ACVR1 gene mutations in four Turkish patients diagnosed as fibrodysplasia ossificans progressiva

Yazıcıoğlu, Çiğdem Eresen; Karatosun, Vasfi; Kızıldağ, Sefa; Özsoylu, Dua; Kavukçu, Salìh

doi:10.1016/j.gene.2012.12.005

Cited by 17 publications

(15 citation statements)

References 13 publications

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“…The diagnosis of FOP is a clinical one and mutational analysis remains a confirmatory study once the diagnosis is suspected [1, 8]. Our data show that the frequency of FOP variant individuals from China is similar to that reported elsewhere in the world [7, 9, 23,24,26–31], and supports the fidelity of this rare disorder across wide racial, ethnic, gender and geographic distributions.…”

Section: Discussionsupporting

confidence: 78%

The phenotype and genotype of fibrodysplasia ossificans progressiva in China: A report of 72 cases

Zhang

Song

et al. 2013

Bone

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Fibrodysplasia ossificans progressiva, an ultra-rare and disabling genetic disorder of skeletal malformations and progressive heterotopic ossification (HO), is the most catastrophic condition of skeletal metamorphosis in humans. We studied 72 patients with FOP in China and analyzed their phenotypes and genotypes comprising the world’s largest ethnically homogeneous population of FOP patients. Ninety-nine percent of patients (71/72 cases) were of Han nationality; one percent of patients (1/72 cases) were of Hui nationality. Based on clinical examination, ninety-two percent of patients (66/72 cases) had classic FOP; four percent of patients (3/72 cases) were FOP-plus, and four percent of patients (3/72) were FOP variants. Importantly, all individuals with FOP had mutations in the protein-coding region of Activin A Receptor, Type I/Activin-like kinase 2 (ACVR1/ALK2). Ninety-seven percent of FOP patients (70/72 cases) had the canonical c.617G>A (p.R206H) mutation, while three percent of FOP patients (2/72 cases) had variant mutations in ACVR1/ALK2. Taken together, the genotypes and phenotypes of individuals with FOP from the Han nationality in China are similar to those reported elsewhere and supports the fidelity of this ultra-rare disorder in the world’s most highly populated nation and across wide racial, ethnic, gender and geographic distributions.

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Section: Discussionsupporting

confidence: 78%

The phenotype and genotype of fibrodysplasia ossificans progressiva in China: A report of 72 cases

Zhang

Song

et al. 2013

Bone

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“…This allele has also been identified in several countries including South Africa, Korea, Spain, Italy, and Turkey (Bocciardi et al, 2009;Lee et al, 2009;Dandara et al, 2012;Morales-Piga et al, 2012;Eresen Yazıcıoglu et al, 2013). Our identification of the c.617G>A; p.Arg206His allele in 12 individuals, combined with the previous report of three Indian patients (Shukla et al, 2013), suggests that in India most cases of FOP result from this allelic variant.…”

Section: Discussionsupporting

confidence: 71%

“…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).…”

Section: Discussionmentioning

confidence: 90%

“…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).…”

Section: Introductionmentioning

confidence: 97%

“…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) …”

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confidence: 99%

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Classical and Atypical Fibrodysplasia Ossificans Progressiva in India

Madhuri

Santhanam

Sugumar

et al. 2015

Annals of Human Genetics

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SummaryFibrodysplasia Ossificans Progressiva (FOP) is a rare debilitating disorder characterized by congenital deformity of the great toes from infancy and postnatal heterotopic ossification. Activating mutations in the activin A receptor type 1 (ACVR1) gene are responsible for the disease. The most common allelic variant leading to FOP is c.617 G>A; p.R206H, however, other alleles have been reported with atypical phenotypes. We report 14 cases presenting to a referral institution in South India over a 3-year period. The patients were clinically diagnosed based on foot abnormality or abnormal ectopic ossification and were screened for ACVR1. The genetic analysis of ACVR1 identified the recurrent allelic variant in 12 of 14 patients. One of the remaining patients had a previously reported allele c.1067G>A; p.G356D in the 9th exon and the second allele c.983G>A; p.G328E in the 8th exon of ACVR1. The most common recurrent allele c.617 G>A; p.R206H is also the most common in Indian patients with FOP.

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Molecular Genetics of Fibrodysplasia Ossificans Progressiva

Hüning

Gillessen‐Kaesbach

2016

Encyclopedia of Life Sciences

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Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is an autosomal‐dominant genetic disorder, caused by heterozygous mutations in the ACVR1 gene. Its defining clinical feature is heterotopic (extraskeletal) ossifications (HO). Almost all patients show also fibular deviation and shortness of the great toes from birth. However, the phenotypes of FOP patients vary and there seem to be a genotype–phenotype correlation even if the number of patients is still small to definitely establish it. Recent literature data support that all of the identified ACVR1 germ line missense mutations influence the postnatal induction of cartilage and bone cell differentiation. Moreover, it has been recently shown that the most common ACVR1 mutation p.R206H leads to a protein which causes FOP by gaining responsiveness to the normally antagonistic ligand activin A, important discovery for new therapeutic approaches. Key Concepts FOP is caused by heterozygous missense activating mutations of the ACVR1 gene. A clear genotype–phenotype correlation in FOP is highly presumable, even though the number of patients is small. Analysis of the mutations, different from the common R206H mutation supply FOP research with valuable knowledge of the mechanisms of disease and possible therapeutic approaches. Understanding of molecular mechanisms causing FOP is a major key step for developing therapy concepts. Understanding FOP and the pathomechanisms of this extremely rare disease may be very helpful for the understanding of other more common forms of heterotopic ossifications, such as Posttraumatic Heterotopic Ossification and Neurogenic Heterotopic Ossification.

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ACVR1 gene mutations in four Turkish patients diagnosed as fibrodysplasia ossificans progressiva

Cited by 17 publications

References 13 publications

The phenotype and genotype of fibrodysplasia ossificans progressiva in China: A report of 72 cases

The phenotype and genotype of fibrodysplasia ossificans progressiva in China: A report of 72 cases

Classical and Atypical Fibrodysplasia Ossificans Progressiva in India

Molecular Genetics of Fibrodysplasia Ossificans Progressiva

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