRMP4 function in neurons. Crmp4-KO mice showed decreased social interaction and several alterations of sensory responses. Most of these changes were more severe in male Crmp4-KO mice than in females. The mRNA expression levels of some genes related to neurotransmission and cell adhesion were altered in the brain of Crmp4-KO mice, mostly in a gender-dependent manner. These results indicate a functional link between a case-specific, rare variant of one gene, Crmp4, and several characteristics of ASD, including sexual differences.
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影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
影响因子：
3.7
作者：
Gatto CL;Broadie K
通讯作者：
Broadie K
影响因子：
5.3
作者：
Alabed, Yazan Z.;Pool, Madeline;Fournier, Alyson E.
通讯作者：
Fournier, Alyson E.
影响因子：
5.3
作者：
Alabed, Yazan Z.;Pool, Madeline;Fournier, Alyson E.
通讯作者：
Fournier, Alyson E.
影响因子：
21.3
作者：
Fukata, Y;Itoh, TJ;Kaibuchi, K
通讯作者：
Kaibuchi, K