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


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.

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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.

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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.

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Correspondence to Peter J Scambler.

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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)

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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).

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