Precocious chondrocyte differentiation disrupts skeletal growth in Kabuki syndrome mice

JCI Insight. 2019 Oct 17;4(20):e129380. doi: 10.1172/jci.insight.129380.


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+/βGeo) 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-CT, we show that Kmt2d+/βGeo mice have shortened long bones and ventral bowing of skulls. In vivo expansion of growth plates within skulls and long bones suggests disrupted endochondral ossification as a common disease mechanism. Stable chondrocyte cell lines harboring inactivating mutations in Kmt2d exhibit precocious differentiation, further supporting 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 potentially novel and plausible explanation for precocious chondrocyte differentiation. Our findings provide insight into the pathogenesis of growth retardation in KS1 and suggest therapeutic approaches for this and related disorders.

Keywords: Epigenetics; Genetic diseases; Genetics.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Animals
  • Cell Differentiation / genetics*
  • Chondrocytes / pathology
  • Chondrogenesis / genetics*
  • Disease Models, Animal
  • Face / abnormalities*
  • Face / pathology
  • Female
  • Hematologic Diseases / genetics*
  • Hematologic Diseases / pathology
  • Histone-Lysine N-Methyltransferase / deficiency*
  • Histone-Lysine N-Methyltransferase / genetics
  • Histones / metabolism
  • Homeodomain Proteins / metabolism*
  • Humans
  • Male
  • Mice
  • Mutation
  • Myeloid-Lymphoid Leukemia Protein / deficiency*
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Oxygen / metabolism
  • SOX9 Transcription Factor / metabolism
  • Skull / cytology
  • Skull / diagnostic imaging
  • Skull / growth & development*
  • Vestibular Diseases / genetics*
  • Vestibular Diseases / pathology
  • X-Ray Microtomography


  • Histones
  • Homeodomain Proteins
  • SOX9 Transcription Factor
  • Shox2 protein, mouse
  • Sox9 protein, mouse
  • histone H3 trimethyl Lys4
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase
  • Kmt2b protein, mouse
  • Oxygen

Supplementary concepts

  • Kabuki syndrome