Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs

Abstract

Fraser syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects1,2 and associated with loss-of-function mutations of the extracellular matrix protein FRAS1. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. The myelencephalic blebs (my) strain has a similar phenotype. We mapped my to Frem2, a gene related to Fras1 and Frem1, and showed that a Frem2 gene-trap mutation was allelic to my. Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. Two individuals with Fraser syndrome were homozygous with respect to the same missense mutation of FREM2, confirming genetic heterogeneity. This is the only missense mutation reported in any blebbing mutant or individual with Fraser syndrome, suggesting that calcium binding in the CALXβ-cadherin motif is important for normal functioning of FREM2.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Mapping the myUcl locus to mouse chromosome 3 (MMU3).
Figure 2: Expression of Frem2 during mouse development.
Figure 3: Analysis of the epidermal basement membrane in wild-type and myUcl/myUcl mutants.
Figure 4: Double mutant bl/bl myUcl/myUcl mice are viable.
Figure 5: Mutation of FREM2 in Fraser syndrome.

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. 1

    Fraser, G.R. Our genetical 'load'. A review of some aspects of genetical variation. Annals of Human Genetics 25, 387–414 (1962).

  2. 2

    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).

  3. 3

    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, 203–208 (2003).

  4. 4

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

  5. 5

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

  6. 6

    Takamiya, K. et al. A direct functional link between the multi-PDZ domain protein GRIP1 and the Fraser syndrome protein Fras1. Nat. Genet. 36, 172–175 (2004).

  7. 7

    Smyth, I. et al. The extracellular matrix gene Frem1 is essential for the normal adhesion of the embryonic epidermis. Proc. Natl. Acad. Sci. USA 101, 13560–13565 (2004).

  8. 8

    Little, C.C. & Bagg, H.J. The occurence of two inheritable types of abnormality among the descendants of x-rayed mice. Am. J. Roentenol. 10, 975–989 (1923).

  9. 9

    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).

  10. 10

    Poschl, E. et al. Collagen IV is essential for basement membrane stability but dispensable for initiation of its assembly during early development. Development 131, 1619–1628 (2004).

  11. 11

    Nagar, B., Overduin, M., Ikura, M. & Rini, J.M. Structural basis of calcium-induced E-cadherin rigidification and dimerization. Nature 380, 360–364 (1996).

  12. 12

    Tamura, K., Shan, W.S., Hendrickson, W.A., Colman, D.R. & Shapiro, L. Structure-function analysis of cell adhesion by neural (N-) cadherin. Neuron 20, 1153–1163 (1998).

  13. 13

    Matsuoka, S. et al. Regulation of the cardiac Na(+)-Ca2+ exchanger by Ca2+. Mutational analysis of the Ca(2+)-binding domain. J. Gen. Physiol 105, 403–420 (1995).

  14. 14

    Philipson, K.D. et al. The Na+/Ca2+ exchange molecule: an overview. Ann. NY Acad. Sci. 976, 1–10 (2002).

  15. 15

    Wilkinson, D. Whole mount in situ hybridisation of vertebrate embryos. in In Situ Hybridisation: A Practical Approach 75–84 (IRL, Oxford, 1992).

Download references

Acknowledgements

We dedicate the paper to the memory of R. Winter, who first drew attention to the link between blebbed mutations and Fraser syndrome. We thank J. Rossant, in whose animal facility the myUcl allele was first discovered; A. Gossler and N. Brown for importing the strain into Germany and the UK, respectively; T. Casals, P. Gallano and F. Paulo for providing Spanish control samples; and all the clinicians and families who have supported our work. BayGenomics, a genomics consortium funded by the US National Heart, Lung, and Blood Institute, provided the KST252 line, which was injected into blastocysts at the Mutant Mouse Regional Resource Centers, University of California at Davis. This work was supported by the Wellcome Trust, the British Heart Foundation, the Medical Research Council, the Kidney Research Aid Fund and the European Union EURSTEMCELLS Network. I.S. was supported by a Traveling Research Fellowship from the Wellcome Trust.

Author information

Correspondence to Peter J Scambler.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

CALXb is homologous, and structurally related to the cadherin protein fold. (PDF 154 kb)

Supplementary Table 1

Primers used in the study. (PDF 121 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Jadeja, S., Smyth, I., Pitera, J. et al. Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs. Nat Genet 37, 520–525 (2005). https://doi.org/10.1038/ng1549

Download citation

Further reading