title: A new mouse model for stationary night blindness with mutant Slc24a1 explains the pathophysiology of the associated human disease.
abstract: Mutations that affect calcium homeostasis (Ca(2+)) in rod photoreceptors are linked to retinal degeneration and visual disorders such as retinitis pigmentosa and congenital stationary night blindness (CSNB). It is thought that the concentration of Ca(2+) in rod outer segments is controlled by a dynamic balance between influx via cGMP-gated (CNG) channels and extrusion via Na(+)/Ca(2+), K(+) exchangers (NCKX1). The extrusion-driven lowering of rod [Ca(2+)]i following light exposure controls their light adaptation and response termination. Mutant NCKX1 has been linked to autosomal-recessive stationary night blindness. However, whether NCKX1 contributes to light adaptation has not been directly tested and the mechanisms by which human NCKX1 mutations cause night blindness are not understood. Here, we report that the deletion of NCKX1 in mice results in malformed outer segment disks, suppressed expression and function of rod CNG channels and a subsequent 100-fold reduction in rod responses, while preserving normal cone responses. The compensating loss of CNG channel function in the absence of NCKX1-mediated Ca(2+) extrusion may prevent toxic Ca(2+) buildup and provides an explanation for the stationary nature of the associated disorder in humans. Surprisingly, the lack of NCKX1 did not compromise rod background light adaptation, suggesting additional Ca(2+)-extruding mechanisms exist in these cells.
authors.affiliation: Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Frans
authors.initials: F
authors.lastname: Vinberg
authors.affiliation: Cell and Neurobiology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA and.
authors.forename: Tian
authors.initials: T
authors.lastname: Wang
authors.affiliation: Biochemistry/Molecular Biology, University of British Columbia, Vancouver, Canada.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Molday
authors.affiliation: Cell and Neurobiology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, CA, USA and.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chen
authors.affiliation: Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, USA, kefalov@wustl.edu.
authors.forename: Vladimir J
authors.initials: VJ
authors.lastname: Kefalov
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D015785:Eye Diseases, Hereditary / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D017353:Gene Deletion; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D009216:Myopia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009755:Night Blindness / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D012374:Rod Cell Outer Segment / Q000378:metabolism* / Q000502:physiology; D019831:Sodium-Calcium Exchanger / Q000235:genetics*
chemical_list: D019831:Sodium-Calcium Exchanger; C074530:potassium-dependent sodium-calcium exchanger; D002118:Calcium