Homozygosity mapping reveals novel and known mutations in Pakistani families with inherited retinal dystrophies

Abstract Inherited retinal dystrophies (IRDs), displaying pronounced genetic and clinical heterogeneity, comprise of a broad range of diseases characterized by progressive retinal cell death and gradual loss of vision. By the combined use of whole exome sequencing (WES), SNP-array and WES-based homozygosity mapping, as well as directed DNA sequencing (Sanger), we have identified nine pathogenic variants in six genes (ABCA4, RPE65, MERTK, USH2A, SPATA7, TULP1) in 10 consanguineous Iranian families. Six of the nine identified variants were novel, including a putative founder mutation in ABCA4 (c.3260A>G, p.Glu1087Gly), detected in two families from Northeastern Iran. Our findings provide additional information to the molecular pathology of IRDs in Iran, hopefully contributing to better genetic counselling and patient management in the respective families from this country.

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An inherited night blindness in Wiltshire sheep

Veterinary Pathology ◽

10.1177/03009858211067461 ◽

2022 ◽

pp. 030098582110674

Author(s):

Hayley Hunt ◽

Keren E. Dittmer ◽

Dorian J. Garrick ◽

Robert A. Fairley ◽

Stephen J. Heap ◽

...

Keyword(s):

Retinal Degeneration ◽

Night Blindness ◽

Autosomal Recessive Inheritance ◽

Homozygosity Mapping ◽

Pedigree Analysis ◽

Rod Photoreceptors ◽

Progressive Retinal Atrophy ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies ◽

Retinal Blood Vessels

Twelve cases of adult-onset blindness were identified in a flock of 130 polled Wiltshire sheep in New Zealand over a 3-year period. Affected sheep developed night blindness between 2 and 3 years of age, which progressed to complete blindness by 4 to 5 years of age. Fundic examination findings included progressive tapetal hyperreflectivity and attenuation of retinal blood vessels. Histologically, the retinas had a selective loss of rod photoreceptors with initial preservation of cone photoreceptors. Retinal degeneration was not accompanied by any other ocular or central nervous system abnormalities, and pedigree analysis suggested an inherited basis for the disease. Mating an affected Wiltshire ram to 2 affected Wiltshire ewes resulted in 6 progeny that all developed retinal degeneration by 2 years of age, while mating of the same affected ram to 6 unaffected ewes resulted in 8 unaffected progeny, consistent with autosomal recessive inheritance. Homozygosity mapping of 5 affected Wiltshire sheep and 1 unaffected Wiltshire sheep using an OvineSNP50 Genotyping BeadChip revealed an identical-by-descent region on chromosome 5, but none of the genes within this region were considered plausible candidate genes. Whole-genome sequencing of 2 affected sheep did not reveal any significant mutations in any of the genes associated with retinitis pigmentosa in humans or progressive retinal atrophy in dogs. Inherited progressive retinal degeneration affecting rod photoreceptors has not been previously reported in sheep, but this disease has several similarities to inherited retinal dystrophies in other species.

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NRL S50T mutation and the importance of ‘founder effects’ in inherited retinal dystrophies

European Journal of Human Genetics ◽

10.1038/sj.ejhg.5200538 ◽

2000 ◽

Vol 8 (10) ◽

pp. 783-787 ◽

Cited By ~ 7

Author(s):

David AR Bessant ◽

Annette M Payne ◽

Catherine Plant ◽

Alan C Bird ◽

Anand Swaroop ◽

...

Keyword(s):

Founder Effects ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies

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Bestrophinopathies: perspectives on clinical disease, Bestrophin-1 function and developing therapies

Therapeutic Advances in Ophthalmology ◽

10.1177/2515841421997191 ◽

2021 ◽

Vol 13 ◽

pp. 251584142199719

Author(s):

Simranjeet Singh Grewal ◽

Joseph J. Smith ◽

Amanda-Jayne F. Carr

Keyword(s):

Pigment Epithelium ◽

Retinal Pigment ◽

Induced Pluripotent Stem Cell ◽

Underlying Disease ◽

Incomplete Penetrance ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies ◽

High Acuity ◽

Induced Pluripotent

Bestrophinopathies are a group of clinically distinct inherited retinal dystrophies that typically affect the macular region, an area synonymous with central high acuity vision. This spectrum of disorders is caused by mutations in bestrophin1 ( BEST1), a protein thought to act as a Ca2+-activated Cl- channel in the retinal pigment epithelium (RPE) of the eye. Although bestrophinopathies are rare, over 250 individual pathological mutations have been identified in the BEST1 gene, with many reported to have various clinical expressivity and incomplete penetrance. With no current clinical treatments available for patients with bestrophinopathies, understanding the role of BEST1 in cells and the pathological pathways underlying disease has become a priority. Induced pluripotent stem cell (iPSC) technology is helping to uncover disease mechanisms and develop treatments for RPE diseases, like bestrophinopathies. Here, we provide a comprehensive review of the pathophysiology of bestrophinopathies and highlight how patient-derived iPSC-RPE are being used to test new genomic therapies in vitro.

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Carbon Dot Nanoparticles: Exploring the Potential Use for Gene Delivery in Ophthalmic Diseases

Nanomaterials ◽

10.3390/nano11040935 ◽

2021 ◽

Vol 11 (4) ◽

pp. 935

Author(s):

Manas R. Biswal ◽

Sofia Bhatia

Keyword(s):

Gene Delivery ◽

Therapeutic Option ◽

Retinal Dystrophy ◽

Retinal Cells ◽

Adeno Associated Virus ◽

Inherited Retinal Dystrophies ◽

Retinal Dystrophies ◽

Efficient Gene ◽

New Type ◽

Viral Nanoparticles

Ocular gene therapy offers significant potential for preventing retinal dystrophy in patients with inherited retinal dystrophies (IRD). Adeno-associated virus (AAV) based gene transfer is the most common and successful gene delivery approach to the eye. These days, many studies are using non-viral nanoparticles (NPs) as an alternative therapeutic option because of their unique properties and biocompatibility. Here, we discuss the potential of carbon dots (CDs), a new type of nanocarrier for gene delivery to the retinal cells. The unique physicochemical properties of CDs (such as optical, electronic, and catalytic) make them suitable for biosensing, imaging, drug, and gene delivery applications. Efficient gene delivery to the retinal cells using CDs depends on various factors, such as photoluminescence, quantum yield, biocompatibility, size, and shape. In this review, we focused on different approaches used to synthesize CDs, classify CDs, various pathways for the intake of gene-loaded carbon nanoparticles inside the cell, and multiple studies that worked on transferring nucleic acid in the eye using CDs.

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Nutraceutical Supplementation Ameliorates Visual Function, Retinal Degeneration, and Redox Status in rd10 Mice

Antioxidants ◽

10.3390/antiox10071033 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1033

Author(s):

Lorena Olivares-González ◽

Sheyla Velasco ◽

Isabel Campillo ◽

David Salom ◽

Emilio González-García ◽

...

Keyword(s):

Oxidative Stress ◽

Retinal Degeneration ◽

Antioxidant Properties ◽

Photoreceptor Cells ◽

Redox Status ◽

Inherited Retinal Dystrophies ◽

Stress Markers ◽

Retinal Dystrophies ◽

Progressive Degeneration ◽

Light Stimuli

Background: Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptor cells. Ocular redox status is altered in RP suggesting oxidative stress could contribute to their progression. In this study, we investigated the effect of a mixture of nutraceuticals with antioxidant properties (NUT) on retinal degeneration in rd10 mice, a model of RP. Methods: NUT was orally administered to rd10 mice from postnatal day (PD) 9 to PD18. At PD18 retinal function and morphology were examined by electroretinography (ERG) and histology including TUNEL assay, immunolabeling of microglia, Müller cells, and poly ADP ribose polymers. Retinal redox status was determined by measuring the activity of antioxidant enzymes and some oxidative stress markers. Gene expression of the cytokines IL-6, TNFα, and IL-1β was assessed by real-time PCR. Results: NUT treatment delayed the loss of photoreceptors in rd10 mice partially preserving their electrical responses to light stimuli. Moreover, it ameliorated redox status and reduced inflammation including microglia activation, upregulation of cytokines, reactive gliosis, and PARP overactivation. Conclusions: NUT ameliorated retinal functionality and morphology at early stages of RP in rd10 mice. This formulation could be useful as a neuroprotective approach for patients with RP in the future.

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