Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-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

illumination1. Within the retina, cells that respond to light increment and light decrement are separated into ON- and OFF-pathways. Hereditary diseases are known to disturb these retinal

pathways, causing either progressive degeneration or stationary deficits2. Congenital stationary night blindness (CSNB) is a group of stable retinal disorders that are characterized by

abnormal night vision. Genetic subtypes of CSNB have been defined and different disease actions have been postulated3,4,5. The molecular bases have been elucidated in several subtypes,

providing a better understanding of the disease mechanisms and developmental retinal neurobiology2. Here we have studied 22 families with 'complete' 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 families from

the United States, in a novel candidate gene, NYX. NYX, which encodes a glycosylphosphatidyl (GPI)-anchored protein called nyctalopin, is a new and unique member of the small leucine-rich

proteoglycan (SLRP) family6. The role of other SLRP proteins suggests that mutant nyctalopin disrupts developing retinal interconnections involving the ON-bipolar cells, leading to the

visual losses seen in patients with complete CSNB.

We thank the patients and their families for participation; K. Boycott, J. Friedman, D. Rancourt, S. Robbins, P. Schnetkamp, W. Stell, M. Walter and R. Winkfein for discussions; and J.

Whitehead, D. Martindale and L. Yong for technical assistance. This research was supported in part by operating grants to N.T.B.-H. from the RP Research Foundation (Foundation Fighting

Blindness), the Medical Research Council of Canada, and the I.D. Bebensee Foundation, and from the Foundation Fighting Blindness to D.G.B., S.G.J. and R.G.W. In addition, R.G.W. was

supported by an unrestricted grant from Research to Prevent Blindness, S.G.J. by NIH grant EY-05627 and D.G.B. by NIH grant EY05235. N.T.B.-H. was also supported by the Roy Allen Endowment,

The Alberta Children's Hospital Foundation and the Department of Ophthalmology, University of Alberta (W.G. Pearce and I.M. MacDonald).

Margaret J. Naylor and Tracy A. Maybaum: These authors contributed equally to this work.

Department of Medical Genetics, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada

N.Torben Bech-Hansen, Margaret J. Naylor, Tracy A. Maybaum & Rebecca L. Sparkes

Department of Biology, and Centre for Environmental Research, University of Victoria, Victoria, British Columbia, Canada

The Netherlands Ophthalmic Research Institute, Amsterdam, The Netherlands

Department of Physiology and Biophysics, University of Calgary, Calgary, Alberta, Canada

Department of Ophthalmology, Children's Hospital, and McGill University, Montreal, Quebec, Canada

Institut fur Humangenetik, Universitats-Klinikum Hamburg-Eppendorf, Hamburg, Germany

Department of Ophthalmology, Emory Eye Center, Atlanta, Georgia, USA

Department of Ophthalmology, SUNY Downstate, Brooklyn Medical Center, Brooklyn, New York

Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Department of Ophthalmology and Visual Sciences, Texas Tech University Health Sciences Center, Lubbock, Texas, USA

Casey Eye Institute, Oregon Health Sciences University, Portland, Oregon, USA

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