title: Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein.
abstract: 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.
authors.affiliation: Molecular Medicine, Institute of Child Health, London WC1N 1EH, UK.
authors.forename: Lesley
authors.initials: L
authors.lastname: McGregor
authors.forename: Ville
authors.initials: V
authors.lastname: Makela
authors.forename: Susan M
authors.initials: SM
authors.lastname: Darling
authors.forename: Sofia
authors.initials: S
authors.lastname: Vrontou
authors.forename: Georges
authors.initials: G
authors.lastname: Chalepakis
authors.forename: Catherine
authors.initials: C
authors.lastname: Roberts
authors.forename: Nicola
authors.initials: N
authors.lastname: Smart
authors.forename: Paul
authors.initials: P
authors.lastname: Rutland
authors.forename: Natalie
authors.initials: N
authors.lastname: Prescott
authors.forename: Jason
authors.initials: J
authors.lastname: Hopkins
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bentley
authors.forename: Alison
authors.initials: A
authors.lastname: Shaw
authors.forename: Emma
authors.initials: E
authors.lastname: Roberts
authors.forename: Robert
authors.initials: R
authors.lastname: Mueller
authors.forename: Shalini
authors.initials: S
authors.lastname: Jadeja
authors.forename: Nicole
authors.initials: N
authors.lastname: Philip
authors.forename: John
authors.initials: J
authors.lastname: Nelson
authors.forename: Christine
authors.initials: C
authors.lastname: Francannet
authors.forename: Antonio
authors.initials: A
authors.lastname: Perez-Aytes
authors.forename: Andre
authors.initials: A
authors.lastname: Megarbane
authors.forename: Bronwyn
authors.initials: B
authors.lastname: Kerr
authors.forename: Brandon
authors.initials: B
authors.lastname: Wainwright
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.forename: Robin M
authors.initials: RM
authors.lastname: Winter
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
mesh_terms: D000818:Animals; D001483:Base Sequence; D001768:Blister / Q000235:genetics* / Q000473:pathology; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D030321:Denys-Drash Syndrome / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype
chemical_list: D016326:Extracellular Matrix Proteins; C475145:FRAS1 protein, human; D004247:DNA