Norrie disease (ND) (MIM 310600) is a severe form of congenital blindness characterized by degenerative and proliferative changes in the neuroretina and vitreous followed by progressive atrophy of the eyes.

Leukokoria, due to retrolental structures and retinal detachment, can be recognized shortly after birth. Other ocular hallmarks of ND are persistent hyperplastic primary vitreous, hyaloid vessels, shallow anterior chamber, and vitreoretinal hemorrhages.

One-third of patients are mentally retarded and develop sensorineural deafness. Occasionally, other clinical features are seen, including hypogonadism and microcephaly, some of which may be due to defects extending to neighboring genes.

The disease is inherited as an X-linked recessive trait. Male-to-male transmission has been excluded, and carrier females are usually healthy.

Linkage and deletion mapping studies have assigned the ND locus to a 600-kb segment of the Xp11.3-p11.4 interval and paved the way for its isolation by positional cloning.

The gene encodes a 133-amino-acid polypeptide with an N-terminal signal sequence and a C-terminal cysteine-knot motif. It shows homology with proteins involved in cell interaction and differentiation processes. Computer modeling and expression studies suggest the formation of homodimers via the C-terminal Cys-knot.

So far mutations have been described in more than 90 patients with ND. Missense mutations are the most frequent (50 percent), followed by deletions (15–20 percent) and nonsense mutations (13 percent). Mutations in this gene can give rise to three clinically distinct phenotypes, i.e., ND, exudative vitreoretinopathy (EVR) (MIM 143200), and retinopathy of prematurity (ROP).

A mouse mutant lacking the N-terminal portion of the ND gene was generated by gene targeting. Mutant mice show histologic and pyhsiologic changes in the innermost layers of the retina, including the ganglion and nerve fiber layers.