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Identification and characterization of regulatory elements in the promoter of ACVR1, the gene mutated in Fibrodysplasia Ossificans Progressiva

Francesca Giacopelli1, Serena Cappato1, Laura Tonachini1, Marzia Mura1, Simona Di Lascio2, Diego Fornasari23, Roberto Ravazzolo14 and Renata Bocciardi14*

Author Affiliations

1 Department of Neurosciences, Rehabilitation, Ophthalmogy, Genetics, Maternal and Child Health and CEBR, Università degli Studi di Genova, Genova, Italy

2 Department of Medical Biotechnology and Translational Medicine, Università degli Studi di Milano, Milano, Italy

3 CNR-Institute of Neuroscience, Milano, Italy

4 Istituto Giannina Gaslini, Medical Genetics Unit, Genova, Italy

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Orphanet Journal of Rare Diseases 2013, 8:145  doi:10.1186/1750-1172-8-145

Published: 18 September 2013



The ACVR1 gene encodes a type I receptor for bone morphogenetic proteins (BMPs). Mutations in the ACVR1 gene are associated with Fibrodysplasia Ossificans Progressiva (FOP), a rare and extremely disabling disorder characterized by congenital malformation of the great toes and progressive heterotopic endochondral ossification in muscles and other non-skeletal tissues. Several aspects of FOP pathophysiology are still poorly understood, including mechanisms regulating ACVR1 expression. This work aimed to identify regulatory elements that control ACVR1 gene transcription.

Methods and results

We first characterized the structure and composition of human ACVR1 gene transcripts by identifying the transcription start site, and then characterized a 2.9 kb upstream region. This region showed strong activating activity when tested by reporter gene assays in transfected cells. We identified specific elements within the 2.9 kb region that are important for transcription factor binding using deletion constructs, co-transfection experiments with plasmids expressing selected transcription factors, site-directed mutagenesis of consensus binding-site sequences, and by protein/DNA binding assays. We also characterized a GC-rich minimal promoter region containing binding sites for the Sp1 transcription factor.


Our results showed that several transcription factors such as Egr-1, Egr-2, ZBTB7A/LRF, and Hey1, regulate the ACVR1 promoter by binding to the -762/-308 region, which is essential to confer maximal transcriptional activity. The Sp1 transcription factor acts at the most proximal promoter segment upstream of the transcription start site. We observed significant differences in different cell types suggesting tissue specificity of transcriptional regulation. These findings provide novel insights into the molecular mechanisms that regulate expression of the ACVR1 gene and that could be targets of new strategies for future therapeutic treatments.

ACVR1; Fibrodysplasia ossificans progressiva (FOP); ACVR1 promoter; Transcriptional regulation; BMP signaling