Autism spectrum disorder model mice: Focus on copy number variation and epigenetics

Abstract

Autism spectrum disorder (ASD) is gathering concerns in socially developed countries. ASD is a neuropsychiatric disorder of genetic origin with high prevalence of 1%-2%. The patients with ASD characteristically show impaired social skills. Today, many genetic studies identify numerous susceptible genes and genetic loci associated with ASD. Although some genetic factors can lead to abnormal brain function linked to ASD phenotypes, the pathogenic mechanism of ASD is still unclear. Here, we discuss a new mouse model for ASD as an advanced tool to understand the mechanism of ASD. copy number variations, DNA methylation, histone modification, ASD model mouse Citation:Nakai N, Otsuka S, Myung J, Takumi T. Autism spectrum disorder model mice: focus on copy number variation and epigenetics. Sci China Life Sci, 2015Sci, , 58: 976 -984, doi: 10.1007 Autism spectrum disorder (ASD) is diagnosed based on behavioral phenotypes usually by the age of three. The ASD patients show three major phenotypes: deficits in social interaction, impaired communication, and repetitive behavior or restricted interest. In the past two decades, the prevalence has greatly increased from 0.01%-0.02% to 1%-2.6% [1]; but even now, the cause is unknown. Through twin studies, ASD has been recognized as a disorder with genetic etiology. Monozygotic twins (MZ) show over 90% concordance of ASD, while dizygotic twins (DZ) show less than 10%. Because genomic information of MZ completely coincides with each other while the coincidence is only 50% in DZ, the high concordance of ASD must have a genetic origin. Recently, a number of genetic variations in ASD patients were found by cytogenetics and genomics studies ( Figure 1) [2][3][4][5][6][7][8][9][10][11][12][13][14]. The genetic variations include single nucleotide variations (SNVs) and copy number variations (CNVs). In the case of SNV, the mutation causes severe functional loss of the genes. CNV, on the other hand, is a large nucleotide change in chromosomal complement and can affect dosage of gene function in various ways (e.g. deletion or duplication). As it stands now, SNV and CNV are responsible for 5%-7% and 10%-20% of all ASD cases, respectively, while other causes of genetic variation remain unknown. A higher rate of CNV mutation is consistent within psychiatric disorders including schizophrenia. Incidentally, it is found that a greater enrichment of CNVs in individuals diagnosed with intellectual disability (ID) have severe craniofacial anomalies and cardiovascular defects compared to those with epilepsy or ASD [15]. CNVs in ASD can have comparatively milder effect than diseases with lethal pathology. In SNV cases, many of the causative genes identified code for cell adhesion molecules or scaffolding proteins (NLGN3, NLGN4, NRXN1, CNTNAP2, and SHANK3) [16]. These genes are important for organization of synaptic connections, which play a fundamental role in neuronal function. Not a few psychiatric syndromes show features of ASD.

Whole exome sequencing reveals inherited and de novo variants in autism spectrum disorder: a trio study from Saudi families

“…Key advances have emerged from such studies, for instance, the identification of cytogenetic abnormalities at multiple loci with chromosomes 15q11–13 and 16p11.2 being the most frequent 5 , as well as recurrent CNVs involving genes like, NRXN1 , SHANK3 and PARK2 6 . However, a causal relationship is often hard to prove for a number of reasons: (i) such events normally span large regions making it difficult to discern the role of single genes in the disorder; (ii) apparently identical alterations have variable phenotypic outcomes or expressivity; (iii) some of these changes are observed in typically developing individuals; (iv) very low rate of replication, as recurrent individual CNVs were observed only in less than 1% of the cases 7 .…”

Distinct Defects in Spine Formation or Pruning in Two Gene Duplication Mouse Models of Autism

“…Up to date, hundreds of genes and genetic alterations have been linked to ASD, including those affecting synaptic function, those regulating gene transcription and post-transcriptional modification, and those involved in other important biological processes [2, 4–6, 8–10, 26–29]. …”

“…All the three mutations share ASD features [27, 30, 36]. The observation that deletion and duplication of the same gene or chromosomal region can result in a similar phenotype underscores the importance of gene dosage to neural circuit development and function [5, 26, 27, 29, 30, 33]. …”

Epigenetic Understanding of Gene-Environment Interaction in Autism Spectrum Disorder

“…29 Furthermore, changes in the copy number of anonymous loci are associated with ASD. 30 These findings suggest that aberrant gene expression caused by a change in the copy number of genes leads to neurological and psychiatric disorders, and further indicate that the brain is an organ in which genes should be properly regulated to maintain a normal function (►Fig. 1, left).…”