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Human CRMP4 mutation and disrupted Crmp4 expression in mice are associated with ASD characteristics and sexual dimorphism
Description
<jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>CRMP4</jats:italic>) 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 <jats:italic>CRMP4</jats:italic> deficiency. Whole-exome sequencing detected a <jats:italic>de novo</jats:italic> variant (S541Y) of <jats:italic>CRMP4</jats:italic> in a male ASD patient. The expression of mutated mouse <jats:italic>CRMP4</jats:italic><jats:sup>S540Y</jats:sup>, which is homologous to human <jats:italic>CRMP4</jats:italic><jats:sup>S541Y</jats:sup>, in cultured hippocampal neurons derived from <jats:italic>Crmp4-</jats:italic>knockout (KO) mice had increased dendritic branching, compared to those transfected with wild-type (WT) <jats:italic>Crmp4</jats:italic>, indicating that this mutation results in altered <jats:italic>CRMP4</jats:italic> function in neurons. <jats:italic>Crmp4</jats:italic>-KO mice showed decreased social interaction and several alterations of sensory responses. Most of these changes were more severe in male <jats:italic>Crmp4</jats:italic>-KO mice than in females. The mRNA expression levels of some genes related to neurotransmission and cell adhesion were altered in the brain of <jats:italic>Crmp4</jats:italic>-KO mice, mostly in a gender-dependent manner. These results indicate a functional link between a case-specific, rare variant of one gene, <jats:italic>Crmp4</jats:italic>, and several characteristics of ASD, including sexual differences.</jats:p>
Journal
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- Scientific Reports
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Scientific Reports 7 (1), 16812-, 2017-12-01
Springer Science and Business Media LLC
