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 aKmt2d-/-chondrocyte model of KS1 exhibits precocious differentiation. Here we characterized growth retardation in a mouse model of KS2,Kdm6atm1d/+. We show thatKdm6atm1d/+mice have decreased femur and tibia length compared to controls and exhibit abnormalities in cortical and trabecular bone structure.Kdm6atm1d/+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 thatKdm6a-/-cells undergo premature, enhanced differentiation towards chondrocytes compared toKdm6a+/+controls. RNA-seq showed thatKdm6a-/-cells have a distinct transcriptomic profile that indicates dysregulation of cartilage development. Finally, we performed RNA-seq simultaneously onKmt2d-/-,Kdm6a-/-, and control lines at Days 7 and 14 of differentiation. This revealed surprising resemblance in gene expression betweenKmt2d-/-andKdm6a-/-at both time points and indicates that the similarity in phenotype between KS1 and KS2 also exists at the transcriptional level.