Fraser syndrome and mouse blebbed phenotype caused by mutations in FRAS1/Fras1 encoding a putative extracellular matrix protein.
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.
McGregor
Lesley
L
Molecular Medicine, Institute of Child Health, London WC1N 1EH, UK.
Makela
Ville
V
Darling
Susan M
SM
Vrontou
Sofia
S
Chalepakis
Georges
G
Roberts
Catherine
C
Smart
Nicola
N
Rutland
Paul
P
Prescott
Natalie
N
Hopkins
Jason
J
Bentley
Elizabeth
E
Shaw
Alison
A
Roberts
Emma
E
Mueller
Robert
R
Jadeja
Shalini
S
Philip
Nicole
N
Nelson
John
J
Francannet
Christine
C
Perez-Aytes
Antonio
A
Megarbane
Andre
A
Kerr
Bronwyn
B
Wainwright
Brandon
B
Woolf
Adrian S
AS
Winter
Robin M
RM
Scambler
Peter J
PJ
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
D016326:Extracellular Matrix Proteins; C475145:FRAS1 protein, human; D004247:DNA