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) and where variable effect on cognitive development and hearing are produced by disease gene mutation. Our recent identification of the disease gene, analysis of its predicted protein product and elaboration of greater than 20 disease mutations within the coding and promoter region of the gene have opened the door for further studies into the developmental expression of this gene and its role in the pathophysiology of the disease phenotype.
Identification of the disease gene has already improved prenatal and carrier testing in families and allowed definitive diagnosis in single affected patients without family history. Understanding of the neurobiology and pathophysiology of the disease process will facilitate the development of rationale therapy.
Cloning of the Norrie disease gene, and its preliminary character-ization, forms the basis for further study of gene structure and of the developmental regulation and expression of this protein. In addition to developmental anatomic expression studies, we propose to make an animal model to study the function of the gene product, its neuro-biologic role in the developmental retinal dysplasia seen in this disease and the protein's function in normal ganglion cell differentiation as well as the broad neurodevelopment of the retina and the visual system.