A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene

Abstract Background Fibrodysplasia Ossificans Progressiva (FOP) is a rare autosomal dominant disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues leading to cumulative disability. The genetic cause of FOP are mutations in the ACV...

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Autores principales:	Serena Cappato, Rasa Traberg, Jolita Gintautiene, Federico Zara, Renata Bocciardi
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	Activin A ACVR1 BMP signaling Fibrodysplasia Ossificans Progressiva p.R258W Genetics QH426-470
Acceso en línea:	https://doaj.org/article/58b92b79a3a946e98f486780a9b02f10
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spelling	oai:doaj.org-article:58b92b79a3a946e98f486780a9b02f102021-11-10T16:39:24ZA case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene2324-926910.1002/mgg3.1774https://doaj.org/article/58b92b79a3a946e98f486780a9b02f102021-10-01T00:00:00Zhttps://doi.org/10.1002/mgg3.1774https://doaj.org/toc/2324-9269Abstract Background Fibrodysplasia Ossificans Progressiva (FOP) is a rare autosomal dominant disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues leading to cumulative disability. The genetic cause of FOP are mutations in the ACVR1 gene that encodes a type I receptor of Bone Morphogenetic Proteins. The most recurrent mutation in FOP patients is R206H affecting the Glycine‐Serine rich domain and causing the hyper‐activation of the receptor and the responsivity to the non‐canonical ligand, Activin A. In the present study, we described a 3‐years old child with early and highly suggestive clinical features of FOP who was found negative for the recurrent p.R206H substitution. Methods Molecular screening of the whole ACVR1 coding sequence and functional characterization in transfection‐based assays. Results and Conclusions We identified a novel, de novo variant in the fifth ACVR1 coding exon (NM_001111067.4:c.772A>T; NP_001104537.1:p.(R258W)). This substitution, never reported in association with FOP, affects a conserved arginine residue in the kinase domain of the protein. In silico analysis predicted the pathogenicity of this substitution, demonstrated by in vitro assays showing that the p.R258W ACVR1 mutated receptor acquires the ability to transduce the aberrant Activin A‐mediated signaling, as observed for the gene variants associated with FOP.Serena CappatoRasa TrabergJolita GintautieneFederico ZaraRenata BocciardiWileyarticleActivin AACVR1BMP signalingFibrodysplasia Ossificans Progressivap.R258WGeneticsQH426-470ENMolecular Genetics & Genomic Medicine, Vol 9, Iss 10, Pp n/a-n/a (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Activin A ACVR1 BMP signaling Fibrodysplasia Ossificans Progressiva p.R258W Genetics QH426-470
spellingShingle	Activin A ACVR1 BMP signaling Fibrodysplasia Ossificans Progressiva p.R258W Genetics QH426-470 Serena Cappato Rasa Traberg Jolita Gintautiene Federico Zara Renata Bocciardi A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene
description	Abstract Background Fibrodysplasia Ossificans Progressiva (FOP) is a rare autosomal dominant disease characterized by congenital malformation of the great toes and progressive heterotopic ossification of soft tissues leading to cumulative disability. The genetic cause of FOP are mutations in the ACVR1 gene that encodes a type I receptor of Bone Morphogenetic Proteins. The most recurrent mutation in FOP patients is R206H affecting the Glycine‐Serine rich domain and causing the hyper‐activation of the receptor and the responsivity to the non‐canonical ligand, Activin A. In the present study, we described a 3‐years old child with early and highly suggestive clinical features of FOP who was found negative for the recurrent p.R206H substitution. Methods Molecular screening of the whole ACVR1 coding sequence and functional characterization in transfection‐based assays. Results and Conclusions We identified a novel, de novo variant in the fifth ACVR1 coding exon (NM_001111067.4:c.772A>T; NP_001104537.1:p.(R258W)). This substitution, never reported in association with FOP, affects a conserved arginine residue in the kinase domain of the protein. In silico analysis predicted the pathogenicity of this substitution, demonstrated by in vitro assays showing that the p.R258W ACVR1 mutated receptor acquires the ability to transduce the aberrant Activin A‐mediated signaling, as observed for the gene variants associated with FOP.
format	article
author	Serena Cappato Rasa Traberg Jolita Gintautiene Federico Zara Renata Bocciardi
author_facet	Serena Cappato Rasa Traberg Jolita Gintautiene Federico Zara Renata Bocciardi
author_sort	Serena Cappato
title	A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene
title_short	A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene
title_full	A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene
title_fullStr	A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene
title_full_unstemmed	A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene
title_sort	case of fibrodysplasia ossificans progressiva associated with a novel variant of the acvr1 gene
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/58b92b79a3a946e98f486780a9b02f10
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A case of Fibrodysplasia Ossificans Progressiva associated with a novel variant of the ACVR1 gene

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