Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the
            <i>GRM6</i>
            gene encoding mGluR6

Dryja, Thaddeus P.; McGee, Terri L.; Berson, Eliot L.; Fishman, Gerald A.; Sandberg, Michael A.; Alexander, Kenneth R.; Derlacki, Deborah J.; Rajagopalan, Aruna S.

doi:10.1073/pnas.0501233102

Cited by 216 publications

(182 citation statements)

References 50 publications

(61 reference statements)

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“…Fourth, recapitulation of the mutation in both mGluR6 and the related mGluR2 receptor in vitro produces a defective protein (Fig 3). Finally, the phenotype is similar both to that described in the mGlur6 knockout mouse and in humans with autosomal recessive congenital stationary night blindness (arCSNB) resulting from a mutation in the GRM6 gene (Dryja et al, 2005;Zeitz et al, 2005;O'Connor et al, 2006). Thus, the conclusion that the identified mutation in Grm6 is responsible for the observed nob 4 visual phenotypes is well-supported.…”

Section: Discussionsupporting

confidence: 61%

Generation, identification and functional characterization of thenob4mutation ofGrm6in the mouse

Pinto¹,

Vitaterna²,

Shimomura³

et al. 2007

Vis Neurosci

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We performed genome-wide chemical mutagenesis of C57BL/6J mice using N-ethyl-Nnitrosourea (ENU). Electroretinographic screening of the third generation offspring revealed two G3 individuals from one G1 family with a normal a-wave but lacking the b-wave that we named nob4.Th e mutation was transmitted with a recessive mode of inheritance and mapped to chromosome 11 in a region containing the Grm6 gene, which encodes a metabotropic glutamate receptor protein, mGluR6. Sequencing confirmed a single nucleotide substitution from T to C in the Grm6 gene. The mutation is predicted to result in substitution of Pro for Ser at position 165 within the extracellular, ligand-binding domain and oocytes expressing the homologous mutation in mGluR6 did not display robust glutamate-induced currents. Retinal mRNA levels for Grm6 were not significantly reduced, but no immunoreactivity for mGluR6 protein was found. Histological and fundus evaluations of nob 4 showed normal retinal morphology. In contrast, the mutation has severe consequences for visual function. In nob4 mice, fewer retinal ganglion cells (RGCs) responded to the onset (ON) of a bright full field stimulus. When ON responses could be evoked, their onset was significantly delayed. Visual acuity and contrast sensitivity, measured with optomotor responses, were reduced under both photopic and scotopic conditions. This mutant will be useful because its phenotype is similar to that of human patients with congenital stationary night blindness and will provide a tool for understanding both retinal circuitry and the role of ganglion cell encoding of visual information.

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Section: Discussionsupporting

confidence: 61%

Generation, identification and functional characterization of thenob4mutation ofGrm6in the mouse

Pinto¹,

Vitaterna²,

Shimomura³

et al. 2007

Vis Neurosci

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“…Like Ezh2, Vsx1, a transcriptional factor regulating terminal differentiation of ON-bipolar cells (26), and Grm6, an ONbipolar cell-specific glutamate metabotropic receptor (27), were also significantly up-regulated at P5 (FDR < 0.05; SI Appendix, Table S1) and gradually fell back to near wild-type levels by P27 (Fig. 6 A and B).…”

Section: Delayed Rod Outer Segment Biogenesis Followed By Early-onsetmentioning

confidence: 95%

Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

Fan

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The polycistronic miR-183/96/182 cluster is preferentially and abundantly expressed in terminally differentiating sensory epithelia. To clarify its roles in the terminal differentiation of sensory receptors in vivo, we deleted the entire gene cluster in mouse germline through homologous recombination. The miR-183/96/ 182 null mice display impairment of the visual, auditory, vestibular, and olfactory systems, attributable to profound defects in sensory receptor terminal differentiation. Maturation of sensory receptor precursors is delayed, and they never attain a fully differentiated state. In the retina, delay in up-regulation of key photoreceptor genes underlies delayed outer segment elongation and possibly mispositioning of cone nuclei in the retina. Incomplete maturation of photoreceptors is followed shortly afterward by early-onset degeneration. Cell biologic and transcriptome analyses implicate dysregulation of ciliogenesis, nuclear translocation, and an epigenetic mechanism that may control timing of terminal differentiation in developing photoreceptors. In both the organ of Corti and the vestibular organ, impaired terminal differentiation manifests as immature stereocilia and kinocilia on the apical surface of hair cells. Our study thus establishes a dedicated role of the miR-183/96/182 cluster in driving the terminal differentiation of multiple sensory receptor cells. M ammalian sensory epithelia, such as those underlying vison, hearing, smell, and balance, consist of ciliated sensory receptor cells. Although highly specialized, similarities in embryonic origin underlie common features in their development (1). Following specification, lineage-restricted postmitotic precursors become structurally and functionally mature through a series of cellular differentiation events, collectively described as terminal differentiation (2). During maturation, sensory receptor cells typically develop microtubule-based primary cilia and in some cases actin-based membrane protrusions on apical membranes, which are sensory organelles, while maintaining apical basal polarity within sensory epithelia. In photoreceptors, for example, the extension of outer segments (OSs), specialized sensory cilia, is central to postmitotic differentiation and necessary for light sensitivity (3). In auditory and vestibular hair cells, the proper formation of hair bundles is indispensable for detecting sound and head positions (4). Similarly, olfactory sensory neurons (OSNs), the odorant receptor cells in the olfactory epithelium, project multiple dendritic cilia into the mucous membrane of the nasal epithelium where olfactory signaling is initiated (5). Mature sensory epithelia are highly structured with specific spatial organization that is tied to their functions. Synchronized planar cell polarity (PCP) of hair cells in the inner ear, for example, provides their directional sensitivity (6), whereas the development of laminar architecture in the retina restricts photoreceptors to proper compartments for efficient wiring with secondary neuro...

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“…The Nob mouse is now sometimes termed the Nob1 mouse because other no b-wave mice, numbering up to Nob4, to date, with different mutations have been characterized. For example, Nob4 (Pinto et al, 2007) is a murine model for patients with mutations in the GRM6 gene encoding mGluR6 (Dryja et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Postreceptoral contributions to the light-adapted ERG of mice lacking b-waves

Shirato

Maeda

Miura

et al. 2008

Experimental Eye Research

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The purpose of this study was to determine the contributions of postreceptoral neurons to the lightadapted ERG of the Nob mouse, a model for complete-type congenital stationary night blindness (CSNB1) that lacks a b-wave from depolarizing bipolar cells. Ganzfeld ERGs were recorded from anesthetized adult control mice, control mice injected intravitreally with L-2-amino-4-phosphonobutyric acid (Control APB mice) to remove On pathway activity, and Nob mice. ERGs also were recorded after PDA (cis-2, 3-piperidine-dicarboxylic acid, 3-5 mM) was injected to block transmission to hyperpolarizing (Off) bipolar and horizontal cells, and all 3rd order neurons. Stimuli were brief (< 4 ms, 0.4 -2.5 log sc td s) and long (200 ms, 2.5 -4.6 log sc td) LED flashes (λmax = 513 nm, on a rod suppressing background (2.6 log sc td). Sinusoidal modulation of the LEDs (mean, 2.6 log sc td; contrast, 100%; 3 to 36 Hz) was used to study flicker ERGs.Brief-flash ERGs of Nob mice presented as long-lasting negative waves with a positive-going intrusion that started about 50 ms after the flash and peaked around 120 ms. Control APB mice had similar responses, and in both cases, PDA removed the positive-going intrusion. For long flashes, PDA removed a small, slow "d-wave" after light offset. With sinusoidal stimulation, the fundamental (F1) amplitude of control mice ERG peaked at 8 Hz (~70 μV). For Nob mice the peak was ~20 μV at 6 Hz before PDA and ~10 μV at 3 Hz or lower after PDA. F1 responses were present up to 21 Hz in control and Nob eyes and 15 Hz in Nob eyes after PDA. Between 3 and 6 Hz, F1 phase was 170°-210° more delayed in Nob than control mice; phase was hardly altered by PDA. With vector analysis, a substantial postreceptoral input to the Nob flicker ERG was revealed. In control mice, the second harmonic (F2) response showed peaks of ~10 μV at 3 Hz and 13 Hz. Nob mice showed almost no F2. In summary, in this study it was found that in Nob mice, postreceptoral neurons from the Off pathway make a positive-going contribution to the light-adapted flash ERG, and contribute substantially to sinusoidal flicker ERG.

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Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6

Cited by 216 publications

References 50 publications

Generation, identification and functional characterization of thenob4mutation ofGrm6in the mouse

Generation, identification and functional characterization of thenob4mutation ofGrm6in the mouse

Maturation arrest in early postnatal sensory receptors by deletion of the miR-183/96/182 cluster in mouse

Postreceptoral contributions to the light-adapted ERG of mice lacking b-waves

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