Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Insights and future directions of potential genetic therapy for Apert syndrome: A systematic review

Subjects

Abstract

Apert syndrome is a genetic disorder characterised by craniosynostosis and structural discrepancy of the craniofacial region as well as the hands and feet. This condition is closely linked with fibroblast growth factor receptor-2 (FGFR2) gene mutations. Gene therapies are progressively being tested in advanced clinical trials, leading to a rise of its potential clinical indications. In recent years, research has made great progress in the gene therapy of craniosynostosis syndromes and several studies have investigated its influences in preventing/diminishing the complications of Apert syndrome. This article reviewed and exhibited different techniques of gene therapy and their influences in Apert syndrome progression. A systematic search was executed using electronic bibliographic databases including PubMed, EMBASE, ScienceDirect, SciFinder and Web of Science for all studies of gene therapy for Apert syndrome. The primary outcomes measurements vary from protein to gene expressions. According to the findings of included studies, we conclude that the gene therapy using FGF in Apert syndrome was critical in the regulation of suture fusion and patency, occurred via alterations in cellular proliferation. The superior outcome could be brought by biological therapies targeting the FGF/FGFR signalling. More studies in molecular genetics in Apert syndrome are recommended. This study reviews the current literature and provides insights to future possibilities of genetic therapy as intervention in Apert syndrome.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: FGFR2 mutation and signaling pathways of Apert Syndrome.
Fig. 2
Fig. 3
Fig. 4

References

  1. Opperman LA, Chhabra A, Cho RW, Ogle RC. Cranial suture obliteration is induced by removal of transforming growth factor (TGF)-beta 3 activity and prevented by removal of TGF-beta 2 activity from fetal rat calvaria in vitro. J Craniofac Genet Dev Biol. 1999;19:164–73.

    CAS  PubMed  Google Scholar 

  2. Panigrahi I. Craniosynostosis genetics: the mystery unfolds. Indian J Hum Genet. 2011;17:48.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Liu C, Cui Y, Luan J, Zhou X, Han J. The molecular and cellular basis of Apert syndrome. Intractable Rare Diseases Res. 2013;2:115.

    Google Scholar 

  4. Kreiborg S, Cohen M Jr. The oral manifestations of Apert syndrome. J Craniofacial Genet Dev Biol. 1991;12:41–8.

    Google Scholar 

  5. ŞOANCĂ A, Dudea D, Gocan H, Roman A, Culic B. Oral manifestations in Apert syndrome: case presentation and a brief review of the literature. Romanian J Morphol Embryol. 2010;51:581–4.

    Google Scholar 

  6. Tiwari A, Agrawal A, Pratap A, Lakshmi R, Narad R. Apert syndrome with septum pellucidum agenesis. Singapore Med J. 2007;48:e62–e5.

    CAS  PubMed  Google Scholar 

  7. Kimonis V, Gold J-A, Hoffman TL, Panchal J, Boyadjiev SA, editors. Genetics of craniosynostosis. Seminars in pediatric neurology; 2007: Elsevier.

  8. Wilkie AO. Craniosynostosis: genes and mechanisms. Hum Mol Genet. 1997;6:1647–56.

    CAS  PubMed  Google Scholar 

  9. Teven CM, Farina EM, Rivas J, Reid RR. Fibroblast growth factor (FGF) signaling in development and skeletal diseases. Genes Diseases. 2014;1:199–213.

    PubMed  PubMed Central  Google Scholar 

  10. Anderson J, Burns HD, Enriquez-Harris P, Wilkie AO, Heath JK. Apert syndrome mutations in fibroblast growth factor receptor 2 exhibit increased affinity for FGF ligand. Hum Mol Genet. 1998;7:1475–83.

    CAS  PubMed  Google Scholar 

  11. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Internal Med. 2009;151:264–9.

    Google Scholar 

  12. Hooijmans CR, Rovers MM, De Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43.

    PubMed  PubMed Central  Google Scholar 

  13. OHAT/NTP. OHAT Risk of Bias Rating Tool for Human and Animal Studies. 2015.

  14. Wheldon LM, Khodabukus N, Patey SJ, Smith TG, Heath JK, Hajihosseini MK. Identification and characterization of an inhibitory fibroblast growth factor receptor 2 (FGFR2) molecule, up-regulated in an Apert Syndrome mouse model. Biochem Journal. 2011;436:71–81.

    CAS  Google Scholar 

  15. Yin L, Du X, Li C, Xu X, Chen Z, Su N, et al. A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis. Bone. 2008;42:631–43.

    CAS  PubMed  Google Scholar 

  16. Shukla V, Coumoul X, Wang R-H, Kim H-S, Deng C-X. RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis. Nat Genet. 2007;39:1145–50.

    CAS  PubMed  Google Scholar 

  17. Pfaff MJ, Xue K, Li L, Horowitz MC, Steinbacher DM, Eswarakumar JVP. FGFR2c-mediated ERK–MAPK activity regulates coronal suture development. Dev Biol. 2016;415:242–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Greenwald JA, Mehrara BJ, Spector JA, Warren SM, Fagenholz PJ, Smith LP, et al. In vivo modulation of FGF biological activity alters cranial suture fate. Am J Pathol. 2001;158:441–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Warren SM, Brunet LJ, Harland RM, Economides AN, Longaker MT. The BMP antagonist noggin regulates cranial suture fusion. Nature. 2003;422:625.

    CAS  PubMed  Google Scholar 

  20. Kim B, Shin H, Kim W, Kim H, Cho Y, Yoon H, et al. PIN1 attenuation improves midface hypoplasia in a mouse model of Apert syndrome. J Dental Res. 2020;99:223–32.

    CAS  Google Scholar 

  21. Xu W, Luo F, Wang Q, Tan Q, Huang J, Zhou S, et al. Inducible activation of FGFR2 in adult mice promotes bone formation after bone marrow ablation. J Bone Min Res. 2017;32:2194–206.

    CAS  Google Scholar 

  22. Mansukhani A, Bellosta P, Sahni M, Basilico C. Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts. J Cell Biol. 2000;149:1297–308.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Shen K, Krakora SM, Cunningham M, Singh M, Wang X, Hu FZ, et al. Medical treatment of craniosynostosis: recombinant noggin inhibits coronal suture closure in the rat craniosynostosis model. Orthodontics Craniofacial Res. 2009;12:254–62.

    CAS  Google Scholar 

  24. Yeh E, Atique R, Ishiy FA, Fanganiello RD, Alonso N, Matushita H, et al. FGFR2 mutation confers a less drastic gain of function in mesenchymal stem cells than in fibroblasts. Stem Cell Rev. 2012;8:685–95.

    CAS  Google Scholar 

  25. Yokota M, Kobayashi Y, Morita J, Suzuki H, Hashimoto Y, Sasaki Y, et al. Therapeutic effect of nanogel-based delivery of soluble FGFR2 with S252W mutation on craniosynostosis. PLoS ONE. 2014;9:e101693.

    PubMed  PubMed Central  Google Scholar 

  26. Morita J, Nakamura M, Kobayashi Y, Deng CX, Funato N, Moriyama K. Soluble form of FGFR2 with S252W partially prevents craniosynostosis of the apert mouse model. Dev Dyn. 2014;243:560–7.

    CAS  PubMed  Google Scholar 

  27. Zhang L, Chen P, Chen L, Weng T, Zhang S, Zhou X, et al. Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the apert syndrome FGFR2S252W/+ Mice. PLoS ONE. 2015;10:e112716.

    PubMed  PubMed Central  Google Scholar 

  28. Suzuki H, Suda N, Shiga M, Kobayashi Y, Nakamura M, Iseki S, et al. Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts. J Cell Physiol. 2012;227:3267–77.

    CAS  PubMed  Google Scholar 

  29. Tanimoto Y, Yokozeki M, Hiura K, Matsumoto K, Nakanishi H, Matsumoto T, et al. A soluble form of fibroblast growth factor receptor 2 (FGFR2) with S252W mutation acts as an efficient inhibitor for the enhanced osteoblastic differentiation caused by FGFR2 activation in Apert syndrome. J Biol Chem. 2004;279:45926–34.

    CAS  PubMed  Google Scholar 

  30. Miraoui H, Ringe J, Häupl T, Marie PJ. Increased EFG-and PDGFα-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. Hum Mol Genet. 2010;19:1678–89.

    CAS  PubMed  Google Scholar 

  31. Wilkie AO, Morriss-Kay GM. Genetics of craniofacial development and malformation. Nat Rev Genet. 2001;2:458.

    CAS  PubMed  Google Scholar 

  32. Perlman RL. Mouse models of human disease: an evolutionary perspective. Evol Med Public Health. 2016;2016:170–6.

    PubMed  PubMed Central  Google Scholar 

  33. Schwerd T, Krause F, Twigg SRF, Aschenbrenner D, Chen Y-H, Borgmeyer U, et al. A variant in IL6ST with a selective IL-11 signaling defect in human and mouse. Bone Res. 2020;8:24.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. McDowell LM, Frazier BA, Studelska DR, Giljum K, Chen J, Liu J, et al. Inhibition or activation of Apert syndrome FGFR2 (S252W) signaling by specific glycosaminoglycans. J Biol Chem. 2006;281:6924–30.

    CAS  PubMed  Google Scholar 

  35. Von Gernet S, Golla A, Ehrenfels Y, Schuffenhauer S, Fairley J. Genotype–phenotype analysis in Apert syndrome suggests opposite effects of the two recurrent mutations on syndactyly and outcome of craniofacial surgery. Clin Genet. 2000;57:137–9.

    Google Scholar 

  36. Shin H-R, Bae H-S, Kim B-S, Yoon H, Cho Y-D, Kim W-J, et al. PIN1 is a new therapeutic target of craniosynostosis. Hum Mol Genet. 2018;27:3827–39.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Miraoui H, Ringe J, Haupl T, Marie PJ. Increased EFG- and PDGFalpha-receptor signaling by mutant FGF-receptor 2 contributes to osteoblast dysfunction in Apert craniosynostosis. Hum Mol Genet. 2010;19:1678–89.

    CAS  PubMed  Google Scholar 

  38. Luo F, Xie Y, Wang Z, Huang J, Tan Q, Sun X, et al. Adeno-associated virus-mediated RNAi against mutant alleles attenuates abnormal calvarial phenotypes in an apert syndrome mouse model. Mol Therapy-Nucleic Acids. 2018;13:291–302.

    CAS  Google Scholar 

  39. Zhang L, Chen P, Chen L, Weng TJ, Zhang SC, Zhou X, et al. Inhibited Wnt signaling causes age-dependent abnormalities in the bone matrix mineralization in the apert syndrome FGFR2(S252W/+) Mice. PLoS ONE. 2015;10:e112716.

    PubMed  PubMed Central  Google Scholar 

  40. Nakamura T, Gulick J, Pratt R, Robbins J. Noonan syndrome is associated with enhanced pERK activity, the repression of which can prevent craniofacial malformations. Proc Natl Acad Sci USA. 2009;106:15436–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Collins M, Thrasher A. Gene therapy: progress and predictions. Proc R Soc B: Biol Sci. 2015;282:20143003.

    Google Scholar 

  42. Barik M, Bajpai M, Das RR, Panda SS. Study of environmental and genetic factors in children with craniosynostosis: a case-control study. J Pediatric Neurosci. 2013;8:89.

    Google Scholar 

  43. Mahale S, Dani N, Ansari SS, Kale T. Gene therapy and its implications in periodontics. J Indian Soc Periodontol. 2009;13:1.

    PubMed  PubMed Central  Google Scholar 

  44. Suwanmanee T, Ferris MT, Hu P, Gui T, Montgomery SA, Pardo-Manuel de Villena F, et al. Toward personalized gene therapy: characterizing the host genetic control of lentiviral-vector-mediated hepatic gene delivery. Mol Therapy Methods Clin Dev. 2017;5:83–92.

    CAS  Google Scholar 

  45. Nam HK, Vesela I, Schutte SD, Hatch NE. Viral delivery of tissue nonspecific alkaline phosphatase diminishes craniosynostosis in one of two FGFR2C342Y/+ mouse models of Crouzon syndrome. PLoS ONE. 2020;15:e0234073.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Mammen B, Ramakrishnan T, Sudhakar U. Principles of gene therapy. Indian J Den Res. 2007;18:196.

    Google Scholar 

  47. Maule G, Casini A, Montagna C, Ramalho AS, De Boeck K, Debyser Z, et al. Allele specific repair of splicing mutations in cystic fibrosis through AsCas12a genome editing. Nat Commun. 2019;10:3556.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Iriart JAB. Precision medicine/personalized medicine: a critical analysis of movements in the transformation of biomedicine in the early 21st century. Cadernos de saude publica. 2019;35:e00153118.

    PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by FRGS grant (FP103-2019A) from the Ministry of Higher Education, Malaysia (Ref: FRGS/1/2019/SKK10/UM/02/3).

Author information

Authors and Affiliations

Authors

Corresponding authors

Correspondence to Nisreen Mohammed Al-Namnam or Mohammed Abdullah Alshawsh.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Al-Namnam, N.M., Jayash, S.N., Hariri, F. et al. Insights and future directions of potential genetic therapy for Apert syndrome: A systematic review. Gene Ther 28, 620–633 (2021). https://doi.org/10.1038/s41434-021-00238-w

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41434-021-00238-w

Search

Quick links