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Spectrum and Frequency of FZD4 Mutations in Familial Exudative Vitreoretinopathy

¹From the Molecular Medicine Unit, University of Leeds, Leeds, United Kingdom; the ²Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, Melbourne, Australia; the ³Department of Ophthalmology, Flinders Medical Centre, Adelaide, Australia; the ⁴Casey Eye Institute, Oregon Health and Science University, Portland, Oregon; the ⁵Doheny Retina Institute of the Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California; the ⁶Department of Ophthalmology and Visual Science, and Program in Human Molecular Biology and Genetics, University of Utah, Salt Lake City, Utah; the ⁷Academic Unit of Ophthalmology, University of Manchester, Manchester Royal Eye Hospital, Manchester, United Kingdom; the ⁸University Department of Medical Genetics and Regional Genetics Service, St. Mary’s Hospital, Manchester, United Kingdom; and the ⁹Regional Clinical Genetics Service, Royal Liverpool University Hospital, Liverpool, United Kingdom.

PURPOSE. Mutations in the frizzled-4 gene (FZD4) have recently been associated with autosomal dominant familial exudative vitreoretinopathy (FEVR) in families linking to the EVR1 locus on the long arm of chromosome 11. The purpose of this study was to screen FZD4 in a panel of 40 patients with FEVR to identify the types and location of mutations and to calculate what proportion of this heterogeneous condition is attributable to FZD4 mutations.

METHODS. PCR products were generated from genomic DNA with primers designed to amplify the coding sequence of FZD4. The PCR products were screened for mutations by single-strand conformational polymorphism-heteroduplex analysis (SSCP-HA) and by direct sequencing.

RESULTS. In total, eight mutations were identified, seven of which were novel. Three were deletions (c957delG, c1498delA, and c1501-1502delCT), one was a nonsense mutation (Q505X), and four were missense mutations (G36D, M105T, M157V, and S497F).

CONCLUSIONS. Eight mutations have been identified in the FZD4 gene in a cohort of 40 unrelated patients with FEVR. This result indicates that FZD4 mutations are responsible for only 20% of FEVR index cases and suggests that the other FEVR loci may account for more cases than previously anticipated.

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				C Toomes, L M Downey, H M Bottomley, H A Mintz-Hittner, and C F Inglehearn Further evidence of genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of EVR1, EVR3, and EVR4 in a large autosomal dominant pedigree Br. J. Ophthalmol., February 1, 2005; 89(2): 194 - 197. [Abstract] [Full Text] [PDF]