Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, causeX-linked complete congenital stationary night blindness

During development, visual photoreceptors, bipolar cells and other neurons establish connections within the retina enabling the eye to process visual images over approximately 7 log units of illumination(1). Within the retina , cells that respond to light increment and light decrement are separated i nto ON- and OFF-pathways. Hereditary diseases are known to disturb these re tinal pathways, causing either progressive degeneration or stationary defic its(2). Congenital stationary night blindness (CSNB) is a group of stable r etinal disorders that are characterized by abnormal night vision. Genetic s ubtypes of CSNB have been defined and different disease actions have been p ostulated(3-5). The molecular bases have been elucidated in several subtype s, providing a better understanding of the disease mechanisms and developme ntal retinal neurobiology(2). Here we have studied 22 families with 'comple te' X-linked CSNB (CSNB1; MIM 310500; ref. 4) in which affected males have night blindness, some photopic vision loss and a defect of the ON-pathway. We have found 14 different mutations, including 1 founder mutation in 7 fam ilies from the United States, in a novel candidate gene, NYX. NYX, which en codes a glycosylphosphatidyl (GPI)-anchored protein called nyctalopin, is a new and unique member of the small leucine-rich proteoglycan (SLRP) family (6). The role of other SLRP proteins suggests that mutant nyctalopin disrup ts developing retinal interconnections involving the ON-bipolar cells, lead ing to the visual losses seen in patients with complete CSNB.