Genomic Context and Mechanisms of the Mutation in Fibrodysplasia Ossificans Progressiva

Overview

Journal Biomedicines

Specialty Biomedical Engineering

Date 2021 Feb 10

PMID 33562470

Citations 4

Authors

Roberto Ravazzolo

Renata Bocciardi

Affiliations

Soon will be listed here.

Abstract

Basic research in Fibrodysplasia Ossificans Progressiva (FOP) was carried out in the various fields involved in the disease pathophysiology and was important for designing therapeutic approaches, some of which were already developed as ongoing or planned clinical trials. Genetic research was fundamental in identifying the FOP causative mutation, and the astonishing progress in technologies for genomic analysis, coupled to related computational methods, now make possible further research in this field. We present here a review of molecular and cellular factors which could explain why a single mutation, the R206H in the gene, is absolutely prevalent in FOP patients. We also address the mechanisms by which FOP expressivity could be modulated by -acting variants in the genomic region in human chromosome 2q. Finally, we also discuss the general issue of genetic modifiers in FOP.

Citing Articles

Role of hedgehog signaling in the pathogenesis and therapy of heterotopic ossification.

Pei Y, Liu F, Zhao Y, Lin H, Huang X Front Cell Dev Biol. 2024; 12:1454058.

PMID: 39364140 PMC: 11447292. DOI: 10.3389/fcell.2024.1454058.

[Recommendations for the healthcare of patients with FOP].

Seefried L, Banholzer D, Fischer R, Grafe I, Huning I, Morhart R Orthopadie (Heidelb). 2023; 52(11):924-930.

PMID: 37603129 PMC: 10622346. DOI: 10.1007/s00132-023-04425-y.

Living with Fibrodysplasia Ossificans Progressiva: Radiological Images of a Patient with Extensive Heterotopic Ossification.

Kotb M, Omar U, Kaliya-Perumal A Diagnostics (Basel). 2023; 13(10).

PMID: 37238196 PMC: 10217482. DOI: 10.3390/diagnostics13101711.

Editorial of Special Issue "Fibrodysplasia Ossificans Progressiva: Studies on Disease Mechanism towards Novel Therapeutic Approaches".

Ravazzolo R Biomedicines. 2022; 10(1).

PMID: 35052819 PMC: 8773764. DOI: 10.3390/biomedicines10010140.

References

Wang H, Lindborg C, Lounev V, Kim J, McCarrick-Walmsley R, Xu M . Cellular Hypoxia Promotes Heterotopic Ossification by Amplifying BMP Signaling. J Bone Miner Res. 2016; 31(9):1652-65. PMC: 5010462. DOI: 10.1002/jbmr.2848. View

Cappato S, Gamberale R, Bocciardi R, Brunelli S . Genetic and Acquired Heterotopic Ossification: A Translational Tale of Mice and Men. Biomedicines. 2020; 8(12). PMC: 7765130. DOI: 10.3390/biomedicines8120611. View

Han H, Jain P, Resnick A . Shared ACVR1 mutations in FOP and DIPG: Opportunities and challenges in extending biological and clinical implications across rare diseases. Bone. 2017; 109:91-100. PMC: 7888549. DOI: 10.1016/j.bone.2017.08.001. View

Peng K, Cheung K, Lee A, Sieberg C, Borsook D, Upadhyay J . Longitudinal Evaluation of Pain, Flare-Up, and Emotional Health in Fibrodysplasia Ossificans Progressiva: Analyses of the International FOP Registry. JBMR Plus. 2019; 3(8):e10181. PMC: 6715827. DOI: 10.1002/jbm4.10181. View

Castel S, Aguet F, Mohammadi P, Ardlie K, Lappalainen T . A vast resource of allelic expression data spanning human tissues. Genome Biol. 2020; 21(1):234. PMC: 7488534. DOI: 10.1186/s13059-020-02122-z. View

Allen R, Tajer B, Shore E, Mullins M . Fibrodysplasia ossificans progressiva mutant ACVR1 signals by multiple modalities in the developing zebrafish. Elife. 2020; 9. PMC: 7478894. DOI: 10.7554/eLife.53761. View

Claussnitzer M, Dankel S, Kim K, Quon G, Meuleman W, Haugen C . FTO Obesity Variant Circuitry and Adipocyte Browning in Humans. N Engl J Med. 2015; 373(10):895-907. PMC: 4959911. DOI: 10.1056/NEJMoa1502214. View

Pacifici M, Shore E . Common mutations in ALK2/ACVR1, a multi-faceted receptor, have roles in distinct pediatric musculoskeletal and neural orphan disorders. Cytokine Growth Factor Rev. 2016; 27:93-104. PMC: 4753137. DOI: 10.1016/j.cytogfr.2015.12.007. View

Goldmann J, Seplyarskiy V, Wong W, Vilboux T, Neerincx P, Bodian D . Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence. Nat Genet. 2018; 50(4):487-492. DOI: 10.1038/s41588-018-0071-6. View

10.

Casal M, Engiles J, Zakosek Pipan M, Berkowitz A, Porat-Mosenco Y, Mai W . Identification of the Identical Human Mutation in in 2 Cats With Fibrodysplasia Ossificans Progressiva. Vet Pathol. 2019; 56(4):614-618. PMC: 6561796. DOI: 10.1177/0300985819835585. View

11.

Chuva de Sousa Lopes S, Roelen B, Monteiro R, Emmens R, Lin H, Li E . BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes Dev. 2004; 18(15):1838-49. PMC: 517404. DOI: 10.1101/gad.294004. View

12.

Nakajima T, Ikeya M . Insights into the biology of fibrodysplasia ossificans progressiva using patient-derived induced pluripotent stem cells. Regen Ther. 2019; 11:25-30. PMC: 6517845. DOI: 10.1016/j.reth.2019.04.004. View

13.

Katagiri T, Tsukamoto S, Nakachi Y, Kuratani M . Recent Topics in Fibrodysplasia Ossificans Progressiva. Endocrinol Metab (Seoul). 2018; 33(3):331-338. PMC: 6145951. DOI: 10.3803/EnM.2018.33.3.331. View

14.

Gao Z, Moorjani P, Sasani T, Pedersen B, Quinlan A, Jorde L . Overlooked roles of DNA damage and maternal age in generating human germline mutations. Proc Natl Acad Sci U S A. 2019; 116(19):9491-9500. PMC: 6511033. DOI: 10.1073/pnas.1901259116. View

15.

Shore E, Kaplan F . Inherited human diseases of heterotopic bone formation. Nat Rev Rheumatol. 2010; 6(9):518-27. PMC: 3551620. DOI: 10.1038/nrrheum.2010.122. View

16.

Jonsson H, Sulem P, Kehr B, Kristmundsdottir S, Zink F, Hjartarson E . Parental influence on human germline de novo mutations in 1,548 trios from Iceland. Nature. 2017; 549(7673):519-522. DOI: 10.1038/nature24018. View

17.

Medici D, Shore E, Lounev V, Kaplan F, Kalluri R, Olsen B . Conversion of vascular endothelial cells into multipotent stem-like cells. Nat Med. 2010; 16(12):1400-6. PMC: 3209716. DOI: 10.1038/nm.2252. View

18.

Yu P, Hong C, Sachidanandan C, Babitt J, Deng D, Hoyng S . Dorsomorphin inhibits BMP signals required for embryogenesis and iron metabolism. Nat Chem Biol. 2007; 4(1):33-41. PMC: 2727650. DOI: 10.1038/nchembio.2007.54. View

19.

Matharu N, Ahituv N . Modulating gene regulation to treat genetic disorders. Nat Rev Drug Discov. 2020; 19(11):757-775. DOI: 10.1038/s41573-020-0083-7. View

20.

Matsuoka M, Tsukamoto S, Orihara Y, Kawamura R, Kuratani M, Haga N . Design of primers for direct sequencing of nine coding exons in the human ACVR1 gene. Bone. 2020; 138:115469. DOI: 10.1016/j.bone.2020.115469. View