.png){kind=icon}
.png){kind=icon}
Return
Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation
.png){kind=icon}
OA
AI
DOI：10.1038/s41467-023-37585-8.png)
.png){kind=icon}
.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGF beta and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGF beta, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease. Heterotopic ossification is a disorder characterized by the transformation of soft tissue to bone. In this study the authors report heterotopic ossification in a child caused by enhancer hijacking at the ARHGAP36 gene, the ectopic activation by an enhancer that it not its own.
Keywords:
TGF-BETA
INACTIVATING MUTATIONS
MISSENSE MUTATION
HEDGEHOG
WNT
CATENIN
CELLS
GENE
BMP
DIFFERENTIATION
AI Summary
Key information extracted from the uploaded paper, including a brief overview, abstract, background, key highlights, visual analysis, and future outlook.
Journal
IF:
15.7
Papers:
9.2W
Citations:
91.2W
View more organizations