Inherited retinal diseases (IRDs) represent a collection of phenotypically and genetically diverse conditions. IRDs phenotype(s) can be isolated to the eye or can involve multiple tissues. These ...conditions are associated with diverse forms of inheritance, and variants within the same gene often can be associated with multiple distinct phenotypes. Such aspects of the IRDs highlight the difficulty met when establishing a genetic diagnosis in patients. Here we provide an overview of cutting-edge next-generation sequencing techniques and strategies currently in use to maximise the effectivity of IRD gene screening. These techniques have helped researchers globally to find elusive causes of IRDs, including copy number variants, structural variants, new IRD genes and deep intronic variants, among others. Resolving a genetic diagnosis with thorough testing enables a more accurate diagnosis and more informed prognosis and should also provide information on inheritance patterns which may be of particular interest to patients of a child-bearing age. Given that IRDs are heritable conditions, genetic counselling may be offered to help inform family planning, carrier testing and prenatal screening. Additionally, a verified genetic diagnosis may enable access to appropriate clinical trials or approved medications that may be available for the condition.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Animal cognition research aims to understand animal minds by using a diverse range of methods across an equally diverse range of species. Throughout its history, the field has sought to mitigate ...various biases that occur when studying animal minds, from experimenter effects to anthropomorphism. Recently, there has also been a focus on how common scientific practices might affect the reliability and validity of published research. Usually, these issues are discussed in the literature by a small group of scholars with a specific interest in the topics. This study aimed to survey a wider range of animal cognition researchers to ask about their attitudes towards classic and contemporary issues facing the field. Two-hundred and ten active animal cognition researchers completed our survey, and provided answers on questions relating to bias, replicability, statistics, publication, and belief in animal cognition. Collectively, researchers were wary of bias in the research field, but less so in their own work. Over 70% of researchers endorsed Morgan's canon as a useful principle but many caveated this in their free-text responses. Researchers self-reported that most of their studies had been published, however they often reported that studies went unpublished because they had negative or inconclusive results, or results that questioned "preferred" theories. Researchers rarely reported having performed questionable research practices themselves-however they thought that other researchers sometimes (52.7% of responses) or often (27.9% of responses) perform them. Researchers near unanimously agreed that replication studies are important but too infrequently performed in animal cognition research, 73.0% of respondents suggested areas of animal cognition research could experience a 'replication crisis' if replication studies were performed. Consistently, participants' free-text responses provided a nuanced picture of the challenges animal cognition research faces, which are available as part of an open dataset. However, many researchers appeared concerned with how to interpret negative results, publication bias, theoretical bias and reliability in areas of animal cognition research. Collectively, these data provide a candid overview of barriers to progress in animal cognition and can inform debates on how individual researchers, as well as organizations and journals, can facilitate robust scientific research in animal cognition.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
RP2 mutations cause a severe form of X-linked retinitis pigmentosa (XLRP). The mechanism of RP2-associated retinal degeneration in humans is unclear, and animal models of RP2 XLRP do not recapitulate ...this severe phenotype. Here, we developed gene-edited isogenic RP2 knockout (RP2 KO) induced pluripotent stem cells (iPSCs) and RP2 patient-derived iPSC to produce 3D retinal organoids as a human retinal disease model. Strikingly, the RP2 KO and RP2 patient-derived organoids showed a peak in rod photoreceptor cell death at day 150 (D150) with subsequent thinning of the organoid outer nuclear layer (ONL) by D180 of culture. Adeno-associated virus-mediated gene augmentation with human RP2 rescued the degeneration phenotype of the RP2 KO organoids, to prevent ONL thinning and restore rhodopsin expression. Notably, these data show that 3D retinal organoids can be used to model photoreceptor degeneration and test potential therapies to prevent photoreceptor cell death.
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•Isogenic RP2 knockouts match the phenotype of RP2 patient-derived organoids•Retinal organoids from RP2 nulls undergo rod photoreceptor cell death•Cell death correlates with rod photoreceptor differentiation•AAV gene therapy improved photoreceptor viability and increased rhodopsin expression
Cheetham and colleagues show that 3D retinal organoids lacking the RP2 protein develop rod photoreceptor degeneration that can be prevented with AAV gene augmentation for RP2.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The challenge of developing gene therapies for genetic forms of blindness is heightened by the heterogeneity of these conditions. However, mechanistic commonalities indicate key pathways that may be ...targeted in a gene-independent approach. Mitochondrial dysfunction and axon degeneration are common features of many neurodegenerative conditions including retinal degenerations. Here we explore the neuroprotective effect afforded by the absence of sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1), a prodegenerative NADase, in a rotenone-induced mouse model of retinal ganglion cell loss and visual dysfunction.
knockout mice retain visual function after rotenone insult, displaying preservation of photopic negative response following rotenone treatment in addition to significantly higher optokinetic response measurements than wild type mice following rotenone. Protection of spatial vision is sustained over time in both sexes and is accompanied by increased RGC survival and additionally preservation of axonal density in optic nerves of
mice insulted with rotenone. Primary fibroblasts extracted from
mice demonstrate an increased oxygen consumption rate relative to those from wild type mice, with significantly higher basal, maximal and spare respiratory capacity. Collectively, our data indicate that
ablation increases mitochondrial bioenergetics and confers histological and functional protection in vivo in the mouse retina against mitochondrial dysfunction, a hallmark of many neurodegenerative conditions including a variety of ocular disorders.
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Leber hereditary optic neuropathy (LHON) is a mitochondrially inherited form of visual dysfunction caused by mutations in several genes encoding subunits of the mitochondrial respiratory ...NADH-ubiquinone oxidoreductase complex (complex I). Development of gene therapies for LHON has been impeded by genetic heterogeneity and the need to deliver therapies to the mitochondria of retinal ganglion cells (RGCs), the cells primarily affected in LHON. The therapy under development entails intraocular injection of a nuclear yeast gene NADH-quinone oxidoreductase (NDI1) that encodes a single subunit complex I equivalent and as such is mutation independent. NDI1 is imported into mitochondria due to an endogenous mitochondrial localisation signal. Intravitreal injection represents a clinically relevant route of delivery to RGCs not previously used for NDI1. In this study, recombinant adenoassociated virus (AAV) serotype 2 expressing NDI1 (AAV-NDI1) was shown to protect RGCs in a rotenone-induced murine model of LHON. AAV-NDI1 significantly reduced RGC death by 1.5-fold and optic nerve atrophy by 1.4-fold. This led to a significant preservation of retinal function as assessed by manganese enhanced magnetic resonance imaging and optokinetic responses. Intraocular injection of AAV-NDI1 overcomes many barriers previously associated with developing therapies for LHON and holds great therapeutic promise for a mitochondrial disorder for which there are no effective therapies.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Retinitis pigmentosa (RP), the group of hereditary conditions involving death of retinal photoreceptors, represents the most prevalent cause of visual handicap among working populations in developed ...countries. Here we provide an overview of the molecular pathologies associated with such disorders, from which it becomes clearly apparent that RP is one of the most genetically heterogeneous of hereditary conditions for which molecular pathologies have so far been elucidated. While heterogeneity of such magnitude would appear to represent a major impediment to the development of therapeutics, mutation‐independent approaches to therapy are being developed to effectively by‐pass such diversity in genetic aetiology. The implications of such technologies in terms of therapeutic intervention in RP, and indeed other genetically heterogeneous conditions, will be addressed.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
When given privileged information of an object's true location, adults often overestimate the likelihood that a protagonist holding a false belief will search in the correct location for that object. ...This type of egocentric bias is often labelled the 'curse of knowledge'. Interestingly, the magnitude of this bias may be modulated by the social distance between the perspective taker and target. However, this social distance effect has yet to be fully demonstrated when adults reason about false beliefs. Using a continuous false belief task, we investigated i) whether adults were biased by their own knowledge when reasoning about another's false belief, ii) whether the magnitude of this egocentric bias was modulated by social distance, and iii) whether this social distance effect extended to a heterospecific out-group, namely a dog. To test these hypotheses we conducted three experiments. In Experiment 1 (N = 283), we used an established continuous false belief task, in Experiment 2 (N = 281) we modified this task, and Experiment 3 (N = 744) was a direct replication of Experiment 2. Across these experiments, the curse of knowledge effect was reliably replicated when adults mentalised about an in-group protagonist, and replicated in two of the three studies (Experiments 1 and 3) when adults mentalised about out-group protagonists. In an internal-meta analysis, the curse of knowledge effect was present across all conditions, and there was no effect of social distance. Hence, overall these data are not consistent with the hypothesis that social distance modulates adults' egocentric biases when reasoning about false beliefs. The finding that egocentric biases of a similar magnitude were observed when adults mentalised about an in-group protagonist and a dog suggests that interpersonal dissimilarity is not in itself sufficient to reduce egocentric bias when reasoning about false beliefs.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Although rare, inherited retinal degenerations (IRDs) are the most common reason for blind registration in the working age population. They are highly genetically heterogeneous (>300 known genetic ...loci), and confirmation of a molecular diagnosis is a prerequisite for many therapeutic clinical trials and approved treatments. First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of ≈70-80%, leaving the remaining more challenging cases to be resolved by second-tier testing methods. This study describes the phenotypic reassessment of patients with a negative result from first-tier pNGS and the rationale, outcomes, and cost of second-tier genetic testing approaches. Removing non-IRD cases from consideration and utilizing case-appropriate second-tier genetic testing techniques, we genetically resolved 56% of previously unresolved pedigrees, bringing the overall resolve rate to 92% (388/423). At present, pNGS remains the most cost-effective first-tier approach for the molecular assessment of diverse IRD populations Second-tier genetic testing should be guided by clinical (i.e., reassessment, multimodal imaging, electrophysiology), and genetic (i.e., single alleles in autosomal recessive disease) indications to achieve a genetic diagnosis in the most cost-effective manner.
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To describe the clinical phenotype and genetic cause underlying the disease pathology in a pedigree (affected n = 9) with X-linked retinoschisis (XLRS1) due to a novel RS1 mutation and to assess ...suitability for novel therapies using multimodal imaging.
The Irish National Registry for Inherited Retinal Degenerations (Target 5000) is a program including clinical history and examination with multimodal retinal imaging, electrophysiology, visual field testing and genetic analysis. Nine affected patients were identified across 3 generations of an XLRS1 pedigree. DNA sequencing was performed for each patient, one carrier female and one unaffected relative. Pedigree mapping revealed a further 4 affected males.
All affected patients had a history of reduced visual acuity and dyschromatopsia; however, the severity of phenotype varied widely between the nine affected subjects. The stage of disease was classified as previously described. Phenotypic severity was not linearly correlated with age. A novel RS1 (Xp22.2) mutation was detected (NM_000330: c.413C > A) resulting in a p.Thr138Asn substitution. Protein modelling demonstrated a change in higher order protein folding that is likely pathogenic.
This family has a novel gene mutation in RS1 with clinical evidence of XLRS1. A proportion of the older generation has developed end-stage macular atrophy; however, the severity is variable. Confirmation of genotype in the affected grandsons of this pedigree in principle may enable them to avail of upcoming gene therapies, provided there is anatomical evidence (from multimodal imaging) of potentially reversible early stage disease.
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