title: A Naturally Occurring Canine Model of Autosomal Recessive Congenital Stationary Night Blindness.
abstract: Congenital stationary night blindness (CSNB) is a non-progressive, clinically and genetically heterogeneous disease of impaired night vision. We report a naturally-occurring, stationary, autosomal recessive phenotype in beagle dogs with normal daylight vision but absent night vision. Affected dogs had normal retinas on clinical examination, but showed no detectable rod responses. They had "negative-type" mixed rod and cone responses in full-field ERGs. Their photopic long-flash ERGs had normal OFF-responses associated with severely reduced ON-responses. The phenotype is similar to the Schubert-Bornschein form of complete CSNB in humans. Homozygosity mapping ruled out most known CSNB candidates as well as CACNA2D4 and GNB3. Three remaining genes were excluded based on sequencing the open reading frame and intron-exon boundaries (RHO, NYX), causal to a different form of CSNB (RHO) or X-chromosome (NYX, CACNA1F) location. Among the genes expressed in the photoreceptors and their synaptic terminals, and mGluR6 cascade and modulators, reduced expression of GNAT1, CACNA2D4 and NYX was observed by qRT-PCR in both carrier (n = 2) and affected (n = 2) retinas whereas CACNA1F was down-regulated only in the affecteds. Retinal morphology revealed normal cellular layers and structure, and electron microscopy showed normal rod spherules and synaptic ribbons. No difference from normal was observed by immunohistochemistry (IHC) for antibodies labeling rods, cones and their presynaptic terminals. None of the retinas showed any sign of stress. Selected proteins of mGluR6 cascade and its modulators were examined by IHC and showed that PKCα weakly labeled the rod bipolar somata in the affected, but intensely labeled axonal terminals that appeared thickened and irregular. Dendritic terminals of ON-bipolar cells showed increased Goα labeling. Both PKCα and Goα labeled the more prominent bipolar dendrites that extended into the OPL in affected but not normal retinas. Interestingly, RGS11 showed no labeling in the affected retina. Our results indicate involvement of a yet unknown gene in this canine model of complete CSNB.
authors.affiliation: Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Mineo
authors.initials: M
authors.lastname: Kondo
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Gautami
authors.initials: G
authors.lastname: Das
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Fujisawa, Japan.
authors.forename: Ryoetsu
authors.initials: R
authors.lastname: Imai
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Santana
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Fujisawa, Japan.
authors.forename: Tomio
authors.initials: T
authors.lastname: Nakashita
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Fujisawa, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Imawaka
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Fujisawa, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Fujisawa, Japan.
authors.forename: Hirohiko
authors.initials: H
authors.lastname: Ohtsuka
authors.affiliation: Kitayama Labes Co., Ltd., Ina, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Sakai
authors.affiliation: Kitayama Labes Co., Ltd., Ina, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Aihara
authors.affiliation: Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Ophthalmology, Mie University Graduate School of Medicine, Tsu, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugimoto
authors.affiliation: Department of Ophthalmology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Ueno
authors.affiliation: Department of Biomedical Sciences, Chubu University, Kasugai, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nishizawa
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Gustavo D
authors.initials: GD
authors.lastname: Aguirre
authors.affiliation: School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States of America.
authors.forename: Keiko
authors.initials: K
authors.lastname: Miyadera
mesh_terms: D000818:Animals; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004285:Dogs; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009216:Myopia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D009755:Night Blindness / Q000235:genetics* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D010375:Pedigree; D017729:Presynaptic Terminals / Q000378:metabolism / Q000502:physiology; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D020710:RGS Proteins / Q000235:genetics / Q000378:metabolism; D012160:Retina / Q000503:physiopathology*; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism / Q000502:physiology
chemical_list: D020746:Calcium Channels, L-Type; D011509:Proteoglycans; D020710:RGS Proteins; D020962:Heterotrimeric GTP-Binding Proteins