Kmt2c/Mll3 Haploinsufficiency Causes Autism-like Behavioral Deficits in Mice

<i>KMT2C</i> (histone lysine N-methyltransferase 2C, also known as <i>MML3</i>, myeloid/lymphoid or mixed-lineage leukemia 3) is a causal gene for Kleefstra syndrome 2, a rare neurodevelopmental disorder. Recent human genetic studies have identified it as a high-risk gene for autism spectrum disorder (ASD), with 79% of patients harboring <i>KMT2C</i> variants having ASD. However, the causal link between <i>KMT2C</i> haploinsufficiency and ASD remains unclear. <i>KMT2C</i>/<i>MLL3</i> encodes a histone methyltransferase, a core protein of the KMT2C/D COMPASS (complex proteins associated with Set1) complex, which plays fundamental roles in chromatin modification, occupancy, and gene expression. The expression of <i>KMT2C</i>/<i>Kmt2c</i> peaks during the developmental period in the human/mouse brain, which indicates the critical roles of <i>KMT2C</i>/<i>Kmt2c</i> in neurodevelopment. Here, we investigated the impact of germline <i>Kmt2c</i> haploinsufficiency on autism-like behavioral deficits in mice, which modeled humans carrying diverse <i>KMT2C</i> variants. Compared with Kmt2c^+/+ controls, <i>Kmt2c</i> haploinsufficiency mice had normal motor function without anxiety-like behaviors. Notably, <i>Kmt2c</i> haploinsufficiency mice exhibited autism-like social deficits and increased self-grooming in both males and females, which recapitulated the core phenotypes of ASD patients. Novel object recognition and spatial memory deficits were observed in male and female <i>Kmt2c</i> haploinsufficiency mice. This study reveals a causal link between <i>Kmt2c</i> haploinsufficiency and ASD-like behavioral deficits. These germline <i>Kmt2c</i> haploinsufficiency mice can be used for further studying the molecular mechanisms and developing therapeutic interventions for <i>KMT2C</i> haploinsufficiency-associated behavioral deficits.