title: Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs.
abstract: Fraser syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects 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 CALXbeta-cadherin motif is important for normal functioning of FREM2.
authors.affiliation: Molecular Medicine Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.
authors.forename: Shalini
authors.initials: S
authors.lastname: Jadeja
authors.forename: Ian
authors.initials: I
authors.lastname: Smyth
authors.forename: Jolanta E
authors.initials: JE
authors.lastname: Pitera
authors.forename: Martin S
authors.initials: MS
authors.lastname: Taylor
authors.forename: Mieke
authors.initials: M
authors.lastname: van Haelst
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Bentley
authors.forename: Lesley
authors.initials: L
authors.lastname: McGregor
authors.forename: Jason
authors.initials: J
authors.lastname: Hopkins
authors.forename: Georges
authors.initials: G
authors.lastname: Chalepakis
authors.forename: Nicole
authors.initials: N
authors.lastname: Philip
authors.forename: Antonio
authors.initials: A
authors.lastname: Perez Aytes
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Watt
authors.forename: Susan M
authors.initials: SM
authors.lastname: Darling
authors.forename: Ian
authors.initials: I
authors.lastname: Jackson
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Woolf
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
mesh_terms: D000818:Animals; D001768:Blister / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005143:Eyelids / Q000002:abnormalities; D005835:Genitalia / Q000002:abnormalities; D006801:Humans; D008526:Medulla Oblongata / Q000473:pathology*; D051379:Mice; D008969:Molecular Sequence Data; D013576:Syndactyly / Q000235:genetics
chemical_list: D016326:Extracellular Matrix Proteins; C500786:FREM2 protein, human; C482018:Fras1 protein, mouse