<scp>BMP</scp> signaling and skeletal development in fibrodysplasia ossificans progressiva (<scp>FOP</scp>)

Towler, O. Will; Shore, Eileen M.

doi:10.1002/dvdy.387

Cited by 19 publications

(13 citation statements)

References 116 publications

(324 reference statements)

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“…BMP signaling is required for various activities during early development, including cell proliferation, apoptosis, and differentiation [ 15 ]. BMPs also serve a critical role in maintaining adult tissue homeostasis, including preservation, vascular remodeling, and the fracture repair [ 53 ]. Any deficit in their production or function mostly results in a visible abnormalities or severe diseases in the tissues [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

[Retracted] Computational Insights into the Structural and Functional Impacts of nsSNPs of Bone Morphogenetic Proteins

Ahmad

Ijaz

Afzal

et al. 2022

BioMed Research International

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BMPs (bone morphogenetic proteins) are multipurpose (transforming growth factor)TGF-superfamily released cytokines. These glycoproteins, acting as disulfide-linked homo- or heterodimers, are highly potent regulators of bone and cartilage production and repair, cell proliferation throughout embryonic development, and bone homeostasis in the adults. Due to the fact that genetic variation might influence structural functions, this study is aimed to determine the pathogenic effect of nonsynonymous single-nucleotide polymorphisms (nsSNPs) in BMP genes. The implications of these variations, investigated using computational analysis and molecular models of the mature TGF-β domain, revealed the impact of modifications on the function of BMP protein. The three-dimensional (3D) structure analysis was performed on the nsSNP Y316S, V386G, E387G, C389G, and C391G nsSNP in the TGF-β domain of chicken BMP2 and H344P, S347P, V357A nsSNP in the TGF-β domain of chicken BMP4 protein that was anticipated to be harmful and of high risk. The ability of the proteins to perform variety of tasks interact with other molecules depends on their tertiary structural composition. The current analysis revealed the four most damaging variants (Y316S, V386G, E387G, C389G, and C391G), highly conserved and functional and are located in the TGF-beta domain of BMP2 and BMP4. The amino acid substitutions E387G, C389G, and C391G are discovered in the binding region. It was observed that the mutations in the TGF-beta domain caused significant changes in its structural organization including the substrate binding sites. Current findings will assist future research focused on the role of these variants in BMP function loss and their role in skeletal disorders, and this will possibly help to develop practical strategies for treating bone-related conditions.

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Section: Discussionmentioning

confidence: 99%

[Retracted] Computational Insights into the Structural and Functional Impacts of nsSNPs of Bone Morphogenetic Proteins

Ahmad

Ijaz

Afzal

et al. 2022

BioMed Research International

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“…The skeletal abnormalities found in patients with p.Arg258Gly ACVR1 were atypical and more severe than those reported in classical FOP patients and other atypical FOP patients in the following points: (1) heterotopic ossification occurred at an earlier age and was more frequent and (2) the feet and hands were both affected, presenting with short fingers and toes and lack of nails [ 7 ]. Through ACVR1, BMP signaling contributes to not only ossification but also large and small joint formation [ 1 , 9 ]. In FOP with pathogenic ACVR1 variants, abnormally increased BMP signaling causes heterotopic ossification, joint dysplasia, growth plate dysplasia, and osteochondroma formation.…”

Section: Discussionmentioning

confidence: 99%

Rapid Progression of Heterotopic Ossification in Severe Variant of Fibrodysplasia Ossificans Progressiva with p.Arg258Gly in ACVR1: A Case Report and Review of Clinical Phenotypes

Hasegawa

Tanaka

Futagawa

et al. 2022

Case Reports in Genetics

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Fibrodysplasia ossificans progressiva (FOP) is a rare skeletal disorder characterized by congenital malformation of the great toes and progressive heterotopic ossification. Malformation of the great toes appears at birth, while heterotopic ossification generally occurs during childhood and rarely occurs during infancy. Classical FOP results from the heterozygous p.Arg206His variant of the ACVR1 gene, which encodes Activin A receptor type 1. Recently, some atypical FOP patients with other ACVR1 gene variants and clinical features that are not observed in classical FOP patients have been reported. Herein, we describe a girl with severe FOP and multiple anomalies, including syndactyly of the hands and feet, nail agenesis, mandibular hypoplasia, heterotopic ossification occurring from infancy, and congenital cardiac malformation. In our patient, we identified de novo occurrence of the heterozygous p.Arg258Gly variant of ACVR1, which has previously been reported in only two severe FOP patients. Heterotopic ossification occurred earlier and more frequently compared with classical FOP patients. We present the time-series changes in heterotopic ossification in our patient and compare her clinical features with those of the previously reported patients with p.Arg258Gly. Our report deepens understanding of the clinical features in severe FOP with p.Arg258Gly and of FOP as a systemic disorder.

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“…Other reports showed that during development components of the FGF, Wnt, Notch, BPM, and Hedgehog signaling orchestrate crucial cellular events including proliferation, migration, differentiation, epithelial-mesenchymal transition (EMT), morphogenesis and somite myogenesis patterning. When gene expression controlling these events is dysregulated, it leads to disease induction ( Hansson et al, 2004 ; Logan and Nusse, 2004 ; Ma et al, 2010 ; Teven et al, 2014 ; Xiao et al, 2017 ; Abreu de Oliveira et al, 2022 ; Alrefaei and Abu-Elmagd, 2022 ; Towler and Shore, 2022 ). Although our RT did not receive microRNA-related manuscripts, it is well-established that microRNAs play an important role in physiology and disease ( Sayed and Abdellatif, 2011 ; Bhaskaran and Mohan, 2014 ; Kalayinia et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Editorial: Advances in genomic and genetic tools, and their applications for understanding embryonic development and human diseases

Abu‐Elmagd

Assidi

Alrefaei

et al. 2022

Front. Cell Dev. Biol.

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Significant advances have been recently made in the development of the genetic and genomic platforms. This has greatly contributed to a better understanding of gene expression and regulation machinery. Consequently, this led to considerable progress in unraveling evidence of the genotype-phenotype correlation between normal/abnormal embryonic development and human disease complexity. For example, advanced genomic tools such as next-generation sequencing, and microarray-based CGH have substantially helped in the identification of gene and copy number variants associated with diseases as well as in the discovery of causal gene mutations. In addition, bioinformatic analysis tools of genome annotation and comparison have greatly aided in data analysis for the interpretation of the genetic variants at the individual level. This has unlocked potential possibilities for real advances toward new therapies in personalized medicine for the targeted treatment of human diseases. However, each of these genomic and bioinformatics tools has its limitations and hence further efforts are required to implement novel approaches to overcome these limitations. It could be possible that the use of more than one platform for genotype-phenotype deep analysis is an effective approach to disentangling the cause and treatment of the disease complexities. Our research topic aimed at deciphering these complexities by shedding some light on the recent applications of the basic and advanced genetic/genomic and bioinformatics approaches. These include studying gene-gene, protein-protein, and gene-environment interactions. We, in addition, aimed at a better understanding of the link between normal/abnormal embryonic development and the cause of human disease induction.

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BMP signaling and skeletal development in fibrodysplasia ossificans progressiva (FOP)

Cited by 19 publications

References 116 publications

[Retracted] Computational Insights into the Structural and Functional Impacts of nsSNPs of Bone Morphogenetic Proteins

[Retracted] Computational Insights into the Structural and Functional Impacts of nsSNPs of Bone Morphogenetic Proteins

Rapid Progression of Heterotopic Ossification in Severe Variant of Fibrodysplasia Ossificans Progressiva with p.Arg258Gly in ACVR1: A Case Report and Review of Clinical Phenotypes

Editorial: Advances in genomic and genetic tools, and their applications for understanding embryonic development and human diseases

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