Overview of the Mutation Spectrum in Familial Exudative Vitreoretinopathy and Norrie Disease with Identification of 21 Novel Variants in FZD4, LRP5, and NDP

Konstantinos Nikopoulos, Hanka Venselaar, Rob W. J. Collin, Rosa Riveiro-Alvarez, F. Nienke Boonstra, Johanna M. M. Hooymans, Arijit Mukhopadhyay, Deborah Shears, Marleen van Bers, Ilse J. de Wijs, Anthonie J. van Essen, Rolf H. Sijmons, Mauk A. D. Tilanus, C. Erik van Nouhuys, Carmen Ayuso, Lies H. Hoefsloot, Frans P. M. Cremers*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

113 Citations (Scopus)

Abstract

Wnt signaling is a crucial component of the cell machinery orchestrating a series of physiological processes such as cell survival, proliferation, and migration. Among the plethora of roles that Wilt signaling plays, its canonical branch regulates eye organogenesis and angiogenesis. Mutations in the genes encoding the low density lipoprotein receptor protein 5 (LRP5) and frizzled 4 (FZD4), acting as coreceptors for Wnt ligands, cause familial exudative vitreoretinopathy (FEVR). Moreover, mutations in the gene encoding NDP, a ligand for these Wnt receptors, cause Norrie disease and FEVR. Both FEVR and Norrie disease share similar phenotypic characteristics, including abnormal vascularization of the peripheral retina and formation of fibrovascular masses in the eye that can lead to blindness. In this mutation update, we report 21 novel variants for FZD4, LRP5, and NDP, and discuss the putative functional consequences of missense mutations. In addition, we provide a comprehensive overview of all previously published variants in the aforementioned genes and summarize the phenotypic characteristics in mouse models carrying mutations in the orthologous genes. The increasing molecular understanding of Wnt signaling, related to ocular development and blood supply, offers more tools for accurate disease diagnosis that may be important in the development of therapeutic interventions. Hum Mutat 31:656-666, 2010. (C) 2010 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)656-666
Number of pages11
JournalHuman Mutation
Volume31
Issue number6
DOIs
Publication statusPublished - Jun-2010

Keywords

  • FZD4
  • LRP5
  • NDP
  • familial exudative vitreoretinopathy
  • FEVR
  • Norrie disease
  • ND
  • RECEPTOR-RELATED PROTEIN-5
  • HIGH-BONE-MASS
  • OSTEOPOROSIS-PSEUDOGLIOMA SYNDROME
  • MANIFESTING FEMALE CARRIER
  • MISSENSE MUTATIONS
  • FRIZZLED-4 GENE
  • RETINAL ANGIOGENESIS
  • OCULAR PHENOTYPE
  • CANDIDATE GENE
  • IDIOPATHIC OSTEOPOROSIS

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