Editors' ChoiceAutism

The riddle of CHD8 haploinsufficiency in autism spectrum disorder

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Science Translational Medicine  19 Jul 2017:
Vol. 9, Issue 399, eaao0972
DOI: 10.1126/scitranslmed.aao0972

Abstract

Leading autism-associated mutation in mouse partially mimics human disorder.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental conditions defined by social and communication deficits accompanied by repetitive and stereotyped behaviors. The core symptoms of ASDs are rarely isolated and most often coexist with other conditions, such as intellectual disability and epilepsy. ASDs have a strong genetic basis as demonstrated by recurrence risk in families and twin studies. In recent years, genetic studies have identified several chromatin remodeling genes with causal roles in neurodevelopmental disorders. Among them the chromodomain helicase DNA-binding 8 (CHD8) gene is the leading ASD-associated gene. CHD8 encodes the chromatin remodeler CDH8 protein, initially identified as a Wnt/β-catenin pathway interactor.

The majority of the ASD-associated CHD8 de novo mutations lead to loss of function and result in gene haploinsufficiency. Patients with such mutations, in addition to autistic behaviors, display gastrointestinal complaints, intellectual disability, and macrocephaly, linking CHD8 haploinsufficiency to abnormal cortical development.

Gompers and colleagues generated two new mouse lines harboring heterozygous deletions in exon 5 of Chd8 to study the effect of Chd8 mutations in vivo. Chd8 mutant mice display signatures of human CHD8 haploinsufficiency, such as macrocephaly and cognitive deficits, but not ASD-related behavioral impairments.

To understand whether Chd8 haploinsufficiency led to changes in specific brain regions, the authors performed structural magnetic resonance imaging in Chd8 mutant mice. The analysis revealed that Chd8 mutations resulted in increased absolute brain volume, particularly evident in cerebral cortex, hippocampus, and amygdala. In contrast, diffusion tensor imaging showed no alterations in white matter organization and long-range connectivity in the mutant animals. These observations may be helpful to identify groups of patients to be tested for CHD8 mutations in future human studies.

On the other hand, the lack of measurable ASD-associated behavioral phenotypes, such as social abnormalities and repetitive behaviors, confirms the difficulties in modeling ASDs in mice, which may be due to the evolutionary divergence of brain connectivity and function between human and mouse. Alternatively, CHD8 gene function might not be fully conserved between the two species. In this respect, Gompers et al. found that in mice Chd8 mutations lead to abnormal expression of genes related to RNA processing and cell cycle. Future studies comparing the molecular function of CHD8 in human and mouse could help to elucidate these behavioral differences.

Last, a possibility remains that CHD8 mutations in humans result in ASDs when combined with other common genetic and/or environmental factors. It will therefore be important to understand the exact mechanisms of defective cortical development and the relation between these defects and the appearance of ASD behaviors.

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