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Letter
Nature Genetics  34, 203 - 208 (2003)
Published online: 25 May 2003; | doi:10.1038/ng1142

Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein

Lesley McGregor1, Ville Makela2, Susan M Darling1, 3, Sofia Vrontou4, Georges Chalepakis4, Catherine Roberts1, Nicola Smart1, Paul Rutland2, Natalie Prescott2, Jason Hopkins3, Elizabeth Bentley3, Alison Shaw3, Emma Roberts5, Robert Mueller5, Shalini Jadeja1, Nicole Philip6, John Nelson7, Christine Francannet8, Antonio Perez-Aytes9, Andre Megarbane10, Bronwyn Kerr11, Brandon Wainwright12, Adrian S Woolf13, Robin M Winter2 & Peter J Scambler1

1  Molecular Medicine, Institute of Child Health, London WC1N 1EH, UK.

2  Clinical and Molecular Genetics Units, Institute of Child Health, London WC1N 1EH, UK.

3  Department of Anatomy & Developmental Biology, University College, London WC1E 6BT, UK.

4  Institute of Molecular Biology and Biotechnology, FORTH, and Department of Biology, University of Crete, Heraklion, Greece.

5  Molecular Medicine Unit, St. James's University Hospital, Leeds LS9 7TF, UK.

6  Hospital d'Enfants de la Timone, Marseille, France.

7  King Edward Memorial Hospital for Women, Perth, Australia.

8  Centre Hospitalier Universitaire de Clermont-Ferrand, France.

9  Hospital Infantil "La Fe", Valencia, Spain.

10  Universite Saint-Joseph, Beirut, Lebanon.

11  Manchester Regional Genetics, St. Mary's Hospital, Manchester, UK.

12  Institute for Molecular Bioscience, University of Queensland, St. Lucia 4072, Australia.

13  Nephro-Urology Unit, Institute of Child Health, London WC1N 1EH, UK.

Correspondence should be addressed to Peter J Scambler pscamble@hgmp.mrc.ac.uk
Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects1. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse2, which has been associated with mutations in at least five loci including bl 3. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.


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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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