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 Brusco; Manfred Gossen; Dirk Strunk; Sven Geißler; Stefan Mundlos; Sigmar Stricker; Petra Knaus; Elisa Giorgio; Malte Spielmann

doi:10.1038/s41467-023-37585-8

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

Institute of Human Genetics

Abstract

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 language	English
Article number	2034
Journal	Nature Communications
Volume	14
Issue number	1
Pages (from-to)	2034
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-023-37585-8
Publication status	Published - 11.04.2023

Research Areas and Centers

Research Area: Medical Genetics

DFG Research Classification Scheme

2.22-03 Human Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-023-37585-8

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Melo, U. S., Jatzlau, J., Prada-Medina, C. A., Flex, E., Hartmann, S., Ali, S., Schöpflin, R., Bernardini, L., Ciolfi, A., Moeinzadeh, M. H., Klever, M. K., Altay, A., Vallecillo-García, P., Carpentieri, G., Delledonne, M., Ort, M. J., Schwestka, M., Ferrero, G. B., Tartaglia, M., ... Spielmann, M. (2023). Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation. Nature Communications, 14(1), 2034. Article 2034. https://doi.org/10.1038/s41467-023-37585-8

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title = "Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation",

abstract = "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.",

author = "Melo, {Uir{\'a} Souto} and Jerome Jatzlau and Prada-Medina, {Cesar A.} and Elisabetta Flex and Sunhild Hartmann and Salaheddine Ali and Robert Sch{\"o}pflin and Laura Bernardini and Andrea Ciolfi and Moeinzadeh, {M. Hossein} and Klever, {Marius Konstantin} and Aybuge Altay and Pedro Vallecillo-Garc{\'i}a and Giovanna Carpentieri and Massimo Delledonne and Ort, {Melanie Jasmin} and Marko Schwestka and Ferrero, {Giovanni Battista} and Marco Tartaglia and Alfredo Brusco and Manfred Gossen and Dirk Strunk and Sven Gei{\ss}ler and Stefan Mundlos and Sigmar Stricker and Petra Knaus and Elisa Giorgio and Malte Spielmann",

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Melo, US, Jatzlau, J, Prada-Medina, CA, Flex, E, Hartmann, S, Ali, S, Schöpflin, R, Bernardini, L, Ciolfi, A, Moeinzadeh, MH, Klever, MK, Altay, A, Vallecillo-García, P, Carpentieri, G, Delledonne, M, Ort, MJ, Schwestka, M, Ferrero, GB, Tartaglia, M, Brusco, A, Gossen, M, Strunk, D, Geißler, S, Mundlos, S, Stricker, S, Knaus, P, Giorgio, E & Spielmann, M 2023, 'Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation', Nature Communications, vol. 14, no. 1, 2034, pp. 2034. https://doi.org/10.1038/s41467-023-37585-8

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T1 - Enhancer hijacking at the ARHGAP36 locus is associated with connective tissue to bone transformation

AU - Melo, Uirá Souto

AU - Jatzlau, Jerome

AU - Prada-Medina, Cesar A.

AU - Flex, Elisabetta

AU - Hartmann, Sunhild

AU - Ali, Salaheddine

AU - Schöpflin, Robert

AU - Bernardini, Laura

AU - Ciolfi, Andrea

AU - Moeinzadeh, M. Hossein

AU - Klever, Marius Konstantin

AU - Altay, Aybuge

AU - Vallecillo-García, Pedro

AU - Carpentieri, Giovanna

AU - Delledonne, Massimo

AU - Ort, Melanie Jasmin

AU - Schwestka, Marko

AU - Ferrero, Giovanni Battista

AU - Tartaglia, Marco

AU - Brusco, Alfredo

AU - Gossen, Manfred

AU - Strunk, Dirk

AU - Geißler, Sven

AU - Mundlos, Stefan

AU - Stricker, Sigmar

AU - Knaus, Petra

AU - Giorgio, Elisa

AU - Spielmann, Malte

PY - 2023/4/11

Y1 - 2023/4/11

N2 - 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.

AB - 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.

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

Abstract

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UN SDGs

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