AI Article Synopsis

  • Growth deficiency is a common feature in both Kabuki syndrome 1 (KS1) and Kabuki syndrome 2 (KS2), which are genetic disorders affecting epigenetic regulation.
  • A mouse model for KS2, specifically Kdm6atm1d/+, showed reduced bone length and structural abnormalities compared to control mice, along with shorter growth plates due to changes in chondrocyte size.
  • RNA sequencing of chondrogenic cell lines from Kdm6a-/- and Kmt2d-/- mice revealed similar gene expression patterns, suggesting that both syndromes share similarities not only in physical characteristics but also at the molecular level.

Article Abstract

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, Kdm6atm1d/+. We show that Kdm6atm1d/+ 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 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.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11192384PMC
http://dx.doi.org/10.1371/journal.pgen.1011310DOI Listing

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