Possible role of mosaic mutations of neurodevelopmental disorder-related genes in bipolar disorder: Lessons from Kmt2c chimeric heterozygous knockout mice

Abstract

We recently found a loss of function mosaic mutation of KMT2C, a causative gene for autism spectrum disorder and Kleefstra syndrome, in a patient with bipolar disorder and reported that somatic mutations in neurodevelopmental disorder-related genes are increased in bipolar disorder by deep exome sequencing analysis. However, causal roles of neurodevelopmental disorder-related mutations in bipolar disorder, a qualitatively different mental disorder, are not known. In this study, we focused on a loss of function mutation of Kmt2c, that causes autism-like phenotypes in mice. To simulate a mosaic mutation found in the patient, we generated mosaic Kmt2c knockout mice using conventional chimera mice technology. We showed that the mosaic Kmt2c knockout mice did not show autism-like behavior but presented anxiety disorder-like symptom, which is avoidance to a corner where the mice previously experienced air puff. The rate of depression-like episodes measured by wheel running recording did not differ from control mosaic mice. These results suggest that mosaic mutations of neurodevelopmental disorder-related genes can cause qualitatively different anxiety disorder-like phenotypes. Because anxiety is one of symptomatic spectrum of bipolar disorder, these findings support the role of mosaic mutations of neurodevelopmental disorder-related genes as a component of the genetic architecture of bipolar disorder.