Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

Johane Robitaille; Marcia L.E. MacDonald; Ajamete Kaykas; Laird C. Sheldahl; Jutta Zeisler; Marie Pierre Dubé; Lin Hua Zhang; Roshni R. Singaraja; Duane L. Guernsey; Binyou Zheng; Lee F. Siebert; Ann Hoskin-Mott; Michael T. Trese; Simon N. Pimstone; Barkur S. Shastry; Randall T. Moon; Michael R. Hayden; Y. Paul Goldberg; Mark E. Samuels

doi:10.1038/ng957

Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

Johane Robitaille, Marcia L.E. MacDonald, Ajamete Kaykas, Laird C. Sheldahl, Jutta Zeisler, Marie Pierre Dubé, Lin Hua Zhang, Roshni R. Singaraja, Duane L. Guernsey, Binyou Zheng, Lee F. Siebert, Ann Hoskin-Mott, Michael T. Trese, Simon N. Pimstone, Barkur S. Shastry, Randall T. Moon, Michael R. Hayden, Y. Paul Goldberg, Mark E. Samuels

Medicine

Research output: Contribution to journal › Article › peer-review

420 Citations (Scopus)

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 (EVRI; 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/Ca²⁺ 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.

Original language	English
Pages (from-to)	326-330
Number of pages	5
Journal	Nature Genetics
Volume	32
Issue number	2
DOIs	https://doi.org/10.1038/ng957
Publication status	Published - Oct 1 2002

Bibliographical note

Funding Information:
The authors thank J. Thompson, T. Pape, J. MacFarlane, B. Payne, C. Radomski, M. Mattice, A. Hogan, P. Samra, and G. Donaldson at Xenon Genetics and C. Tatlidil at Dalhousie University for technical support; F. Mikelberg for discussion; and the members of the affected families for their enthusiasm and participation. This work was supported in part by a grant from the Nova Scotia Health Research Foundation and the IWK Health Centre to J.R. B.S.S. was supported in part by the Fight for Sight research division of Prevent Blindness America. R.T.M. is an Investigator of the Howard Hughes Medical Institute. M.R.H. holds a Canada Research Chair. A.K. was supported by an US National Institutes of Health Reproductive Biology Training Grant.

ASJC Scopus Subject Areas

Genetics

PubMed: MeSH publication types

Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/ng957

Cite this

Robitaille, J., MacDonald, M. L. E., Kaykas, A., Sheldahl, L. C., Zeisler, J., Dubé, M. P., Zhang, L. H., Singaraja, R. R., Guernsey, D. L., Zheng, B., Siebert, L. F., Hoskin-Mott, A., Trese, M. T., Pimstone, S. N., Shastry, B. S., Moon, R. T., Hayden, M. R., Paul Goldberg, Y., & Samuels, M. E. (2002). Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nature Genetics, 32(2), 326-330. https://doi.org/10.1038/ng957

Robitaille, J, MacDonald, MLE, Kaykas, A, Sheldahl, LC, Zeisler, J, Dubé, MP, Zhang, LH, Singaraja, RR, Guernsey, DL, Zheng, B, Siebert, LF, Hoskin-Mott, A, Trese, MT, Pimstone, SN, Shastry, BS, Moon, RT, Hayden, MR, Paul Goldberg, Y & Samuels, ME 2002, 'Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy', Nature Genetics, vol. 32, no. 2, pp. 326-330. https://doi.org/10.1038/ng957

@article{c0843aeec3784cbd9df92a9defc11461,

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 (EVRI; 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/Ca2+ 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.",

author = "Johane Robitaille and MacDonald, {Marcia L.E.} and Ajamete Kaykas and Sheldahl, {Laird C.} and Jutta Zeisler and Dub{\'e}, {Marie Pierre} and Zhang, {Lin Hua} and Singaraja, {Roshni R.} and Guernsey, {Duane L.} and Binyou Zheng and Siebert, {Lee F.} and Ann Hoskin-Mott and Trese, {Michael T.} and Pimstone, {Simon N.} and Shastry, {Barkur S.} and Moon, {Randall T.} and Hayden, {Michael R.} and {Paul Goldberg}, Y. and Samuels, {Mark E.}",

note = "Funding Information: The authors thank J. Thompson, T. Pape, J. MacFarlane, B. Payne, C. Radomski, M. Mattice, A. Hogan, P. Samra, and G. Donaldson at Xenon Genetics and C. Tatlidil at Dalhousie University for technical support; F. Mikelberg for discussion; and the members of the affected families for their enthusiasm and participation. This work was supported in part by a grant from the Nova Scotia Health Research Foundation and the IWK Health Centre to J.R. B.S.S. was supported in part by the Fight for Sight research division of Prevent Blindness America. R.T.M. is an Investigator of the Howard Hughes Medical Institute. M.R.H. holds a Canada Research Chair. A.K. was supported by an US National Institutes of Health Reproductive Biology Training Grant.",

year = "2002",

month = oct,

day = "1",

doi = "10.1038/ng957",

language = "English",

volume = "32",

pages = "326--330",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "2",

}

TY - JOUR

T1 - Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

AU - Robitaille, Johane

AU - MacDonald, Marcia L.E.

AU - Kaykas, Ajamete

AU - Sheldahl, Laird C.

AU - Zeisler, Jutta

AU - Dubé, Marie Pierre

AU - Zhang, Lin Hua

AU - Singaraja, Roshni R.

AU - Guernsey, Duane L.

AU - Zheng, Binyou

AU - Siebert, Lee F.

AU - Hoskin-Mott, Ann

AU - Trese, Michael T.

AU - Pimstone, Simon N.

AU - Shastry, Barkur S.

AU - Moon, Randall T.

AU - Hayden, Michael R.

AU - Paul Goldberg, Y.

AU - Samuels, Mark E.

N1 - Funding Information: The authors thank J. Thompson, T. Pape, J. MacFarlane, B. Payne, C. Radomski, M. Mattice, A. Hogan, P. Samra, and G. Donaldson at Xenon Genetics and C. Tatlidil at Dalhousie University for technical support; F. Mikelberg for discussion; and the members of the affected families for their enthusiasm and participation. This work was supported in part by a grant from the Nova Scotia Health Research Foundation and the IWK Health Centre to J.R. B.S.S. was supported in part by the Fight for Sight research division of Prevent Blindness America. R.T.M. is an Investigator of the Howard Hughes Medical Institute. M.R.H. holds a Canada Research Chair. A.K. was supported by an US National Institutes of Health Reproductive Biology Training Grant.

PY - 2002/10/1

Y1 - 2002/10/1

N2 - 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 (EVRI; 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/Ca2+ 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.

AB - 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 (EVRI; 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/Ca2+ 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.

UR - http://www.scopus.com/inward/record.url?scp=0036789449&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036789449&partnerID=8YFLogxK

U2 - 10.1038/ng957

DO - 10.1038/ng957

M3 - Article

C2 - 12172548

AN - SCOPUS:0036789449

SN - 1061-4036

VL - 32

SP - 326

EP - 330

JO - Nature Genetics

JF - Nature Genetics

IS - 2

ER -

Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy

Abstract

Bibliographical note

ASJC Scopus Subject Areas

PubMed: MeSH publication types

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this