Skip to main content

Thank you for visiting 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.

Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice


Loss of tight association between epidermis and dermis underlies several blistering disorders and is frequently caused by impaired function of extracellular matrix (ECM) proteins1,2. Here we describe a new protein in mouse, Fras1, that is specifically detected in a linear fashion underlying the epidermis and the basal surface of other epithelia in embryos. Loss of Fras1 function results in the formation of subepidermal hemorrhagic blisters as well as unilateral or bilateral renal agenesis during mouse embryogenesis. Postnatally, homozygous Fras1 mutants have fusion of the eyelids and digits and unilateral renal agenesis or dysplasia. The defects observed in Fras1−/− mice phenocopy those of the existing bl (blebbed) mouse mutants3,4, which have been considered a model for the human genetic disorder Fraser syndrome5,6. We show that bl/bl homozygous embryos are devoid of Fras1 protein, consistent with the finding that Fras1 is mutated in these mice6. In sum, our data suggest that perturbations in the composition of the extracellular space underlying epithelia could account for the onset of the blebbed phenotype in mouse and Fraser syndrome manifestation in human.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Schematic representation of Fras1 and detection of the mRNA and protein.
Figure 2: Targeted disruption of Fras1.
Figure 3: Onset and progression of blister formation in Fras1−/− embryos on the C57BL/10 background.
Figure 4: Fras1−/− mice on the NMRI background have fusions of eyelids and digits as well as renal agenesis or dysgenesis.
Figure 5: Comparative analysis of the DEJ zone of wild-type, Fras1−/− and bl/bl embryos.
Figure 6: Analysis of the DEJ zone of blistered skin in Fras1−/− embryos.

Accession codes




  1. Bruckner-Tuderman, L. & Bruckner, P. Genetic diseases of the extracellular matrix: more than just connective tissue disorders. J. Mol. Med. 76, 226–237 (1998).

    Article  CAS  Google Scholar 

  2. Gustafsson, E. & Fassler, R. Insights into extracellular matrix functions from mutant mouse models. Exp. Cell Res. 261, 52–68 (2000).

    Article  CAS  Google Scholar 

  3. Darling, S. & Gossler, A. A mouse model for Fraser syndrome? Clin. Dysmorph. 3, 91–95 (1994).

    Article  CAS  Google Scholar 

  4. Lyon, M.F., Rastan, S. & Brown, S.D. Genetic Variants and Strains of the Laboratory Mouse 3rd edn. (Oxford University Press, New York, 1996).

    Google Scholar 

  5. Winter, R.M. Fraser syndrome and mouse “bleb” mutants. Clin. Genet. 37, 494–495 (1990).

    Article  CAS  Google Scholar 

  6. McGregor, L. et al. Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein. Nat. Genet. 34, ′–′ (2003). [Ed: page numbers for Scambler]

  7. Sadler, J.E. Biochemistry and genetics of von Willebrand factor. Annu. Rev. Biochem. 67, 395–424 (1998).

    Article  CAS  Google Scholar 

  8. Roebroek, A.J.M. et al. Cloning and functional expression of Dfurin2, a Subtilisin-like proprotein processing enzyme of Drosophila melanogaster with multiple repeats of a cysteine motif. J. Biol. Chem. 267, 17208–17215 (1992).

    CAS  PubMed  Google Scholar 

  9. Nishiyama, A., Dahlin, K.J., Price, J.T., Johnstone, S.R. & Stallcup, W.B. The primary structure of NG2, a novel membrane-spanning proteoglycan. J. Cell Biol. 114, 359–371 (1991).

    Article  CAS  Google Scholar 

  10. Schwarz, E.M. & Benzer, S. Calx, a Na-Ca exchanger gene in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 94, 10249–10254 (1997).

    Article  CAS  Google Scholar 

  11. Hodor, P.G., Illies, M.R., Broadley, S. & Ettensohn, C.A. Cell-substrate interactions during sea urchin gastrulation: migrating primary mesenchyme cells interact with and align extracellular matrix fibers that contain ECM3, a molecule with NG2-like and multiple calcium-binding domains. Dev. Biol. 222, 181–194 (2000).

    Article  CAS  Google Scholar 

  12. Spirito, F. et al. Reduced expression of the epithelial adhesion ligand laminin 5 in the skin causes intradermal tissue separation. J. Biol. Chem. 276, 18828–18835 (2001).

    Article  CAS  Google Scholar 

  13. Arin, M.J. & Roop, D.R. Disease model: heritable skin blistering. Trends Mol. Med. 7, 422–424 (2001).

    Article  CAS  Google Scholar 

  14. McGowan, K.A. & Marinkovich, M.P. Laminins and human disease. Microsc. Res. Tech. 51, 262–279 (2000).

    Article  CAS  Google Scholar 

  15. Kuure, S., Vuolteenaho, R. & Vainio, S. Kidney morphogenesis: cellular and molecular regulation. Mech. Dev. 92, 31–45 (2000).

    Article  CAS  Google Scholar 

  16. Muller, U. et al. Integrin α8β1 is critically important for epithelial-mesenchymal interactions during kidney morphogenesis. Cell 88, 603–613 (1997).

    Article  CAS  Google Scholar 

  17. Willem, M. et al. Specific ablation of the nidogen-binding site in the laminin gamma1 chain interferes with kidney and lung development. Development 129, 2711–2722 (2002).

    CAS  PubMed  Google Scholar 

  18. Tillet, E., Ruggiero, F., Nishiyama, A. & Stallcup, W.B. The membrane-spanning proteoglycan NG2 binds to collagens V and VI through the central nonglobular domain of its core protein. J. Biol. Chem. 272, 10769–10776 (1997).

    Article  CAS  Google Scholar 

  19. Slavotinek, A.M. & Tifft, C.J. Fraser syndrome and cryptophthalmos: review of the diagnostic criteria and evidence for phenotypic modules in complex malformation syndromes. J. Med. Genet. 39, 623–633 (2002).

    Article  CAS  Google Scholar 

  20. Snyder, P.B., Galanopoulos, V.K. & Kafatos, F.C. Trans-acting amplification mutants and other eggshell mutants of the third chromosome in Drosophila melanogaster. Proc. Natl. Acad. Sci. USA 83, 3341–3345 (1986).

    Article  CAS  Google Scholar 

  21. Mouellic, H.L., Lallemand, Y. & Brulet, P. Targeted replacement of the Homeobox gene Hox-3.1 by the Escherichia coli LacZ in mouse chimeric embryos. Proc. Natl. Acad. Sci. USA 87, 4712–4716 (1990).

    Article  Google Scholar 

Download references


We thank S. Meyer and S. Mahsur for help with the mouse stem cells and morula aggregation; E. Pavlakis for technical assistance; R. Timpl for the antibodies for laminin α5, laminin γ1, agrin and nidogen 1; P. Bonaldo for the collagen VI antibody; L. Bruckner-Tuderman for collagen VII antibodies; H. Krambovitis for the generation of Fras1 antibodies; L. Panagis, C. Dermon and G. Mavrothalassitits for help with the TUNEL assay; A. Argyrokastritis and S. Theophilou for critical reading of the manuscript; and P. Gruss for providing expertise and facilities of his laboratory. This work was supported by a grant from the Greek General Secretariat for Science and Technology and the British Heart Foundation (to P.J.S.).

Author information

Authors and Affiliations


Corresponding author

Correspondence to Georges Chalepakis.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Vrontou, S., Petrou, P., Meyer, B. et al. Fras1 deficiency results in cryptophthalmos, renal agenesis and blebbed phenotype in mice. Nat Genet 34, 209–214 (2003).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing