Identification of a new gene mutated in Fraser syndrome and mouse myelencephalic blebs.
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.
Jadeja
Shalini
S
Molecular Medicine Unit, Institute of Child Health, University College London, London WC1N 1EH, UK.
Smyth
Ian
I
Pitera
Jolanta E
JE
Taylor
Martin S
MS
van Haelst
Mieke
M
Bentley
Elizabeth
E
McGregor
Lesley
L
Hopkins
Jason
J
Chalepakis
Georges
G
Philip
Nicole
N
Perez Aytes
Antonio
A
Watt
Fiona M
FM
Darling
Susan M
SM
Jackson
Ian
I
Woolf
Adrian S
AS
Scambler
Peter J
PJ
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
D016326:Extracellular Matrix Proteins; C500786:FREM2 protein, human; C482018:Fras1 protein, mouse