PT  - JOURNAL ARTICLE
AU  - Jill A. Fahrner
AU  - Wan-Ying Lin
AU  - Ryan C. Riddle
AU  - Leandros Boukas
AU  - Valerie B. DeLeon
AU  - Sheetal Chopra
AU  - Susan E. Lad
AU  - Teresa Romeo Luperchio
AU  - Kasper D. Hansen
AU  - Hans T. Bjornsson
TI  - Precocious Chondrocyte Differentiation Disrupts Skeletal Growth in Kabuki Syndrome Mice
AID  - 10.1101/599878
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 599878
4099  - http://biorxiv.org/content/early/2019/04/05/599878.short
4100  - http://biorxiv.org/content/early/2019/04/05/599878.full
AB  - Kabuki syndrome 1 (KS1) is a Mendelian disorder of the epigenetic machinery caused by mutations in the gene encoding KMT2D, which methylates lysine 4 on histone H3 (H3K4). KS1 is characterized by intellectual disability, postnatal growth retardation, and distinct craniofacial dysmorphisms. A mouse model (Kmt2d+/ β Geo) exhibits features of the human disorder and has provided insight into other phenotypes; however, the mechanistic basis of skeletal abnormalities and growth retardation remains elusive. Using high-resolution micro-computed tomography we show that Kmt2d+/βGeo mice have shortened long bones and ventral bowing of skulls. In vivo expansion of growth plates within both the skull and long bones suggests disrupted endochondral ossification as a common disease mechanism. Stable chondrocyte cell lines harboring inactivating mutations in Kmt2d exhibit increased proliferation and differentiation, which further supports this mechanism. A known inducer of chondrogenesis, SOX9, and its targets show markedly increased expression in Kmt2d-/- chondrocytes. By transcriptome profiling, we identify Shox2 as a putative KMT2D target. We propose that decreased KMT2D-mediated H3K4me3 at Shox2 releases Sox9 inhibition and thereby leads to enhanced chondrogenesis, providing a novel and plausible explanation for precocious chondrocyte differentiation. Our findings not only provide insight into the pathogenesis of growth retardation in KS1, but also suggest novel therapeutic targets to rescue growth retardation in KS1 and related disorders.