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Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. 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 mouse, which has been associated with mutations in at least five loci including bl. 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.

Original publication

DOI

10.1038/ng1142

Type

Journal article

Journal

Nat Genet

Publication Date

06/2003

Volume

34

Pages

203 - 208

Keywords

Animals, Base Sequence, Blister, Chromosomes, Human, Pair 4, DNA, DNA Mutational Analysis, Denys-Drash Syndrome, Disease Models, Animal, Extracellular Matrix Proteins, Female, Humans, Male, Mice, Mice, Inbred Strains, Mice, Mutant Strains, Molecular Sequence Data, Pedigree, Phenotype