Identification of a Novel R41T Missense Mutation in the NDP Gene in a Mexican Family With Norrie Disease

Abstract

Purpose:: Norrie disease (ND) is an X-linked recessive disorder characterized by bilateral fibrosis and detachment of the retina which leads to early blindness. About one third of ND patients develop sensorineural hearing loss and mental retardation of variable degree. ND features include bilateral retinal folds, retinal detachment, vitreoretinal hemorrhages, and retrolental fibrous masses mainly composed of vascular and glial tissue (vitreoretinal dysplasia). ND is caused by mutations in NDP, a gene located on Xp11.4 and highly expressed in retina, choroid and brain. Mutations in NDP have also been identified in another retinal disorder known as X-linked familial exudative vitreoretinopathy (FEVR) and characterized by abnormal vascularization of the peripheral retina and retinal exudates. The NDP gene encodes a protein of 133 residues known as Norrin. To date, no genotype-phenotype correlation exists in the disease as affected individuals within a same family can exhibit very different symptoms. Approximately 100 mutations have been described to date in ND in subjects with these phenotypes. We present the clinical and molecular analysis of a Mexican patient with Norrie disease in which a novel NDP missense mutation was identified.

Methods:: Methods included complete ophthalmologic examination, phenotypic characterization of retinal status, and NDP gene analysis in genomic DNA from the propositus and her mother by PCR amplification and direct DNA sequencing of the 2 coding exons and exon/intron junctions

Results:: Genealogic analysis indicated an X-linked recessive segregation of the disease. The propositus was a 4-month aged patient who presented bilateral nystagmus with no light fixation. Funduscopic and echographic examination revealed retinal traction, retinal detachment, fibrovascular retrolental membrane, and vitreoretinal hemorrhage in both eyes. NDP gene analysis demonstrated a guanine to cytosine transversion at nucleotide position 122 in exon 2. This change predicts a missense mutation from arginine to threonine at residue 41 of the norrin protein (R41T). NDP analysis in DNA from the mother demonstrated her carrier status.

Conclusions:: The R41T mutation described in this patient with ND has not been previously described. Interestingly, an R41K mutation was demonstrated recently in an American family with FEVR. Our data indicates that distinct mutations affecting Norrin amino acid 41 can result in different retinal phenotypes.

Keywords: retinal degenerations: hereditary • genetics • mutations