Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy.
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.
Robitaille
Johane
J
Department of Ophthalmology, Izaak Walton Killam (IWK) Health Centre, Dalhousie University, Halifax, Nova Scotia B3H 2Y9, Canada.
MacDonald
Marcia L E
ML
Kaykas
Ajamete
A
Sheldahl
Laird C
LC
Zeisler
Jutta
J
Dubé
Marie-Pierre
MP
Zhang
Lin-Hua
LH
Singaraja
Roshni R
RR
Guernsey
Duane L
DL
Zheng
Binyou
B
Siebert
Lee F
LF
Hoskin-Mott
Ann
A
Trese
Michael T
MT
Pimstone
Simon N
SN
Shastry
Barkur S
BS
Moon
Randall T
RT
Hayden
Michael R
MR
Goldberg
Y Paul
YP
Samuels
Mark E
ME
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
C402930:FZD4 protein, human; D051157:Frizzled Receptors; D005819:Genetic Markers; D011506:Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled