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

by Christine W. Gao, WanYing. Lin, Ryan C. Riddle, Sheetal. Chopra, Jiyoung. Kim, Leandros. Boukas, Kasper D. Hansen, Hans T. Björnsson, Jill A. Fahrner

Growth deficiency 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 deficiency in a mouse model of KS1 and further established that a Kmt2d^-/- chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth deficiency 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.