Background The high heritability and heterogeneity of autism spectrum disorder (ASD) are fundamentally determined by its varying genetic alterations including over 100 confident ASD-risk genes/genomic regions. Lysine Methyltransferase 2E (KMT2E, also named MLL5), a distinct chromatin/transcription regulator, is recently identified as a confident ASD-risk gene with germline de novo mutations in ASD probands. Clarifying the function and mechanism of KMT2E haploinsufficiency in ASD-like behaviours is important for the comprehensive understanding of ASD pathogenesis. Methods A CRISPR/Cas9-based mouse model of KMT2E (i.e., MLL5) deficiency (reading frame shift followed by a stop codon induction in exon 3) was used to characterize and define behavioural, metabolic and neuroanatomical phenotypes of ASD-linked loss-of-function mutation in KMT2E. Social/motor/repetitive behaviours and anxiety/anhedonia-like behaviours were determined in adult KMT2E+/− mice. Small-animal PET/CT was used to measure and analyse regional glycometabolic alterations in whole brain. Cerebral Cortical sizes and neuronal size/number in cortex/amygdala were measured. Spatial-temporal expression of KMT2E in developing human brain was analysed by using RNA-seq data from BrainSpan Atlas of Developing Human Brain. Results Adult KMT2E+/− haploinsufficiency mice exhibited robust social deficits in two/three-chamber behavioural paradigms, increased repetitive grooming/jumping behaviour, anxiety in open-field test and anhedonia in sucrose-preference test. 18F-FDG-PET/CT identified a selective reduction of glucose metabolism in amygdala and striatum in KMT2E+/− mice. Morphologically, cerebral cortical size was decreased while neuronal soma size/numbers in amygdala subregions were prominently increased in KMT2E+/− mice. Female and male mice were affected similarly by KMT2E haploinsufficiency. Bioinformatics showed that KMT2E mRNA levels were significantly decreased after birth in human brain overall and various subregions including amygdala and striatum. Limitations: The behaviour, metabolic and morphological analyses were performed in adult mice but not in other developmental stages due to the low fertility of KMT2E+/− mice. The effect of KMT2E knockdown or knockout on neuronal development is not verified at cellular level in vitro. Conclusions KMT2E haploinsufficiency is sufficient for causing sustained ASD-like social behaviours that is highly associated to amygdala malfunction. KMT2E+/− mice may serve as a valuable diagnostic/therapeutic ASD-model for related ASD subgroups.
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