Retinal Diseases with Ciliopathies

2021 ◽  
pp. 271-278
Keyword(s):  
Retinitis Pigmentosa ◽  
Outer Segment ◽  
Usher Syndrome ◽  
Joubert Syndrome ◽  
Retinal Diseases ◽  
Bardet Biedl Syndrome ◽  
Retinal Photoreceptors ◽  
Underlying Mechanisms ◽  
Larsson Syndrome ◽  
Functional Defects

Ciliopathies are a group of diseases that affects cells containing the cilia organel. Retinal involvement is frequent in ciliopathies. The outer segment of retinal photoreceptors is composed of the cilium. Functional defects limited to the photoreceptors cilia, in particular, are classified as non-syndromic ciliopathies like Leber congenital amaurosis and retinitis pigmentosa. Photoreceptor disease also manifests as a part of syndromic ciliopathies with the involvement of multiple tissues as Usher syndrome, Joubert syndrome, Meckel-Gruber syndrome, Senior-Loken syndrome, Sjögren-Larsson syndrome, Bardet-Biedl syndrome, and Alstrom syndrome. Underlying mechanisms of pathology remain largely unclear in these diseases. Symptoms are treated using current methods. This paper describes the pathogenesis, clinics, diagnosis, and treatment of retinal diseases occurring due to ciliopathy.

scholarly journals Specialization of the photoreceptor transcriptome by Srrm3-dependent microexons is required for outer segment maintenance and vision

2021 ◽  
Author(s):  
Ludovica Ciampi ◽  
Federica Mantica ◽  
Laura Lopez-Blanch ◽  
Cristina Rodríguez-Marin ◽  
Damiano Cianferoni ◽  
...  
Keyword(s):  
Outer Segment ◽  
Cellular Morphology ◽  
Retinal Diseases ◽  
Cell Type ◽  
Vertebrate Retina ◽  
Retinal Photoreceptors ◽  
Cell Type Specific ◽  
And Function ◽  
Shed Light

ABSTRACTRetinal photoreceptors differ in their transcriptomic profiles from other neuronal subtypes, likely as a reflection of their unique cellular morphology and function in the detection of light thorough the ciliary outer segment. We discovered a new layer of this molecular specialization by revealing that the vertebrate retina expresses the largest number of tissue-enriched microexons of all tissue types. A subset of these microexons is included exclusively in photoreceptor transcripts, particularly in genes involved in cilia biogenesis and in vesicle-mediated transport. This microexon program is regulated by Srrm3, a paralog of the neural microexon regulator Srrm4. Despite both proteins positively regulate retina microexons in vitro, only Srrm3 is highly expressed in mature photoreceptors and its deletion in zebrafish results in widespread downregulation of microexon inclusion, severe photoreceptor alterations and blindness. These results shed light into photoreceptor’s transcriptomic specialization and functionality, uncovering new cell type-specific roles for Srrm3 and microexons with implication for retinal diseases.

scholarly journals Ciliary Genes arl13b, ahi1 and cc2d2a Differentially Modify Expression of Visual Acuity Phenotypes but do not Enhance Retinal Degeneration due to Mutation of cep290 in Zebrafish

2019 ◽  
Author(s):  
Emma M. Lessieur ◽  
Ping Song ◽  
Gabrielle C. Nivar ◽  
Ellen M. Piccillo ◽  
Joseph Fogerty ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Retinal Degeneration ◽  
Joubert Syndrome ◽  
Genetic Modifiers ◽  
Photoreceptor Degeneration ◽  
Optokinetic Response ◽  
Bardet Biedl Syndrome ◽  
Leber Congenital Amaurosis ◽  
Outer Segments ◽  
Rhodopsin Kinase

ABSTRACTMutations in the gene Centrosomal Protein 290 kDa (CEP290) result in multiple ciliopathies ranging from the neonatal lethal disorder Meckel-Gruber Syndrome to multi-systemic disorders such as Joubert Syndrome and Bardet-Biedl Syndrome to nonsyndromic diseases like Leber Congenital Amaurosis (LCA) and retinitis pigmentosa. Results from model organisms and human genetics studies, have suggest that mutations in genes encoding protein components of the transition zone (TZ) and other cilia-associated proteins can function as genetic modifiers and be a source for CEP290 pleiotropy. We investigated the zebrafish cep290fh297/fh297 mutant, which encodes a nonsense mutation (p.Q1217*). This mutant is viable as adults, exhibits scoliosis, and undergoes a slow, progressive cone degeneration. The cep290fh297/fh297 mutants showed partial mislocalization of the transmembrane protein rhodopsin but not of the prenylated proteins rhodopsin kinase (GRK1) or the rod transducin subunit GNB1. Surprisingly, photoreceptor degeneration did not trigger proliferation of Müller glia, but proliferation of rod progenitors in the outer nuclear layer was significantly increased. To determine if heterozygous mutations in other cilia genes could exacerbate retinal degeneration, we bred cep290fh297/fh297 mutants to arl13b, ahi1, and cc2d2a mutant zebrafish lines. While cep290fh297/fh297 mutants lacking a single allele of these genes did not exhibit accelerated photoreceptor degeneration, loss of one alleles of arl13b or ahi1 reduced visual performance in optokinetic response assays at 5 days post fertilization. Our results indicate that the cep290fh297/fh297 mutant is a useful model to study the role of genetic modifiers on photoreceptor degeneration in zebrafish and to explore how progressive photoreceptor degeneration influences regeneration in adult zebrafish.Nonstandard abbreviationsBBSBardet-Biedl SyndromeCOScone outer segmentsDpfDays post fertilizationGNB1rod transducin β subunitGRK1rhodopsin kinaseJTBSJoubert SyndromeLCALeber Congenital AmaurosisMKSMeckel SyndromeNPHPnephronophthisisOKRoptokinetic responsePNApeanut agglutinin lectinROSrod outer segmentsRP2Retinitis Pigmentosa 2

scholarly journals Accumulation of non-outer segment proteins in the outer segment underlies photoreceptor degeneration in Bardet–Biedl syndrome

2015 ◽  
Vol 112 (32) ◽  
pp. E4400-E4409 ◽  
Author(s):  
Poppy Datta ◽  
Chantal Allamargot ◽  
Joseph S. Hudson ◽  
Emily K. Andersen ◽  
Sajag Bhattarai ◽  
...  
Keyword(s):  
Protein Trafficking ◽  
Outer Segment ◽  
Primary Cilia ◽  
Leucine Zipper ◽  
Photoreceptor Cells ◽  
Photoreceptor Degeneration ◽  
Photoreceptor Outer Segment ◽  
Bardet Biedl Syndrome ◽  
Major Function ◽  
Underlying Mechanisms

Compartmentalization and polarized protein trafficking are essential for many cellular functions. The photoreceptor outer segment (OS) is a sensory compartment specialized for phototransduction, and it shares many features with primary cilia. As expected, mutations disrupting protein trafficking to cilia often disrupt protein trafficking to the OS and cause photoreceptor degeneration. Bardet–Biedl syndrome (BBS) is one of the ciliopathies associated with defective ciliary trafficking and photoreceptor degeneration. However, precise roles of BBS proteins in photoreceptor cells and the underlying mechanisms of photoreceptor degeneration in BBS are not well understood. Here, we show that accumulation of non-OS proteins in the OS underlies photoreceptor degeneration in BBS. Using a newly developed BBS mouse model [Leucine zipper transcription factor-like 1 (Lztfl1)/Bbs17 mutant], isolated OSs, and quantitative proteomics, we determined 138 proteins that are enriched more than threefold in BBS mutant OS. In contrast, only eight proteins showed a more than threefold reduction. We found striking accumulation of Stx3 and Stxbp1/Munc18-1 and loss of polarized localization of Prom1 within the Lztfl1 and Bbs1 mutant OS. Ultrastructural analysis revealed that large vesicles are formed in the BBS OS, disrupting the lamellar structure of the OS. Our findings suggest that accumulation (and consequent sequestration) of non-OS proteins in the OS is likely the primary cause of photoreceptor degeneration in BBS. Our data also suggest that a major function of BBS proteins in photoreceptors is to transport proteins from the OS to the cell body or to prevent entry of non-OS proteins into the OS.

Study of Patterns of Inheritance in Affected Patients with Retinitis Pigmentosa in Iranian Populations

2020 ◽  
Author(s):  
Fahimeh Beigi ◽  
Mohammad Yahya Vahidi Mehrjardi ◽  
Masoud Reza Manaviat ◽  
Hamid Reza Ashrafzadeh ◽  
Nasrin Ghasemi
Keyword(s):  
Retinitis Pigmentosa ◽  
Autosomal Recessive ◽  
Usher Syndrome ◽  
Field Measurements ◽  
Fundus Photography ◽  
Medical Sciences ◽  
Bardet Biedl Syndrome ◽  
Clinical Center ◽  
Preconception Genetic Counseling ◽  
Inherited Retinal Degeneration

Background and Aims: Retinitis pigmentosa (RP) is the most common form of inherited retinal degeneration, photoreceptors loss of which in the retina causes visual loss. The purpose of the present study was to determine patterns of inheritance in RP patients in Yazd to help the health professional for designing suitable laboratory testing for the high risk families. Materials and Methods: Thirty affected RP patients referred to the Genetics Clinic of Research and Clinical Center for Infertility, in Yazd Medical Sciences University from 2010-2016. Full medical and family histories were taken from all family members. Ophthalmology examinations were performed in members of the families including electroretinogram, fundus photography, visual-field measurements and spectral-domain optical coherence tomography. Results: In this study, the most commonly pattern was inheritance of autosomal recessive. The patients were diagnosed as having Usher syndrome, Bardet-Biedl syndrome and Posterior Column Ataxia with Retinitis Pigmentosa. The study also reported a patient with Kreans-Sayer syndrome, a mitochondrial disease. Conclusions: We identified different inheritance patterns in RP patients. Identifying patterns of inheritance is important for pre-marriage and preconception genetic counseling.

scholarly journals USH2A-Related Retinitis Pigmentosa: Staging of Disease Severity and Morpho-Functional Studies

Diagnostics ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 213
Author(s):  
Benedetto Falsini ◽  
Giorgio Placidi ◽  
Elisa De Siena ◽  
Maria Cristina Savastano ◽  
Angelo Maria Minnella ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Usher Syndrome ◽  
Collaborative Study ◽  
Staging System ◽  
International Standards ◽  
Full Field ◽  
Functional Studies ◽  
Cumulative Score

Usher syndrome type 2A (USH2A) is a genetic disease characterized by bilateral neuro-sensory hypoacusia and retinitis pigmentosa (RP). While several methods, including electroretinogram (ERG), describe retinal function in USH2A patients, structural alterations can be assessed by optical coherence tomography (OCT). According to a recent collaborative study, RP can be staged considering visual acuity, visual field area and ellipsoid zone (EZ) width. The aim of this study was to retrospectively determine RP stage in a cohort of patients with USH2A gene variants and to correlate the results with age, as well as additional functional and morphological parameters. In 26 patients with established USH2A genotype, RP was staged according to recent international standards. The cumulative staging score was correlated with patients’ age, amplitude of full-field and focal flicker ERGs, and the OCT-measured area of sub-Retinal Pigment Epithelium (RPE) illumination (SRI). RP cumulative score (CS) was positively correlated (r = 0.6) with age. CS was also negatively correlated (rho = −0.7) with log10 ERG amplitudes and positively correlated (r = 0.5) with SRI. In USH2A patients, RP severity score is correlated with age and additional morpho-functional parameters not included in the international staging system and can reliably predict their abnormality at different stages of disease.

scholarly journals A 13-year-old Female with Bardet- Biedl Syndrome - A Case Report

2015 ◽  
Vol 26 (1) ◽  
pp. 31-34
Author(s):  
Syed Nesar Ahmed ◽  
Md Abu Shahin ◽  
Romal Chowdhury ◽  
Alamgir Mustak Ahammad ◽  
Md Nahiduzzaman Shazzad ◽  
...  
Keyword(s):  
Case Report ◽  
Retinitis Pigmentosa ◽  
Rare Disease ◽  
Clinical Features ◽  
Night Blindness ◽  
Learning Difficulties ◽  
Laboratory Findings ◽  
Bardet Biedl Syndrome

Bardet Biedl syndrome is a rare disease. A case report is presented here where a 13 years old girl presented with obesity, night blindness, learning difficulties and polydactyly. Obesity and night blindness started from since childhood. Her milestones of development were normal but having some learning difficulties. Her parents are healthy as well as her siblings. On examination she looks apathy, extreme obese, having polydactyly and retinitis pigmentosa and high B.P. On laboratory findings there is only dyslipidaemia. On the basis of clinical features she was diagnosed as a case of Bardet-Biedl syndrome.Bangladesh J Medicine Jan 2015; 26 (1) : 31-34

scholarly journals Usher syndrome gene mutation spectrum in Russian patients

2020 ◽  
pp. 38-39
Author(s):  
М.Е. Иванова ◽  
А.М. Демчинский ◽  
В.С. Каймонов ◽  
И.В. Миронова ◽  
И.В. Володин ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinitis Pigmentosa ◽  
Gene Mutation ◽  
Clinical Diagnosis ◽  
Usher Syndrome ◽  
Gene Mutations ◽  
Mutation Spectrum ◽  
Initial Sample ◽  
New Mutations

Изучение спектра мутаций и совершенствование диагностики синдрома Ашера (СА) особо актуальны в связи с разрабатываемыми подходами к генной терапии заболевания. Среди 46 пациентов с признаками СА патогенные мутации выявлены нами у 40 (87%) пациентов. СА I и II типов определены у 26% и 57% пробандов исходной выборки, соответственно. У пациентов с СА I выявлены мутации в генах MYO7A (73%), CDH23 (7%), PCDH15 (7%), и USH1C (13%). Наибольшую частоту показала мутация MYO7A p.Q18*. Описано 6 новых мутаций в гене MYO7A, и две - в гене PCDH15. У пациентов с СА II выявлена 21 мутация гена USH2A, 5 из которых описаны впервые. Наибольшую частоту показала мутация USH2A p.W3955*. У двух пациентов выявлены мутации в генах несиндромального пигментного ретинита RHO и RPGR, что позволило уточнить клинический диагноз. Studying the mutation spectrum and improvement of molecular verification of the Usher syndrome (USH) are of particular relevance as gene therapy emerges. Among 46 patients with signs of Usher syndrome we identified mutations in 40 (85%) patients, establishing a diagnosis of USH1 and USH2 for 26% and 57% of the probands of the initial sample, respectively. Patients with USH1 showed mutations in the MYO7A (73%), CDH23 (7%), PCDH15 (7%), and USH1C (13%) genes. MYO7A p.Q18* mutation showed the highest frequency. We have identified 6 new mutations in the MYO7A gene, and 2 in the PCDH15 gene. In USH2 patients, 21 USH2A gene mutations were identified, 5 of which are novel. The USH2A mutation p.W3955* was most frequent. Two patients showed mutations in the non-syndromic retinitis pigmentosa genes RHO and RPGR, which made it possible to clarify the clinical diagnosis.

Comprehensive screening of the USH2A gene in Usher syndrome type II and non-syndromic recessive retinitis pigmentosa

2004 ◽  
Vol 79 (2) ◽  
pp. 167-173 ◽  
Author(s):  
Babak Jian Seyedahmadi ◽  
Carlo Rivolta ◽  
Julia A. Keene ◽  
Eliot L. Berson ◽  
Thaddeus P. Dryja
Keyword(s):  
Retinitis Pigmentosa ◽  
Usher Syndrome ◽  
Syndrome Type ◽  
Type Ii ◽  
Usher Syndrome Type
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