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Cryptophthalmos, dental anomalies, oral vestibule defect, and a novel FREM2 mutation

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Abstract

FREM2 is a member of the FREM2–FRAS1–FREM1 protein complex which contributes to epithelial–mesenchymal coupling. We report a Thai woman with cryptophthalmos, dental anomalies, and oral vestibule defect. A compound heterozygous mutation (c.6499C>T; p.Arg2167Trp and c.641_642del; p.Glu214GlyfsTer135) in the FREM2 gene was identified. The frameshift variant p.Glu214GlyfsTer135 is de novo and novel. It is predicted to result in the loss of most of the functional domains. The p.Arg2167Trp mutation was predicted to disrupt both Ca2+ binding and conformational change. The Arg2167Trp mutant protein has been shown to cause partial loss of function, decrease its interaction with FREM1 and result in impaired function of the FRAS1–FREM2–FREM1 complex. Frem2 was shown to be expressed in the developing tooth and vestibular lamina. It is hypothesized that these mutations resulted in aberration of the FRAS1–FREM2–FREM1 protein complex, resulting in loss of nephronectin, basement membrane disruption, and abnormal epithelial–mesenchymal interactions leading to dental and oral vestibule malformations.

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References

  1. 1.

    Richardson RJ, Gebauer JM, Zhang JL, Kobbe B, Keene DR, Karlsen KR. et al. AMACO is a component of the basement membrane-associated Fraser complex. J Investig Dermatol. 2014;134:1313–22. https://doi.org/10.1038/jid.2013.492.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Kiyozumi D, Takeichi M, Nakano I, Sato Y, Fukuda T, Sekiguchi K. Basement membrane assembly of the integrin α8β1 ligand nephronectin requires Fraser syndrome-associated proteins. J Cell Biol. 2012;197:677–89. https://doi.org/10.1083/jcb.201203065.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Pavlakis E, Chiotaki R, Chalepakis G. The role of Fras1/Frem protein in the structure and function of basement membrane. Int J Biochem Cell Biol. 2011;43:487–95. https://doi.org/10.1016/j.biocel.2010.12.016.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Kiyozumi D, Sugimoto N, Sekiguchi K. Breakdown of the reciprocal stabilization of QBRICK/Frem1, Fras1, and Frem2 at the basement membrane provokes Fraser syndrome-like defects. Proc Natl Acad Sci USA. 2006;103:11981–6. https://doi.org/10.1073/pnas.0601011103.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Petrou P, Makrygiannis AK, Chalepakis G. The Fras1/Frem family of extracellular matrix proteins: structure, function, and association with Fraser syndrome and the mouse bleb phenotype. Connect Tissue Res. 2008;49:277–82. https://doi.org/10.1080/03008200802148025.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Kunz F, Kayserili H, Midro A, de Silva D, Basnayake S, Güven Y. et al. Characteristic dental pattern with hypodontia and short roots in Fraser syndrome. Am J Med Genet Part A. 2020;182:1681–9. https://doi.org/10.1002/ajmg.a.61610.

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Kantaputra P, Eiumtrakul P, Matin T, Opastirakul, Visrutaratna P, Mevate U. Cryptophthalmos, dental and oral abnormalities, and brachymesophalangy of second toes: new syndrome or Fraser syndrome?. Am J Med Genet. 2001;98:263–8. 10.1002/1096-8628(20010122)98:3<263::aid-ajmg1092>3.0.co;2-1.

    CAS  Article  Google Scholar 

  8. 8.

    Qiu T, Teshima T, Hovorakova M, Tucker AS. Development of the vestibular lamina in human embryos: morphogenesis and vestibule formation. Front Physiol. 2020;11:753 https://doi.org/10.3389/fphys.2020.00753.

    Article  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Visel A, Thaller C, Eichele G. GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res. 2004;32:D552–6. https://doi.org/10.1093/nar/gkh029.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Timmer JR, Mak TW, Manova K, Anderson KV, Niswander L. Tissue morphogenesis and vascular stability require the Frem2 protein, product of the mouse myelencephalic blebs gene. Proc Natl Acad Sci USA. 2005;102:11746–50. https://doi.org/10.1073/pnas.0505404102.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Jernvall J, Aberg T, Kettunen P, Keränen S, Thesleff I. The life history of an embryonic signaling center: BMP-4 induces p21 and is associated with apoptosis in the mouse tooth enamel knot. Development 1998;125:161–9.

    CAS  Article  Google Scholar 

  12. 12.

    Arai C, Yoshizaki K, Miyazaki K, Saito K, Yamada A, Han X. et al. Nephronectin plays critical roles in Sox2 expression and proliferation in dental epithelial stem cells via EGF-like repeat domains. Sci Rep.2017;7:45181. https://doi.org/10.1038/srep45181.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Lee MJ, Kim EJ, Otsu K, Harada, Jung HS. Sox2 contributes to tooth development via Wnt signaling. Cell Tissue Res. 2016;365:77–84. https://doi.org/10.1007/s00441-016-2363-4.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Al-Hamed MH, Sayer JA, Alsahan N, Tulbah M, Kurdi W, Ambusaidi Q. et al. Novel loss of function variants in FRAS1 and FREM2 underlie renal agenesis in consanguineous families. J Nephrol. 2021;34:893–900. https://doi.org/10.1007/s40620-020-00795-0.

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Yu Q, Lin B, Xie S, Gao S, Li W, Liu Y. et al. A homozygous mutation p.Arg2167Trp in FREM2 causes isolated cryptophthalmos. Hum Mol Genet. 2018;27:2357–66. https://doi.org/10.1093/hmg/ddy144.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Zhang X, Wang D, Dongye M, Zhu Y, Chen C, Wang R. et al. Loss-of-function mutations in FREM2 disrupt eye morphogenesis. Exp Eye Res. 2019;181:302–12. https://doi.org/10.1016/j.exer.2019.02.013.

    CAS  Article  PubMed  Google Scholar 

  17. 17.

    Zhang X, Wang R, Wang T, Zhang X, Dongye M, Wang D. et al. The metabolic reprogramming of Frem2 mutant mice embryos in cryptophthalmos development. Front Cell Dev Biol. 2021;8:625492. https://doi.org/10.3389/fcell.2020.625492.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Kantaputra PN, Hutsadaloi A, Kaewgahya M, Intachai W, German R, Koparal M. et al. WNT10B mutations associated with isolated dental anomalies. Clin Genet. 2018;93:992–9. https://doi.org/10.1111/cge.13218.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    van Haelst MM, Scambler PJ. Fraser Syndrome Collaboration Group, Hennekam RC. Fraser syndrome: a clinical study of 59 cases and evaluation of diagnostic criteria. Am J Med Genet Part A. 2007;143A:3194–203. https://doi.org/10.1002/ajmg.a.31951.

    Article  PubMed  Google Scholar 

  20. 20.

    van Haelst MM, Maiburg M, Baujat G, Jadeja S, Monti E, Bland E. et al. Molecular study of 33 families with Fraser syndrome new data and mutation review. Am J Med Genet Part A. 2008;146A:2252–7. https://doi.org/10.1002/ajmg.a.32440.

    CAS  Article  PubMed  Google Scholar 

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Acknowledgements

We thank our patient and her families for their kind cooperation and for allowing us to use their medical and dental information for the benefit of others. This work was supported by the Thailand Research Fund (BRG6180007) and Genomics Thailand Research Grant of Health System Research Institute (HSRI) of Thailand.

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Correspondence to Piranit Nik Kantaputra.

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Kantaputra, P.N., Wangtiraumnuay, N., Ngamphiw, C. et al. Cryptophthalmos, dental anomalies, oral vestibule defect, and a novel FREM2 mutation. J Hum Genet (2021). https://doi.org/10.1038/s10038-021-00972-4

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