title: Genetic variants of FZD4 and LRP5 genes in patients with advanced retinopathy of prematurity.
abstract: OBJECTIVE
  Retinopathy of prematurity (ROP) is a complex disease with a genetic predisposition, but little is known about its genetic background. It has a clinical resemblance to familial exudative vitreoretinopathy (FEVR), a hereditary disease characterized by defects in the development of retinal vessels. Several studies have suggested that mutations in the causative genes for FEVR may account for a proportion of advanced ROP, but conflicting data have also been reported for some variants. To address the possibility of genetic involvement of FEVR genes in ROP, we performed comprehensive sequence analyses of 53 Japanese patients with advanced ROP for the FEVR-causing genes.
  
  
  METHODS
  Peripheral blood DNA was obtained from 53 patients referred to our hospitals for retinal surgery. Polymerase chain reaction followed by direct sequencing of the coding regions of the known FEVR-causing genes (FZD4, LRP5, TSPAN12, and NDP) and a noncoding exon of the NDP gene was performed. Possible pathogenicity of the sequence changes were analyzed by orthologous protein sequence alignment and by computational predictions.
  
  
  RESULTS
  We identified six different nonsynonymous DNA variants in the coding region of either the FZD4 gene (p.H69Y, p.R127H, and p.Y211H) or the LRP5 gene (p.R1219H, p.H1383P, and p.T1540M) in seven patients. The corresponding codons of these changes were highly conserved among species, and these changes were predicted to be pathogenic by at least two of four computational prediction programs. No such changes were found in the TSPAN12 and NDP genes.
  
  
  CONCLUSIONS
  Six possibly pathogenic variants of FZD4 or LRP5 were found in seven advanced ROP patients. Although these variants do not yet provide definitive evidence that they are causal, the results imply a role of the FZD4 and LRP5 genes in the development of advanced ROP.
authors: Department of Ophthalmology, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan. kondohi@med.uoeh-u.ac.jp
authors: Hiroyuki
authors: H
authors: Kondo
authors: Shunji
authors: S
authors: Kusaka
authors: Aki
authors: A
authors: Yoshinaga
authors: Eiichi
authors: E
authors: Uchio
authors: Akihiko
authors: A
authors: Tawara
authors: Tomoko
authors: T
authors: Tahira
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics*; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D060492:Low Density Lipoprotein Receptor-Related Protein-5 / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D012178:Retinopathy of Prematurity / Q000209:etiology / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D059470:Tetraspanins / Q000235:genetics
chemical_list: C402930:FZD4 protein, human; D051157:Frizzled Receptors; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C545100:TSPAN12 protein, human; D059470:Tetraspanins