Mutational screening of ACVR1 gene in Brazilian fibrodysplasia ossificans progressiva patients

Abstract

Fibrodysplasia ossificans progressiva (FOP) is a severe genetic disorder reported worldwide. A specific heterozygous mutation (c.617G> A; p.R206H) in the activin A type I receptor gene (ACVR1) is regarded as the genetic cause of FOP in all classically affected individuals worldwide. However, a few patients with FOP variants harbor distinct mutations in ACVR1. We screened a group of FOP Brazilian population for mutations in ACVR1. Of 16 patients with a classic FOP phenotype (10 males and 6 females, age range of 3-42 years), all had the classic mutation (p.R206H). One 21-year-old woman with a variant FOP phenotype had the previously reported c.983G> A mutation (p.G328E). Our study contributes to the understanding of the predominant FOP phenotype and genotype and suggests that variant FOP phenotypes are associated with specific mutations in ACVR1 gene.

Classical and Atypical Fibrodysplasia Ossificans Progressiva in India

“…She developed rapidly progressive heterotopic ossification at 12 years of age. Other novel alleles have also been described from specific regions around the world, for example, c.774G>T; p.Arg258Ser in Turkey, Spain, and Morocco (Ratbi et al, 2010;Morales-Piga et al, 2012;Eresen Yazıcıoglu et al, 2013), c.605G>T; p.Arg202Ile in the United Kingdom (Petrie et al, 2009), and c.983G>A; p.Gly328Glu in Brazil (Connor & Evans, 1982;Kaplan et al, 2009;Carvalho et al, 2010;Stefanova et al, 2012). All of these reported variant alleles were found between exons 6 and 9 of ACVR1 (Table 2).…”

“…In addition to this, some novel allelic variants in the ACVR1 gene have been described among other populations; these include c.774G>T; p.Arg258Ser in Turkey, Spain, and Morocco (Ratbi et al, 2010;Morales-Piga et al, 2012;Eresen Yazıcıoglu et al, 2013), c.605G>T; p.Arg202Ile in the UK (Petrie et al, 2009) and c.974G>C; p.Gly325Ala in the United States (Whyte et al, 2012), c.1067G>A; p.Gly356Asp in Japan, Germany, and China (Furuya et al, 2008;Kaplan et al, 2009;Stefanova et al, 2012;Zhang et al, 2013), and c.983G>A; p.Gly328Glu in Brazil, Great Britain, and Germany (Connor & Evans, 1982;Kaplan et al, 2009;Carvalho et al, 2010;Stefanova et al, 2012). The ACVR1 gene encodes a protein located at the cell membrane which acts as a receptor for BMP ligands (Nakahara et al, 2014).…”

“…Korea, France, Italy, Brazil, Spain, South, Africa, India, Mexico, Egypt, Turkish, China, Germany (Lin et al, 2006), (Nakajima et al, 2007), , (Lucotte et al, 2008), (Bocciardi et al, 2009), (Carvalho et al, 2010), (Morales-Piga et al, 2012), (Dandara et al, 2012), (Shukla et al, 2013), (Herrera-Esparza et al, 2013), (Al-Haggar et al, 2013), (Eresen Yazıcıoglu et al, 2013), (Zhang et al, 2013), (Stefanova et al, 2012) (Connor & Evans, 1982), (Stefanova et al, 2012), (Carvalho et al, 2010) Exons 8 and 9 c.1067 G>A p.Gly356Asp Present Japan, Germany, China (Kaplan et al, 2009), 3 (Furuya et al, 2008), (Stefanova et al, 2012), (Zhang et al, 2013) Exon 9 c.1124 G>C p.Arg375Pro Absent Unspecified (Kaplan et al, 2009) …”

ACVR1 (activin A receptor, type I)

“…Recurrent associations betweem R206H mutation and FOP were subsequently confirmed in unrelated sporadic FOP patients (Lin et al, 2006;Nakajima et al, 2007;Bocciardi et al, 2009;Kaplan et al, 2009;Lee et al, 2009;Sun et al, 2009;Carvalho et al, 2010;Du et al, 2010;Guo et al, 2010;Dandara et al, 2012;Eresen Yazicioglu et al, 2013 ;Morales-Piga et al, 2012).…”

Genetic abnormalities in Fibrodysplasia Ossificans Progressiva

“…Further two unique mutations (c.605G>T and c.983G>A) in ACVR1 in two FOP patients with some atypical digit abnormalities and other clinical features, have also been reported by Petrie et al (2009). A group of 16 Brazilian individual with FOP phenotypes was screened by Carvalho et al (2010), all having the classical mutation c.617G>A; p.R206H. In this study, one woman had mutation in the position of c.983G>A (p.G328E).…”