Human CRMP4 mutation and disrupted Crmp4 expression in mice are associated with ASD characteristics and sexual dimorphism

Atsuhiro Tsutiya,Yui Nakano,Benjamin Kelly,Yoshio Goshima,Peter White,Emily Hansen-Kiss,Ritsuko Ohtani-Kaneko,Masugi Nishihara,Don Corsmeier,Gail E Herman

doi:10.1038/s41598-017-16782-8

Abstract

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 CRMP4S540Y, which is homologous to human CRMP4S541Y, 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.

Highlights

Since Leo Kanner first reported ‘autistic disturbances of affective contact’ in eight males and three females with symptoms of what would later be called autism[1], it has been well established that a consistent feature of autism spectrum disorder (ASD) in humans is male predominance
As a part of the efforts to identify genes involved in the pathogenesis of Autism spectrum disorders (ASD), the Central Ohio Registry for Autism (CORA)[13] was initiated to enroll isolated cases and multiplex families with one or more children diagnosed with ASD
We examined the mRNA expression of Crmp[4] and several genes for receptors, synthetic enzymes for neurotransmitters and transporters, most of which have been implicated in relation to ASD, such as glutamate, γ-aminobutyric acid (GABA) and dopamine receptor genes[32,33,34]

Summary

Introduction

Since Leo Kanner first reported ‘autistic disturbances of affective contact’ in eight males and three females with symptoms of what would later be called autism[1], it has been well established that a consistent feature of autism spectrum disorder (ASD) in humans is male predominance. The Autism and Developmental Disabilities Monitoring Network conducted a multi-site, population-based study in the United States that revealed an increase in the ratio of males to females among 8-year-old children with ASD over the past 10 years[3]. This ratio increased from 4.25:1 in children born in 1994 to 4.54:1 in children born in 1998 and to 4.65:1 in children born in 2000. We identified another likely pathogenic missense variant in the CRMP4 gene in a male with ASD using exome sequencing. Through the assessment of behaviour as well as gene expression in Crmp4-knockout (KO) mice of both sexes, we examined the role of Crmp[4] dysfunction in ASD pathogenesis

Methods

Results

Conclusion