Growth retardation in a mouse model of Kabuki syndrome 2 bears mechanistic similarities to Kabuki syndrome 1

ABSTRACT Growth retardation is a characteristic feature of both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), Mendelian disorders of the epigenetic machinery with similar phenotypes but distinct genetic etiologies. We previously described skeletal growth retardation in a mouse model of KS1 and further established that a Kmt2d −/− chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth retardation in a mouse model of KS2, Kdm6a tm1d/+ . We show that Kdm6a tm1d/+ mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure. Kdm6a tm1d/+ growth plates are also shorter, due to decreases in hypertrophic chondrocyte size and hypertrophic zone height. Given these disturbances in the growth plate, we generated Kdm6a −/− chondrogenic cell lines. Similar to our prior in vitro model of KS1, we found that Kdm6a −/− cells undergo premature, enhanced differentiation towards chondrocytes compared to Kdm6a +/+ controls. RNA-seq showed that Kdm6a −/− cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously on Kmt2d −/− , Kdm6a −/− , and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression between Kmt2d −/− and Kdm6a −/− at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.