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A. Gal, U. Orth, I. Berndt, H. Gerding, H. Laqua, C.E. van Nouhuys; Analysis of the frizzled–4 gene in patients with autosomal dominant exudative vitreoretinopathy (FEVR) suggests a mutation hot spot and a high penetrance of the mutated allele. . Invest. Ophthalmol. Vis. Sci. 2004;45(13):4734.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Exudative vitreoretinopathy (EVR) is an autosomal dominant (ad) trait affecting primarily the development of the human retinal vascular system. Ophthalmological diagnosis is often complicated by the extremely variable expression of the mutant gene. adEVR is genetically heterogeneous with at least two loci on chromosome 11, EVR1 and EVR3 mapped in q13–q23 and p12–p13, respectively. Recently, FZD4, encoding frizzled–4, a putative seven–transmembrane–domain Wnt receptor, has been shown to be the gene corresponding to EVR1. To date, 6 different FZD4 mutations have been reported in families with adEVR. Methods: We performed mutation screening of FZD4 of a total of 22 unrelated patients with ophthalmological signs typical for EVR. Eight of the patients belong to larger families from the Netherlands and Germany. In these pedigrees, the disease locus was mapped previously on chromosome 11. Results: We detected 6 novel mutations (W319X, c.1282del4, c.1286del5, T445P, G492R, and W496X). Both Thr–445 and Gly–492 are conserved in members of the human frizzled protein family. Of the eight chromosome 11–linked families analysed here, four turned out to segregate for a mutation in FZD4. Analysis of these latter families detected a total of 31 individuals carrying the family–specific mutation. Of these 31 heterozygotes, only 2 (female 34y and male 5y) were not diagnosed clinically affected at the time of clinical assessment. No obvious difference was seen in the eye phenotype of patients with FZD4 mutations compared to that of affected individuals of likely EVR3–related families. Conclusions: While expressivity of FZD4 mutations seems to be largely variable both within the same family and among different families, our data suggest that penetrance of the mutated allele is high (>90%). About half of the chromosome 11–linked families carry a FZD4 mutation, whereas a clinical differentiation is not yet obvious. Remarkably, the majority of FZD4 mutations identified to date (10 out of 12) is clustered in the last third of exon 2, with six mutations for which a truncated protein or a functional null allele is predicted. Human frizzled–4 has a key role in retinal angiogenesis and the spectrum of FZD4 mutations suggests that haploinsufficiency may be one of the genetic pathomechanisms leading to FEVR.
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