Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation

This study identifies a genetic cause for a rare and severe form of heterotopic ossification (HO), where soft tissues turn into bone. The condition is linked to a structural variant that leads to the misexpression of a gene called ARHGAP36 in fibroblasts. The researchers found that the abnormal activation of ARHGAP36 interferes with important signaling pathways involved in bone formation, such as TGFβ and hedgehog signaling, and also affects the production of the extracellular matrix. This research provides new insights into the role of ARHGAP36 in bone formation and metabolism, contributing to a better understanding of the genetic factors involved in bone disorders and potential future gene therapies.

• 1
  An inter-chromosomal insertional duplication disrupts a topologically associating domain, causing an ultra-rare progressive form of heterotopic ossification.
• 2
  This structural variant leads to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated by in vitro studies.
• 3
  ARHGAP36 overexpression inhibits TGFβ, activates hedgehog signaling, and influences genes/proteins related to extracellular matrix production.