Gene editing in monogenic autism spectrum disorder: animal models and gene therapies

Abstract

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disease, and its diagnosis is dependent on behavioral manifestation, such as impaired reciprocal social interactions, stereotyped repetitive behaviors, as well as restricted interests. However, ASD etiology has eluded researchers to date. In the past decades, based on strong genetic evidence including mutations in a single gene, gene editing technology has become an essential tool for exploring the pathogenetic mechanisms of ASD via constructing genetically modified animal models which validates the casual relationship between genetic risk factors and the development of ASD, thus contributing to developing ideal candidates for gene therapies. The present review discusses the progress in gene editing techniques and genetic research, animal models established by gene editing, as well as gene therapies in ASD. Future research should focus on improving the validity of animal models, and reliable DNA diagnostics and accurate prediction of the functional effects of the mutation will likely be equally crucial for the safe application of gene therapies.

Keywords: animal model; autism spectrum disorder; gene editing; pathogenesis; therapy.

Figure 1

Gene-editing technologies and single gene-edited animal models of ASD as well as the synaptic and cellular functions of modified genes. (A) The main genomic editing technologies available at the moment. (a) Zinc Finger Nucleases—ZFNs; (b) Transcription Activator-Like Effector Nucleases—TALENs; (c) CRISPR/Cas9; and (d) Cre-loxP recombinase system. (B) Single gene-edited animal models of ASD. Functions of the shown genes: Foxp1. forkhead box protein 1, encodes a transcription factor important for the early development of many organ systems, including the brain. Abca13: ATP-binding cassette protein A13, is predicted to have the typical structure of full-size ABC proteins, consisting of two transmembrane domains (TMDs). Fmr1: fragile X mental retardation 1, is primarily associated with neuro/psychiatric risks. dyrk1a: dual specificity tyrosine phosphorylation regulated kinase 1A, is a murine homolog of the Drosophila minibrain gene and has been found to be involved in many biological processes during development and adulthood. shank3b: SH3 and multiple ankyrin repeat domains 3, are predicted to enable ionotropic glutamate receptor binding activity and synaptic receptor adaptor activity. Pten: phosphatase and tensin homolog, is an essential gene for proper control of cell movement and migration. Arid1b: ATT-rich interaction domain 1B, encodes a chromatin remodeling factor, and its haploinsufficiency can cause abnormal gene expression in the brain and induce ASD-like behaviors in mice. Arhgef10: Rho guanine nucleotide exchange factor 10, is a known guanine nucleotide exchange factor (GEF) for RhoA with proposed roles in various diseases. Oxtr: oxytocin receptor, shows close association with prosocial behavior, and produced numerous pro-social effects through intranasal applications of oxytocin. Pogz: pogo transposable element derived with ZNF domain, encodes a multidomain nuclear protein involved in transcriptional regulation and its defective function has been recently associated with a syndromic neurodevelopmental disorder. Iqsec2: isoleucine-glutamine motif and Sec7 domain-containing protein 2, is an X-linked gene that is associated with an autism spectrum disorder. Chd8: chromodomain helicase DNA binding protein 8, functions in several processes that include transcriptional regulation, epigenetic remodeling, promotion of cell proliferation, and regulation of RNA synthesis. Pk1: prokineticin 1, encodes a nuclear receptor that may be a negative regulator of the Wnt/beta-catenin signaling pathway. MECP2: methyl-CpG binding protein 2, is an X chromosome-linked protein coding gene encoding the MECP2 protein, which is important for the function of nerve cells and plays a role in maintaining connections (synapses) between neurons. SHANK3: SH3 and multiple ankyrin repeat domains 3, play a role in the functioning of synapses, and act as a scaffold that supports the connections between neurons, ensuring that the signals sent by one neuron are received by another. ANK2: giant ankyrin 2, plays a role in endocytosis and intracellular protein transport, and is required for synapse stability. (C) Synaptic function of modified genes in the ASD model. AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; PSD95, postsynaptic density 95; NRG1, neuregulin; NMDARS, N-methyl D-aspartate (NMDA) receptors; NLGNS, Neuroligins. (D) Cellular function of modified genes in the ASD model. mGLUR, metabotropic glutamate receptors; GABAR, gamma-aminobutyric acid receptor; PI3K, phosphoinositide 3-kinase; TSC1/2, tuberous sclerosis 1/2; mTOR, mammalian target of rapamycin; FMRP: CNTNAP2, contactin associated protein 2; CTNNB1, catenin beta 1.