Molecular Genetic Analysis of Norrie Disease Pseudoglioma (NDP) Gene in Indian Familial Exudative Vitreo Retinopathy (FEVR) and Retinopathy of Prematurity (ROP) Patients

Abstract

Purpose: : Norrin β-catenin signaling pathway defects are known for their involvement in the pathogenesis of FEVR however its role in ROP is unclear. Norrin protein encoded by norrie disease pseudoglioma (NDP) gene is responsible for the activation of β-catenin signaling in the retina. The present study aimed to understand the involvement of NDP gene in FEVR and ROP patients from South India using genetic and bioinformatics tools.

Methods: : 188 unrelated patients with FEVR (110) and ROP (78) and 192 controls were screened for mutations/variants in the entire coding and untranslated (UTR) regions of NDP gene by PCR based direct sequencing. The missense variants were further analysed by generating 3D structure models for wild and mutant norrin proteins using the I-TASSER server.

Results: : A total of 10 mutations were identified in 12 FEVR patients, of which 6 were novel including 3 missense, 2 frameshift, and one UTR mutation. Three variants in the UTR region of gene including a 14bp deletion, an intronic variation and a novel SNP were identified in four different ROP patients. The missense mutations identified were predicted to be pathogenic as they replaced evolutionarily highly conserved amino acids with a SIFT score < 0.005 and possible changes in the local conformation and multimerization of norrin protein.

Conclusions: : NDP gene variants were identified in 12% and 5% of the FEVR and ROP cases respectively, indicating its potential role in FEVR and ROP pathogenesis in the Indian patients.

Keywords: genetics • gene screening • retinopathy of prematurity