The ACVR1 617G&gt;A mutation is also recurrent in three Japanese patients with fibrodysplasia ossificans progressiva

Nakajima, Masahiro; Haga, Nobuhiko; Takikawa, Kazuharu; Manabe, Noriyo; Nishimura, Gen; Ikegawa, Shiro

doi:10.1007/s10038-007-0128-3

Cited by 43 publications

(26 citation statements)

References 15 publications

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“…Recently, a recurrent mutation in the juxtamembrane glycine-serine domain of the ALK2 (ACVR1, ActRIA) was reported in all sporadic and familial cases of classic FOP [48]. The ACVR1 617G>A mutation is recurrent in all the affected FOP patients including Japanese and Taiwanese [49] (Fig. 1).…”

Section: B Bone Formationmentioning

confidence: 99%

Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

et al. 2008

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Abstract. Activin, myostatin and other members of the TGF-β superfamily signal through a combination of type II and type I receptors, both of which are transmembrane serine/threonine kinases. Activin type II receptors, ActRIIA and ActRIIB, are primary ligand binding receptors for activins, nodal, myostatin and GDF11. ActRIIs also bind a subset of bone morphogenetic proteins (BMPs). Type I receptors that form complexes with ActRIIs are dependent on ligands. In the case of activins and nodal, activin receptor-like kinases 4 and 7 (ALK4 and ALK7) are the authentic type I receptors. Myostatin and GDF11 utilize ALK5, although ALK4 could also be activated by these growth factors. ALK4, 5 and 7 are structurally and functionally similar and activate receptor-regulated Smads for TGF-β, Smad2 and 3. BMPs signal through a combination of three type II receptors, BMPRII, ActRIIA, and ActRIIB and four type I receptors, ALK1, 2, 3, and 6. BMPs activate BMP-specific Smads, Smad1, 5 and 8. Smad proteins undergo multimerization with co-mediator Smad, Smad4, and translocated into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. The signal transduction pathway through activin type II receptors, ActRIIA and ActRIIB, with type I receptors is involved in various human diseases. In this review, we discuss the role of signaling through activin receptors as therapeutic targets of intractable neuromuscular diseases, endocrine disorders and cancers.

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Section: B Bone Formationmentioning

confidence: 99%

Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

et al. 2008

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“…All familial and sporadic cases of classic FOP reported to date are heterozygous for the same mutation, c.617G4A, leading to the amino-acid substitution, R206H. 4,6,7 A series of patients with phenotypic and genotypic variants of FOP was recently described. 4,6 -8 An additional patient with an FOP variant was recently identified with a de novo ACVR1 mutation, G356R, associated with the disease.…”

Section: Introductionmentioning

confidence: 99%

Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements

Bocciardi¹,

Bordo²,

Duca

et al. 2008

Eur J Hum Genet

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Fibrodysplasia ossificans progressiva (FOP, MIM 135100) is a rare genetic disorder characterized by congenital great toe malformations and progressive heterotopic ossification transforming skeletal muscles and connective tissues to bone following a well-defined anatomic pattern of progression. Recently, FOP has been associated with a specific mutation of ACVR1, the gene coding for a bone morphogenetic protein type I receptor. The identification of ACVR1 as the causative gene for FOP now allows the genetic screening of FOP patients to identify the frequency of the identified recurrent ACVR1 mutation and to investigate genetic variability that may be associated with this severely debilitating disease. We report the screening for mutations in the ACVR1 gene carried out in a cohort of 17 Italian patients. Fifteen of these displayed the previously described c.617G4A mutation, leading to the R206H substitution in the GS domain of the ACVR1 receptor. In two patients, we found a novel mutation c.774G4C, leading to the R258S substitution in the kinase domain of the ACVR1 receptor. In the three-dimensional model of protein structure, R258 maps in close proximity to the GS domain, a key regulator of ACVR1 activity, where R206 is located. The GS domain is known to bind the regulatory protein FKBP12 and to undergo multiple phosphorylation events that trigger a signaling cascade inside the cell. The novel amino-acid substitution is predicted to influence either the conformation/stability of the GS region or the binding affinity with FKBP12, resulting in a less stringent inhibitory control on the ACVR1 kinase activity.

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“…Recently, a recurrent heterozygous mutation in the ACVR1/ ALK2 gene was identified at 617G3 A in both familial and sporadic patients with FOP (21,22). This mutation causes an amino acid substitution of Arg to His at codon 206 (R206H) within the GS domain of the ALK2 receptor (21).…”

mentioning

confidence: 99%

Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva

Fukuda

Kohda

Kanomata

et al. 2009

Journal of Biological Chemistry

195

180

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Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal dominant disorder characterized by congenital malformation of the great toes and by progressive heterotopic bone formation in muscle tissue. Recently, a mutation involving a single amino acid substitution in a bone morphogenetic protein (BMP) type I receptor, ALK2, was identified in patients with FOP. We report here that the identical mutation, R206H, was observed in

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The ACVR1 617G>A mutation is also recurrent in three Japanese patients with fibrodysplasia ossificans progressiva

Cited by 43 publications

References 15 publications

Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

Mutational analysis of the ACVR1 gene in Italian patients affected with fibrodysplasia ossificans progressiva: confirmations and advancements

Constitutively Activated ALK2 and Increased SMAD1/5 Cooperatively Induce Bone Morphogenetic Protein Signaling in Fibrodysplasia Ossificans Progressiva

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