Norrie disease (ND) is an X-linked recessive disorder characterized by congenital blindness secondary to a retinal dysplasia, mental retardation and a progressive sensorineural hearing loss. We consider this disease an excellent model for the molecular genetic and biologic study of a neurodevelopmental disorder whose defect is critical to early retinal development (ganglion cell aplasia, apoptosis) and where variable effect on cognitive development and hearing are produced by disease gene mutation. Our recent identification of the disease gene and analysis of its predicted protein product have opened the door for further studies into the regulatory control and developmental expression of this gene. Although the protein is one never previously identified it has significant sequence homology to two classes of protein (immediate early genes) which are known DNA transcription factors (gene expression regulatory factors) and 3' cysteine-rich region of mucins (extracellular matrix proteins) both believed critical in a variety of developmental processes including neuronal differentiation and survival. Recent molecular modeling suggests norrin may have tertiary structural features seen in members of the cystine knot growth factor family. Our mutational studies in Norrie patients support the observation of critical cysteine bridge regions required and predicted by this model. Preliminary work has begun in what will be a systematic study of the developmental expression of this gene and protein in the mouse. Expression studies will characterize tissue and cell-specific expression and allow refined hypothesis to be generated as to protein function in the disease process as well as normal neurodevelopment. initial studies will focus on the retinal component of this genetic disease and concurrently on the role that expression of this gene/protein may play in normal retinal ganglion cell differentiation and retinal apoptosis. Collaborative studies are planned to create an animal model of this disease in order to facilitate more extended and manipulative analysis of the anatomic and pathophysiology of this disease process. Experimental data from this model system will yield important insights into the retinal pathology and disease process, as well as into the ontogeny, differentiation and maintenance of the mature retinal ganglion cell phenotype, the role of this cellular differentiation in overall retinal development and visual function and into basic underlying principles important in the more broad neurobiology of neuronal differentiation and survival.
