Rhodopsin p.N78I dominant mutation causing sectorial retinitis pigmentosa in a pedigree with intrafamilial clinical heterogeneity

Objective

The purpose of this study was to determine the molecular basis of retinitis pigmentosa (RP) in a 4 affected sib-family segregating this retinal phenotype.

Methods

Affected sibs underwent complete ophthalmologic examination including funduscopic inspection, electroretinogram, fluorescein angiography, visual field measurement, and optical coherence tomography. Both parents were deceased after their sixties and were reported with no visual handicap. Molecular analysis included direct nucleotide sequencing of the rhodopsin gene (RHO), at chromosome 3q21–q24, in DNA from a total of 4 affected sibs. A total of 200 ethnically matched alleles were included as mutation controls.

Results

Sector RP was clinically documented in this family. Wide phenotypic variability was observed with visual acuities ranging from 20/20 to 20/200 and variable funduscopic appearance. Molecular analysis disclosed a c.233A>T mutation at RHO exon 1, predicting a missense p.N78I substitution.

Conclusions

Even though RP can be caused by mutations in a variety of genes, the RHO gene was chosen to be investigated in this RP family since it has been previously associated to sector disease. This case exemplifies the value of guiding RP molecular analysis based on funduscopic features.     

Retinal Anatomy of hatchling sea turtles: Anatomical specializations and behavioral correlates

The eyes of three species of sea turtle hatchlings (loggerheads, green turtles, and leatherbacks) possess visual streaks, areas of densely packed ganglion cells running along the antero‐posterior retinal axis. These probably function to provide heightened visual acuity along the horizon. The vertical extent and absolute concentration of cells within the streak, compared to the rest of the retina, differ among the species. Leatherbacks have an additional specialized region (area temporalis) that might enhance their ability to detect prey below them in the water column. Green turtles and loggerheads, but not leatherbacks, show compensatory eye reflexes that keep the visual streak horizontal. Species differences in retinal structure and eye reflexes probably reflect their unique specializations in visual ecology and behaviour.     

Inhibition of complement alternative pathway suppresses experimental autoimmune anterior uveitis by modulating T cell responses

The objective of the current study was to delineate the pathway of complement activation that is crucial for the induction of experimental autoimmune anterior uveitis (EAAU). We studied the development of EAAU in melanin-associated antigen (MAA)-sensitized Lewis rats treated with antibody against C4 or factor B. Control animals received isotype IgG control. Antibody against C4 had no effect on EAAU, and all of the animals developed EAAU similar to those injected with control IgG. In contrast, EAAU was completely inhibited in all MAA-sensitized Lewis rats injected with factor B antibody. Treatment with anti-factor B antibody resulted in suppression of ocular complement activation. Adoptive transfer of T lymphocytes harvested from draining lymph nodes of donor animals treated with anti-factor B did not transfer EAAU to naïve syngenic rats. Anti-factor B antibody inhibited the ability of MAA-specific CD4⁺ T cells to proliferate (in vitro) in response to MAA in a dose-dependent manner. Level of TNF-α and IFN-γ decreased in the presence of anti-factor B. Collectively, our results provide the novel finding that complement activation via the alternative pathway contributes to intraocular inflammation in EAAU, and anti-factor B-mediated inhibition of EAAU is due to diminished antigen-specific CD4⁺ T cell responses to MAA. Our findings explain the interactions between the complement system and T cells that are critical for the induction of EAAU and may lead to the development of therapy for idiopathic anterior uveitis based on selective blockade of the alternative pathway.     

Probing mechanisms of photoreceptor degeneration in a new mouse model of the common form of autosomal dominant retinitis pigmentosa due to P23H opsin mutations

Rhodopsin, the visual pigment mediating vision under dim light, is composed of the apoprotein opsin and the chromophore ligand 11-cis-retinal. A P23H mutation in the opsin gene is one of the most prevalent causes of the human blinding disease, autosomal dominant retinitis pigmentosa. Although P23H cultured cell and transgenic animal models have been developed, there remains controversy over whether they fully mimic the human phenotype; and the exact mechanism by which this mutation leads to photoreceptor cell degeneration remains unknown. By generating P23H opsin knock-in mice, we found that the P23H protein was inadequately glycosylated with levels 1-10% that of wild type opsin. Moreover, the P23H protein failed to accumulate in rod photoreceptor cell endoplasmic reticulum but instead disrupted rod photoreceptor disks. Genetically engineered P23H mice lacking the chromophore showed accelerated photoreceptor cell degeneration. These results indicate that most synthesized P23H protein is degraded, and its retinal cytotoxicity is enhanced by lack of the 11-cis-retinal chromophore during rod outer segment development.     

用显示器测量办公亮度环境下的人眼对比度敏感视觉特性

对比度敏感是描述人眼视觉系统空间特性的主要指标之一,对比度敏感函数是反映不同条件下的对比度敏感与空间频率之间的关系。人眼对比度敏感数据的测量受到环境亮度较大的影响,为了研究常用办公环境条件下的人眼对比度敏感情况,对6位青年在环境亮度分别为153,312,470 cd/m2和暗室条件下,在距离为2米处观测11种空间频率的矩形光栅进行测量,光栅用显示器进行显示,其平均亮度分别为60和90 cd/m2。实验结果表明,对于相同频率的光栅,人眼对比度敏感程度随着环境亮度的增加而减小,而且人眼在暗室环境下比在办公环境条件下对亮度光栅更敏感;但是在观测平均亮度为60cd/m2的光栅时,人眼特殊地对在环境亮度为312 cd/m2的条件下更敏感。     

Crystal structure of rhodopsin: a template for cone visual pigments and other G protein-coupled receptors

The crystal structure of rhodopsin has provided the first three-dimensional molecular model for a G-protein-coupled receptor (GPCR). Alignment of the molecular model from the crystallographic structure with the helical axes seen in cryo-electron microscopic (cryo-EM) studies provides an opportunity to investigate the properties of the molecule as a function of orientation and location within the membrane. In addition, the structure provides a starting point for modeling and rational experimental approaches of the cone pigments, the GPCRs in cone cells responsible for color vision. Homology models of the cone pigments provide a means of understanding the roles of amino acid sequence differences that shift the absorption maximum of the retinal chromophore in the environments of different opsins.     

Spectral sensitivity differences in two Mysis sibling species (Crustacea, Mysida): Adaptation or phylogenetic constraints?

The variation in eye spectral sensitivities of the closely related mysid species Mysis relicta Lovén, 1862 and Mysis salemaai Audzijonyt? and Väinölä, 2005 was studied in sympatric and allopatric populations from the brackish Baltic Sea and from two lakes representing different light environments. In the Baltic Sea the maximum spectral sensitivity of M. relicta, measured by the electroretinogram (ERG) technique, was shifted by ca 20 nm to longer wavelengths than in M. salemaai (564 and 545 nm, respectively). The spectral sensitivity of M. salemaai was closer to that of marine mysid species, which is consistent with its broader euryhalinity and the presumed longer brackish-water history. The species-specific sensitivities in the Baltic Sea were not affected by regional differences in light environments. In two lake populations of M. relicta, the spectral sensitivity was further shifted by ca 28 nm towards the longer wavelengths compared with the conspecific Baltic Sea populations. The spectral sensitivities in the four M. relicta populations were not correlated to the current light conditions, but rather to the phylogeographic histories and fresh- vs. brackish-water environments. A framework to further explore factors affecting spectral sensitivities in Mysis is suggested.     

Role of statistical symmetries in sensory coding: an optimal scale invariant code for vision

The visual system is the most studied sensory pathway, which is partly because visual stimuli have rather intuitive properties. There are reasons to think that the underlying principle ruling coding, however, is the same for vision and any other type of sensory signal, namely the code has to satisfy some notion of optimality--understood as minimum redundancy or as maximum transmitted information. Given the huge variability of natural stimuli, it would seem that attaining an optimal code is almost impossible; however, regularities and symmetries in the stimuli can be used to simplify the task: symmetries allow predicting one part of a stimulus from another, that is, they imply a structured type of redundancy. Optimal coding can only be achieved once the intrinsic symmetries of natural scenes are understood and used to the best performance of the neural encoder. In this paper, we review the concepts of optimal coding and discuss the known redundancies and symmetries that visual scenes have. We discuss in depth the only approach which implements the three of them known so far: translational invariance, scale invariance and multiscaling. Not surprisingly, the resulting code possesses features observed in real visual systems in mammals.     

Modelling attention in individual cells leads to a system with realistic saccade behaviours

Single cell recordings in monkey inferior temporal cortex (IT) and area V4 during visual search tasks indicate that modulation of responses by the search target object occurs in the late portion of the cell’s sensory response (Chelazzi et al. in J Neurophysiol 80:2918–2940, 1998; Cereb Cortex 11:761–772, 2001) whereas attention to a spatial location influences earlier responses (Luck et al. in J Neurophysiol 77:24–42, 1997). Previous computational models have not captured differences in the latency of these attentional effects and yet the more protracted development of the object-based effect could have implications for behaviour. We present a neurodynamic biased competition model of visual attention in which we aimed to model the timecourse of spatial and object-based attention in order to simulate cellular responses and saccade onset times observed in monkey recordings. In common with other models, a top-down prefrontal signal, related to the search target, biases activity in the ventral visual stream. However, we conclude that this bias signal is more complex than modelled elsewhere: the latency of object-based effects in V4 and IT, and saccade onset, can be accurately simulated when the target object feedback bias consists of a sensory response component in addition to a mnemonic response. These attentional effects in V4 and IT cellular responses lead to a system that is able to produce search scan paths similar to those observed in monkeys and humans, with attention being guided to locations containing behaviourally relevant stimuli. This work demonstrates that accurate modelling of the timecourse of single cell responses can lead to biologically realistic behaviours being demonstrated by the system as a whole.     

Polarization vision in crayfish motion detectors

Motion detector interneurons were examined to determine their responsiveness to the motion of polarized light images (i.e. images segmented by spatial variations in e-vector angle). Computer generated images were displayed as intensity contrasts or polarization contrasts on a modified LCD projection panel. The stimuli included the motion of a single stripe (45 degrees -55 degrees /s) and the global motion of a square wave grating (3.3 degrees /s). Neurons were impaled in the medulla interna. Of the neurons which exhibited a directional response to the motion of intensity contrast stimuli, about 2/3 were also directional in the response to polarized light images. Transient (nondirectional) stimuli included looming and jittery motions. The responses to the transient motions of the polarized light images were roughly comparable to those elicited by intensity contrast. The results imply that behavioral responses to polarized light images (i.e. optokinetic and defense reflexes) may have a basis in the polarization sensitivity and synaptic organization of the medulla interna.