title: Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy.
abstract: Familial exudative vitreoretinopathy (FEVR) is a hereditary ocular disorder characterized by a failure of peripheral retinal vascularization. Loci associated with FEVR map to 11q13-q23 (EVR1; OMIM 133780, ref. 1), Xp11.4 (EVR2; OMIM 305390, ref. 2) and 11p13-12 (EVR3; OMIM 605750, ref. 3). Here we have confirmed linkage to the 11q13-23 locus for autosomal dominant FEVR in one large multigenerational family and refined the disease locus to a genomic region spanning 1.55 Mb. Mutations in FZD4, encoding the putative Wnt receptor frizzled-4, segregated completely with affected individuals in the family and were detected in affected individuals from an additional unrelated family, but not in normal controls. FZD genes encode Wnt receptors, which are implicated in development and carcinogenesis. Injection of wildtype and mutated FZD4 into Xenopus laevis embryos revealed that wildtype, but not mutant, frizzled-4 activated calcium/calmodulin-dependent protein kinase II (CAMKII) and protein kinase C (PKC), components of the Wnt/Ca(2+) signaling pathway. In one of the mutants, altered subcellular trafficking led to defective signaling. These findings support a function for frizzled-4 in retinal angiogenesis and establish the first association between a Wnt receptor and human disease.
authors.affiliation: Department of Ophthalmology, Izaak Walton Killam (IWK) Health Centre, Dalhousie University, Halifax, Nova Scotia B3H 2Y9, Canada.
authors.forename: Johane
authors.initials: J
authors.lastname: Robitaille
authors.forename: Marcia L E
authors.initials: ML
authors.lastname: MacDonald
authors.forename: Ajamete
authors.initials: A
authors.lastname: Kaykas
authors.forename: Laird C
authors.initials: LC
authors.lastname: Sheldahl
authors.forename: Jutta
authors.initials: J
authors.lastname: Zeisler
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Dubé
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Zhang
authors.forename: Roshni R
authors.initials: RR
authors.lastname: Singaraja
authors.forename: Duane L
authors.initials: DL
authors.lastname: Guernsey
authors.forename: Binyou
authors.initials: B
authors.lastname: Zheng
authors.forename: Lee F
authors.initials: LF
authors.lastname: Siebert
authors.forename: Ann
authors.initials: A
authors.lastname: Hoskin-Mott
authors.forename: Michael T
authors.initials: MT
authors.lastname: Trese
authors.forename: Simon N
authors.initials: SN
authors.lastname: Pimstone
authors.forename: Barkur S
authors.initials: BS
authors.lastname: Shastry
authors.forename: Randall T
authors.initials: RT
authors.lastname: Moon
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.forename: Y Paul
authors.initials: YP
authors.lastname: Goldberg
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
mesh_terms: D000595:Amino Acid Sequence; D002675:Child, Preschool; D005260:Female; D051157:Frizzled Receptors; D005819:Genetic Markers; D006239:Haplotypes; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010375:Pedigree; D011110:Polymorphism, Genetic; D011506:Proteins / Q000235:genetics*; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012160:Retina / Q000473:pathology; D012164:Retinal Diseases / Q000235:genetics* / Q000473:pathology; D012171:Retinal Vessels / Q000473:pathology*; D016415:Sequence Alignment; D015398:Signal Transduction
chemical_list: C402930:FZD4 protein, human; D051157:Frizzled Receptors; D005819:Genetic Markers; D011506:Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled