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

Uirá Souto Melo*, Jerome Jatzlau, Cesar A. Prada-Medina, Elisabetta Flex, Sunhild Hartmann, Salaheddine Ali, Robert Schöpflin, Laura Bernardini, Andrea Ciolfi, M. Hossein Moeinzadeh, Marius Konstantin Klever, Aybuge Altay, Pedro Vallecillo-García, Giovanna Carpentieri, Massimo Delledonne, Melanie Jasmin Ort, Marko Schwestka, Giovanni Battista Ferrero, Marco Tartaglia, Alfredo BruscoManfred Gossen, Dirk Strunk, Sven Geißler, Stefan Mundlos, Sigmar Stricker, Petra Knaus, Elisa Giorgio*, Malte Spielmann*

*Corresponding author for this work


Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ 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 TGFβ, 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.

Original languageEnglish
Article number2034
JournalNature Communications
Issue number1
Pages (from-to)2034
Publication statusPublished - 11.04.2023

Research Areas and Centers

  • Research Area: Medical Genetics

DFG Research Classification Scheme

  • 205-03 Human Genetics


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