scholarly journals Identification of a new mutant allele, Grm6nob7, for complete congenital stationary night blindness

2015 ◽  
Vol 32 ◽  
Author(s):  
HAOHUA QIAN ◽  
RUI JI ◽  
RONALD G. GREGG ◽  
NEAL S. PEACHEY
Keyword(s):  
Night Blindness ◽  
Frameshift Mutation ◽  
Metabotropic Glutamate Receptor ◽  
Bipolar Cells ◽  
Human Condition ◽  
Congenital Stationary Night Blindness ◽  
Base Pairs ◽  
Reading Frame ◽  
Mouse Mutants ◽  
The Impact

AbstractElectroretinogram (ERG) studies identified a new mouse line with a normal a-wave but lacking the b-wave component. The ERG phenotype of this new allele, nob7, matched closely that of mouse mutants for Grm6, Lrit3, Trpm1, and Nyx, which encode for proteins expressed in depolarizing bipolar cells (DBCs). To identify the underlying mutation, we first crossed nob7 mice with Grm6nob3 mutants and measured the ERGs in offspring. All the offspring lacked the b-wave, indicating that nob7 is a new allele for Grm6: Grm6nob7. Sequence analyses of Grm6nob7 cDNAs identified a 28 base pair insertion between exons 8 and 9, which would result in a frameshift mutation in the open reading frame that encodes the metabotropic glutamate receptor 6 (Grm6). Sequencing both the cDNA and genomic DNA from exon 8 and intron 8, respectively, from the Grm6nob7 mouse revealed a G to A transition at the last position in exon 8. This mutation disrupts splicing and the normal exon 8 is extended by 28 base pairs, because splicing occurs 28 base pairs downstream at a cryptic splice donor. Consistent with the impact of the resulting frameshift mutation, there is a loss of mGluR6 protein (encoded by Grm6) from the dendritic tips of DBCs in the Grm6nob7 retina. These results indicate that Grm6nob7 is a new model of the complete form of congenital stationary night blindness, a human condition that has been linked to mutations of GRM6.

scholarly journals Pathogenesis and clinical features of congenital stationary night blindness in case of c.283delC NYX gene mutation

2019 ◽  
Vol 12 (3) ◽  
pp. 77-84
Author(s):  
M. E. Ivanova ◽  
K. V. Gorgisheli ◽  
I. V. Zolnikova ◽  
D. S. Atarshchikov ◽  
D. Barh ◽  
...  
Keyword(s):  
Clinical Features ◽  
Night Blindness ◽  
Gene Replacement ◽  
Congenital Stationary Night Blindness ◽  
Base Pairs ◽  
Blind Test ◽  
Reading Frame ◽  
Whole Exome ◽  
The Family ◽  
Complete Form

The complete form of X-linked congenital stationary night blindness (CSNB) is a rare genetic disease caused by a mutation in the NYX gene. CSNB is associated with the mutations taking place in 17 genes, whilst its CSNB1A form is caused by the mutations in the NYX gene, which were characterized earlier, although nothing had been reported so far about the Russian founder principle. The paper analyzes the pathogenetic mechanisms in a family with diagnosed CSNB1A and a new genetically confirmed mutation in the NYX gene in four members of one Russian family. Two brothers of the four siblings (two boys, two girls) with congenital stationary night blindness, diagnosed in early childhood, and high myopia underwent a standard ophthalmic examination, supplemented with OCT, electroretinography and color blind test with tables by Rabkin and Farnsworth test, whereupon they were sent to molecular genetics confirmation of the diagnosis by whole exome sequencing with subsequent Sanger sequencing confirmation of the detected mutation in the proband and proband’s relatives. In members of the family with clinical features of CSNB1A the reading frame shift mutation was genetically confirmed in the NYX gene (c.283delC, p.His95fs, NM_022567.2). This mutation is inherited in X-linked form. This is the first report of a case with a novel and probable founder mutation from Russia associated with CSNB1A. Since the mRNA of a NYX gene consists of only 2696 base pairs, a gene replacement therapy, or CRISPR-based gene editing, or a similar approach may be envisaged for the correction of frameshift in His95fs position.

scholarly journals Intravitreal delivery of a novel AAV vector targets ON bipolar cells and restores visual function in a mouse model of complete congenital stationary night blindness

2015 ◽  
Vol 24 (21) ◽  
pp. 6229-6239 ◽  
Author(s):  
Miranda L. Scalabrino ◽  
Sanford L. Boye ◽  
Kathryn M. H. Fransen ◽  
Jennifer M. Noel ◽  
Frank M. Dyka ◽  
...  
Keyword(s):  
Mouse Model ◽  
Visual Function ◽  
Night Blindness ◽  
Bipolar Cells ◽  
Congenital Stationary Night Blindness ◽  
Aav Vector

scholarly journals 498. Optimization of rAAV Targets ON Bipolar Cells and Rescues the nobnyx Mouse Model of X-Linked Congenital Stationary Night Blindness

2015 ◽  
Vol 23 ◽  
pp. S199
Author(s):  
Miranda L. White ◽  
Sanford L. Boye ◽  
Frank M. Dyka ◽  
Kathryn M. Fransen ◽  
Charles N. de Leeuw ◽  
...  
Keyword(s):  
Mouse Model ◽  
Night Blindness ◽  
Bipolar Cells ◽  
Congenital Stationary Night Blindness

scholarly journals Nyctalopin Expression in Retinal Bipolar Cells Restores Visual Function in a Mouse Model of Complete X-Linked Congenital Stationary Night Blindness

2007 ◽  
Vol 98 (5) ◽  
pp. 3023-3033 ◽  
Author(s):  
Ronald G. Gregg ◽  
Maarten Kamermans ◽  
Jan Klooster ◽  
Peter D. Lukasiewicz ◽  
Neal S. Peachey ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Visual Function ◽  
Night Blindness ◽  
Fusion Gene ◽  
Ganglion Cells ◽  
Normal Function ◽  
Bipolar Cells ◽  
Congenital Stationary Night Blindness ◽  
Electron Microscopic ◽  
Ultrastructural Studies

Mutations in the NYX gene that encodes the protein nyctalopin cause congenital stationary night blindness type 1. In no b-wave ( nob) mice, a mutation in Nyx results in a functional phenotype that includes the absence of the electroretinogram b-wave and abnormal spontaneous and light-evoked activity in retinal ganglion cells (RGCs). In contrast, there is no morphological abnormality in the retina at either the light or electron microscopic levels. These functional deficits suggest that nyctalopin is required for normal synaptic transmission between retinal photoreceptors and depolarizing bipolar cells (DBCs). However, the synaptic etiology and, specifically, the exact location and function of nyctalopin, remain uncertain. We show that nob DBCs fail to respond to exogenous application of the photoreceptor neurotransmitter, glutamate, thus demonstrating a postsynaptic deficit in photoreceptor to bipolar cell communication. To determine if postsynaptic expression of nyctalopin is necessary and sufficient to rescue the nob phenotype, we constructed transgenic mice that expressed an EYFP-nyctalopin fusion protein on the dendritic tips of the DBCs. Immunohistochemical and ultrastructural studies verified that fusion protein expression was limited to the DBC dendritic tips. Fusion gene expression in nob mice restored normal outer and inner visual function as determined by the electroretinogram and RGC spontaneous and evoked responses. Together, our data show that nyctalopin expression on DBC dendrites is required for normal function of the murine retina.

scholarly journals Functional impact of a congenital stationary night blindness type 2 mutation depends on subunit composition of Cav1.4 Ca2+ channels

2020 ◽  
Vol 295 (50) ◽  
pp. 17215-17226
Author(s):  
Brittany Williams ◽  
Josue A. Lopez ◽  
J. Wesley Maddox ◽  
Amy Lee
Keyword(s):  
Night Blindness ◽  
Splice Variants ◽  
Ion Selectivity ◽  
Reversal Potential ◽  
Congenital Stationary Night Blindness ◽  
Auxiliary Subunits ◽  
Retinal Photoreceptors ◽  
Channel Opening ◽  
The Impact

Voltage-gated Cav1 and Cav2 Ca2+ channels are comprised of a pore-forming α1 subunit (Cav1.1-1.4, Cav2.1-2.3) and auxiliary β (β1-4) and α2δ (α2δ−1−4) subunits. The properties of these channels vary with distinct combinations of Cav subunits and alternative splicing of the encoding transcripts. Therefore, the impact of disease-causing mutations affecting these channels may depend on the identities of Cav subunits and splice variants. Here, we analyzed the effects of a congenital stationary night blindness type 2 (CSNB2)-causing mutation, I745T (IT), in Cav1.4 channels typical of those in human retina: Cav1.4 splice variants with or without exon 47 (Cav1.4+ex47 and Cav1.4Δex47, respectively), and the auxiliary subunits, β2X13 and α2δ-4. We find that IT caused both Cav1.4 splice variants to activate at significantly more negative voltages and with slower deactivation kinetics than the corresponding WT channels. These effects of the IT mutation, along with unexpected alterations in ion selectivity, were generally larger in channels lacking exon 47. The weaker ion selectivity caused by IT led to hyperpolarizing shifts in the reversal potential and large outward currents that were evident in channels containing the auxiliary subunits β2X13 and α2δ-4 but not in those with β2A and α2δ-1. We conclude that the IT mutation stabilizes channel opening and alters ion selectivity of Cav1.4 in a manner that is strengthened by exclusion of exon 47 and inclusion of β2X13 and α2δ-4. Our results reveal complex actions of IT in modifying the properties of Cav1.4 channels, which may influence the pathological consequences of this mutation in retinal photoreceptors.

scholarly journals Targeting ON-bipolar cells by AAV gene therapy stably reverses LRIT3-congenital stationary night blindness

2021 ◽  
Author(s):  
Keiko Miyadera ◽  
Evelyn Santana ◽  
Karolina Roszak ◽  
Sommer Iffrig ◽  
Meike Visel ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Night Blindness ◽  
Canine Model ◽  
Bipolar Cells ◽  
Large Animal Model ◽  
Transduction Efficiency ◽  
Large Animal ◽  
Congenital Stationary Night Blindness ◽  
Scotopic Vision ◽  
Large Animal Models

AAV gene therapies aimed at curing inherited retinal diseases to date have typically focused on photoreceptors and retinal pigmented epithelia within the relatively accessible outer retina. However, therapeutic targeting in diseases such as congenital stationary night blindness (CSNB) that involve defects in ON-bipolar cells (ON-BCs) within the mid-retina has been challenged by the relative inaccessibility of the target cell in intact retinas, the limited transduction efficiency of these cells by existing AAV serotypes, poor availability of established ON-BC-specific promoters, and absence of appropriate patient-relevant large animal models. Here, we demonstrate safe and effective ON-BC targeting by AAV gene therapy in a recently characterized naturally-occurring canine model of CSNB, LRIT3-CSNB. To effectively target ON-BCs, new AAV capsid variants with ON-BC tropism and ON-BC specific modified GRM6 promoters were adopted to ensure cell-specific transgene expression. Notably, subretinal injection of one vector, AAVK9#4-shGRM6-cLRIT3-WPRE, significantly recovered rod-derived b-wave in all treated eyes (6/6) of adult dogs injected at 1-3 years of age. The robust therapeutic effect was evident 7 weeks post-injection and was sustained for at least 1 year in all treated eyes. Scotopic vision was significantly improved in treated eyes based on visually-guided obstacle course navigation. Restoration of LRIT3 signals was confirmed by immunohistochemistry. Thus, we report on the first ON-BC functional rescue in a large animal model using a novel AAV capsid variant and modified promoter construct optimized for ON-BC specificity, thereby establishing both proof-of-concept and a novel translational platform for treatment of CSNB in patients with defects in photoreceptor-to-bipolar signaling.

Novel frameshift mutation in NYX gene in a Russian family with complete congenital stationary night blindness

2019 ◽  
Vol 40 (6) ◽  
pp. 558-563
Author(s):  
Marianna E. Ivanova ◽  
Inna V. Zolnikova ◽  
Ketevan V. Gorgisheli ◽  
Dmitry S. Atarshchikov ◽  
Preetam Ghosh ◽  
...  
Keyword(s):  
Night Blindness ◽  
Frameshift Mutation ◽  
Congenital Stationary Night Blindness

scholarly journals A New Mouse Model for Complete Congenital Stationary Night Blindness Due to Gpr179 Deficiency

2021 ◽  
Vol 22 (9) ◽  
pp. 4424
Author(s):  
Elise Orhan ◽  
Marion Neuillé ◽  
Miguel de Sousa Dias ◽  
Thomas Pugliese ◽  
Christelle Michiels ◽  
...  
Keyword(s):  
Mouse Model ◽  
Night Blindness ◽  
Signal Transmission ◽  
Bipolar Cells ◽  
Congenital Stationary Night Blindness ◽  
Knock Out ◽  
Intron 1 ◽  
Knock Out Mice

Mutations in GPR179 lead to autosomal recessive complete congenital stationary night blindness (cCSNB). This condition represents a signal transmission defect from the photoreceptors to the ON-bipolar cells. To confirm the phenotype, better understand the pathogenic mechanism in vivo, and provide a model for therapeutic approaches, a Gpr179 knock-out mouse model was genetically and functionally characterized. We confirmed that the insertion of a neo/lac Z cassette in intron 1 of Gpr179 disrupts the same gene. Spectral domain optical coherence tomography reveals no obvious retinal structure abnormalities. Gpr179 knock-out mice exhibit a so-called no-b-wave (nob) phenotype with severely reduced b-wave amplitudes in the electroretinogram. Optomotor tests reveal decreased optomotor responses under scotopic conditions. Consistent with the genetic disruption of Gpr179, GPR179 is absent at the dendritic tips of ON-bipolar cells. While proteins of the same signal transmission cascade (GRM6, LRIT3, and TRPM1) are correctly localized, other proteins (RGS7, RGS11, and GNB5) known to regulate GRM6 are absent at the dendritic tips of ON-bipolar cells. These results add a new model of cCSNB, which is important to better understand the role of GPR179, its implication in patients with cCSNB, and its use for the development of therapies.

Challenges and opportunities for the affective sciences.

2018 ◽  
Author(s):  
Andrew S. Fox ◽  
Regina Lapate ◽  
Alexander J. Shackman ◽  
Richard J Davidson
Keyword(s):  
Well Being ◽  
Human Condition ◽  
Emotional States ◽  
Quarter Century ◽  
Core Feature ◽  
Challenges And Opportunities ◽  
The Mind ◽  
The Impact ◽  
Improved Methods ◽  
Health And Well Being

Emotion is a core feature of the human condition, with profound consequences for health, wealth, and wellbeing. Over the past quarter-century, improved methods for manipulating and measuring different features of emotion have yielded steady advances in our scientific understanding emotional states, traits, and disorders. Yet, it is clear that most of the work remains undone. Here, we highlight key challenges facing the field of affective sciences. Addressing these challenges will provide critical opportunities not just for understanding the mind, but also for increasing the impact of the affective sciences on public health and well-being.

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