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1.
BMC Ophthalmol ; 21(1): 360, 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34635090

RESUMO

BACKGROUND: To explore the molecular genetic cause of a four-generation autosomal dominant retinitis pigmentosa family in China. METHODS: Targeted region sequencing was performed to detect the potential mutation, and Sanger sequencing was used to validate the mutation. Multiple sequence alignment from different species was performed by CLUSTALW. The structures of wild-type and the mutant RHO were modeled by Swiss-Model Server and shown using a PyMOL Molecular Graphic system. RESULTS: A novel heterozygous nonsense mutation (c.1015 A > T, p.Lys339Ter, p.K339X) within RHO, which cosegregated with retinitis pigmentosa phenotype was detected in this family. Bioinformatics analysis showed the mutation was located in a highly conserved region, and the mutation was predicted to be pathogenic. CONCLUSIONS: We identified a novel heterozygous nonsense mutation of RHO gene in a Chinese family with retinitis pigmentosa by target region sequencing and our bioinformatics analysis indicated that the mutation is pathogenic. Our results can broaden the spectrum of RHO gene mutation and enrich the phenotype-genotype correlation of retinitis pigmentosa.


Assuntos
Códon sem Sentido , Retinite Pigmentosa , China/epidemiologia , Heterozigoto , Humanos , Linhagem , Retinite Pigmentosa/genética
2.
BMC Bioinformatics ; 22(1): 435, 2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34511072

RESUMO

BACKGROUND: Proteins are integral part of all living beings, which are building blocks of many amino acids. To be functionally active, amino acids chain folds up in a complex way to give each protein a unique 3D shape, where a minor error may cause misfolded structure. Genetic disorder diseases i.e. Alzheimer, Parkinson, etc. arise due to misfolding in protein sequences. Thus, identifying patterns of amino acids is important for inferring protein associated genetic diseases. Recent studies in predicting amino acids patterns focused on only simple protein misfolded disease i.e. Chromaffin Tumor, by association rule mining. However, more complex diseases are yet to be attempted. Moreover, association rules obtained by these studies were not verified by usefulness measuring tools. RESULTS: In this work, we analyzed protein sequences associated with complex protein misfolded diseases (i.e. Sickle Cell Anemia, Breast Cancer, Cystic Fibrosis, Nephrogenic Diabetes Insipidus, and Retinitis Pigmentosa 4) by association rule mining technique and objective interestingness measuring tools. Experimental results show the effectiveness of our method. CONCLUSION: Adopting quantitative experimental methods, this work can form more reliable, useful and strong association rules i. e. dominating patterns of amino acid of complex protein misfolded diseases. Thus, in addition to usual applications, the identified patterns can be more useful in discovering medicines for protein misfolded diseases and thereby may open up new opportunities in medical science to handle genetic disorder diseases.


Assuntos
Retinite Pigmentosa , Sequência de Aminoácidos , Aminoácidos , Humanos , Rodopsina
3.
BMC Ophthalmol ; 21(1): 322, 2021 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-34488687

RESUMO

BACKGROUND: Full-thickness macular hole (FTMH) is a rare complication in retinitis pigmentosa (RP) patients and may increase intraoperative challenges. Furthermore, lens capsular flap transplantation and inverted internal limiting membrane (ILM) flap were reported to close complicated FTMH successfully. Here, we present a case of bilateral advanced RP complicated by a FTMH treated with a novel lens capsular flap transplantation and inverted internal limiting membrane flap. CASE PRESENTATION: A 46-year-old presented to our hospital with a complaint of progressively blurred vision and metamorphopsia in both eyes. Spectral-domain optical coherence tomography revealed a FTMH with retinoschisis in the right eye and another FTMH in the left eye. ILM peeling with inverted ILM flap technique was performed on the right eye and ILM peeling with anterior lens capsular flap technique was performed on the left eye. Post-operative follow-up showed successful closure of the FTMH and improved vision in both eyes. CONCLUSIONS: In our present case, flap-assisted techniques for retinitis pigmentosa with macular hole result in excellent visual and anatomic outcomes.


Assuntos
Perfurações Retinianas , Retinite Pigmentosa , Membrana Basal , Humanos , Pessoa de Meia-Idade , Perfurações Retinianas/diagnóstico , Perfurações Retinianas/etiologia , Perfurações Retinianas/cirurgia , Retinite Pigmentosa/complicações , Estudos Retrospectivos , Tomografia de Coerência Óptica , Acuidade Visual , Vitrectomia
4.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502064

RESUMO

Retinitis pigmentosa (RP) is an inherited retinal disease (IRD) with an overall prevalence of 1 in 4000 individuals. Mutations in EYS (Eyes shut homolog) are among the most frequent causes of non-syndromic autosomal recessively inherited RP and act via a loss-of-function mechanism. In light of the recent successes for other IRDs, we investigated the therapeutic potential of exon skipping for EYS-associated RP. CRISPR/Cas9 was employed to generate zebrafish from which the region encompassing the orthologous exons 37-41 of human EYS (eys exons 40-44) was excised from the genome. The excision of these exons was predicted to maintain the open reading frame and to result in the removal of exactly one Laminin G and two EGF domains. Although the eysΔexon40-44 transcript was found at levels comparable to wild-type eys, and no unwanted off-target modifications were identified within the eys coding sequence after single-molecule sequencing, EysΔexon40-44 protein expression could not be detected. Visual motor response experiments revealed that eysΔexon40-44 larvae were visually impaired and histological analysis revealed a progressive degeneration of the retinal outer nuclear layer in these zebrafish. Altogether, the data obtained in our zebrafish model currently provide no indications for the skipping of EYS exons 37-41 as an effective future treatment strategy for EYS-associated RP.


Assuntos
Modelos Animais de Doenças , Proteínas do Olho/genética , Retinite Pigmentosa/genética , Proteínas de Peixe-Zebra/genética , Animais , Sistemas CRISPR-Cas , Éxons , Proteínas do Olho/química , Proteínas do Olho/metabolismo , Terapia Genética/métodos , Fenótipo , Domínios Proteicos , Retinite Pigmentosa/patologia , Retinite Pigmentosa/terapia , Peixe-Zebra , Proteínas de Peixe-Zebra/química , Proteínas de Peixe-Zebra/metabolismo
9.
Medicina (Kaunas) ; 57(9)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34577815

RESUMO

We report a unique case of coexisting pigmentary retinopathy and ocular toxoplasmosis in a young male patient. A 23-year-old man presented with sudden visual deterioration in the left eye (LE). The fundus findings revealed bone spicule-shaped pigment deposits, a slightly pale optic disc, arteriole constriction, cystoid macular edema with an epiretinal membrane, and two small inflammatory chorioretinal scars in the right eye, with a concentric narrowing of the visual field and a nonrecordable multifocal electroretinogram (ERG). An active inflammatory lesion at the border of a pre-existing chorioretinal scar in the macula was found in the LE, with a central scotoma in the visual field. Moreover, the patient tested positive for anti-Toxoplasma gondii immunoglobulin G antibodies and showed positive results in polymerase chain reaction testing of aqueous humor. Fluorescein angiography revealed hyperfluorescence in the early phase with fluorescein leakage. A multifocal ERG of the LE showed selective loss of responses from the central 10 degrees. Genetic testing revealed heterozygosity in the RP1 and CELSR1 genes. Our case illustrates challenges in the diagnosis of unilateral pigmentary retinopathy. Based on the typical toxoplasmic lesions in the LE and two scars likely caused by inflammation, our patient was diagnosed with pigmentary retinopathy probably related to toxoplasmosis. Genetic consultation did not confirm the diagnosis of retinitis pigmentosa, but more advanced tests might be needed to definitively exclude it.


Assuntos
Retinite Pigmentosa , Toxoplasmose Ocular , Adulto , Eletrorretinografia , Humanos , Masculino , Retina , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/genética , Toxoplasmose Ocular/complicações , Toxoplasmose Ocular/diagnóstico , Campos Visuais , Adulto Jovem
10.
Nat Commun ; 12(1): 4934, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400638

RESUMO

Rhodopsin (RHO) gene mutations are a common cause of autosomal dominant retinitis pigmentosa (ADRP). The need to suppress toxic protein expression together with mutational heterogeneity pose challenges for treatment development. Mirtrons are atypical RNA interference effectors that are spliced from transcripts as short introns. Here, we develop a novel mirtron-based knockdown/replacement gene therapy for the mutation-independent treatment of RHO-related ADRP, and demonstrate efficacy in a relevant mammalian model. Splicing and potency of rhodopsin-targeting candidate mirtrons are initially determined, and a mirtron-resistant codon-modified version of the rhodopsin coding sequence is validated in vitro. These elements are then combined within a single adeno-associated virus (AAV) and delivered subretinally in a RhoP23H knock-in mouse model of ADRP. This results in significant mouse-to-human rhodopsin RNA replacement and is associated with a slowing of retinal degeneration. This provides proof of principle that synthetic mirtrons delivered by AAV are capable of reducing disease severity in vivo.


Assuntos
Terapia Genética , RNA/genética , Retinite Pigmentosa/genética , Retinite Pigmentosa/terapia , Animais , Dependovirus/genética , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Vetores Genéticos , Células HEK293 , Humanos , Camundongos , MicroRNAs/genética , MicroRNAs/metabolismo , RNA/metabolismo , Interferência de RNA , Splicing de RNA , Retina , Degeneração Retiniana , Rodopsina/genética , Rodopsina/metabolismo
11.
BMC Ophthalmol ; 21(1): 302, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399712

RESUMO

BACKGROUND: Retinitis pigmentosa (RP) is a rare, progressive, and hereditary disorder that leads to the progressive loss of vision and visual field, and in some cases blindness. The specific relationship between RP and glaucoma has been debated for decades. METHODS: In this study, we examined a Han RP family with concomitant angle-closure glaucoma (ACG), performed an inductive analysis of their clinical features and assistant results, and applied whole-exome sequencing (WES) technology for a molecular diagnosis. RESULTS: A novel transversion mutation (c.626 T > A) was identified in the peripherin-2 (PRPH2) gene in the proband, resulting in the substitution of Valine to aspartic acid in codon 209. A full ophthalmic examination showed that the proband with the c.626 T > A mutation had a typical RP manifestation, with close angles; however, the proband's elder brother, who lacked the novel mutation, had a normal fundus and open angles. CONCLUSION: Our results extend the genetic mutation spectrum of PRPH2 in RP, and provide evidence to support a genetic correlation between RP and ACG.


Assuntos
Glaucoma de Ângulo Fechado , Retinite Pigmentosa , Idoso , China , Glaucoma de Ângulo Fechado/genética , Humanos , Masculino , Mutação , Linhagem , Periferinas , Retinite Pigmentosa/genética
12.
Adv Exp Med Biol ; 1331: 255-263, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453304

RESUMO

Nerve growth factor (NGF) is a neuroprotective molecule performing not only on central and peripheral neurons but also on cells of the visual system. Human retinitis pigmentosa (RP) is a major cause of blindness worldwide, and a resolute therapy is still lacking. Recent studies have shown that ocular NGF administration exerts a protective action on damaged retinal cells of mammalians, including human beings, although whether NGF also protects photoreceptors is not clear.We used the Royal College of Surgeons (RCS) strain in this study. The RCS is a rodent affected by inherited retinitis pigmentosa (RP) during postnatal life. For this study, we investigated whether ocular NGF treatment reduces/stops the progression of photoreceptor degeneration of rats with RP.This study was carried out in vitro on isolated photoreceptors to further investigate the action on these cells and whether the action is direct or mediated.The results indicate that ocular NGF administration can protect photoreceptors from degeneration into a model developing inherited RP and that the NGF action is direct. In this regard, we observed that binding of NGF to its receptor modulates expression of rhodopsin, a specific biological marker for photoreceptor survival and functionality.Part of the data reported in this chapter has been published in a previous study.


Assuntos
Degeneração Retiniana , Retinite Pigmentosa , Animais , Modelos Animais de Doenças , Fator de Crescimento Neural/genética , Células Fotorreceptoras , Ratos , Retinite Pigmentosa/tratamento farmacológico , Retinite Pigmentosa/genética , Rodopsina/genética
13.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360582

RESUMO

Although considered a rare retinal dystrophy, retinitis pigmentosa (RP) is the primary cause of hereditary blindness. Given its diverse genetic etiology (>3000 mutations in >60 genes), there is an urgent need for novel treatments that target common features of the disease. TLR2 is a key activator of innate immune response. To examine its role in RP progression we characterized the expression profile of Tlr2 and its adaptor molecules and the consequences of Tlr2 deletion in two genetically distinct models of RP: Pde6brd10/rd10 (rd10) and RhoP23H/+ (P23H/+) mice. In both models, expression levels of Tlr2 and its adaptor molecules increased in parallel with those of the proinflammatory cytokine Il1b. In rd10 mice, deletion of a single Tlr2 allele had no effect on visual function, as evaluated by electroretinography. However, in both RP models, complete elimination of Tlr2 attenuated the loss of visual function and mitigated the loss of photoreceptor cell numbers. In Tlr2 null rd10 mice, we observed decreases in the total number of microglial cells, assessed by flow cytometry, and in the number of microglia infiltrating the photoreceptor layers. Together, these results point to TLR2 as a mutation-independent therapeutic target for RP.


Assuntos
Modelos Animais de Doenças , Deleção de Genes , Microglia/metabolismo , Fármacos Neuroprotetores , Degeneração Retiniana/prevenção & controle , Retinite Pigmentosa/complicações , Receptor 2 Toll-Like/fisiologia , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microglia/citologia , Degeneração Retiniana/etiologia , Degeneração Retiniana/metabolismo , Degeneração Retiniana/patologia
15.
Vestn Oftalmol ; 137(4): 145-151, 2021.
Artigo em Russo | MEDLINE | ID: mdl-34410070

RESUMO

The article presents recent worldwide achievements in the area of diagnosis and treatment of inherited retinal degenerations (IRDs) from the standpoint of ophthalmic genetics. Clinical studies conducted in patients with Leber congenital amaurosis and retinitis pigmentosa caused by biallelic mutations in the RPE65 gene have provided the basis for future genes studies associated with IRDs. The conducted studies highlight the importance of fundamental understanding of function of the gene, timely diagnosis and study of natural history of the disease. Currently, surgical techniques are being improved for the efficient delivery of gene preparations to target cells, as well as the criteria for evaluating treatment outcomes.


Assuntos
Amaurose Congênita de Leber , Degeneração Retiniana , Retinite Pigmentosa , Terapia Genética , Humanos , Amaurose Congênita de Leber/diagnóstico , Amaurose Congênita de Leber/genética , Amaurose Congênita de Leber/terapia , Mutação , Degeneração Retiniana/diagnóstico , Degeneração Retiniana/genética , Degeneração Retiniana/terapia , Retinite Pigmentosa/diagnóstico , Retinite Pigmentosa/genética , Retinite Pigmentosa/terapia
16.
Biomolecules ; 11(8)2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34439829

RESUMO

Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well.


Assuntos
Antirreumáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Fator Inibidor de Leucemia/farmacologia , Mutação , Retina/efeitos dos fármacos , Retinite Pigmentosa/tratamento farmacológico , Rodopsina/genética , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/imunologia , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/patologia , NF-kappa B/genética , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Retina/imunologia , Retina/patologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/imunologia , Retinite Pigmentosa/patologia , Rodopsina/deficiência , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de Sinais , Transgenes , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
17.
Transl Vis Sci Technol ; 10(8): 31, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34323953

RESUMO

Purpose: To compare the detection sensitivities of the progression of retinitis pigmentosa (RP) by automated perimetry to obtain the mean deviation (MD) and total point score and by optical coherence tomography (OCT) to determine the residual ellipsoid zone (EZ) length and thickness of retinal layers. Methods: Twenty-two eyes of 22 patients with RP who underwent annual automated perimetry (Humphrey Field Analyzer 10-2) and OCT examinations during the same period more than four times were included. Disease progression was evaluated using linear regression analysis with the least-squares method. The disease progression speed and interinspection fluctuations for the different examinations were compared using standardized values. The progression detection ability factor, defined as the average of the least squares divided by the square of annual change, was used to compare the sensitivities of the examinations for detecting the progression of RP. Results: EZ length showed a high correlation with MD (R = 0.87; P = 1.12E-07) at baseline. Disease progression was detected more frequently using EZ length (12/22 eyes) than using MD (3/22 eyes; P = 0.004) or central retinal thickness (1/11 eyes; P = 0.012). Linear regression using standardized values showed that the EZ length had the fastest annual change, with the smallest least absolute values. EZ length was more sensitive for detecting RP progression than MD, total point score, visual acuity, or central retinal thickness. Conclusions: EZ measurement was sensitive for detecting RP progression, and the results of this study indicate that EZ length is appropriate for end points in clinical trials. Translational Relevance: The study provides a basis for conducting future clinical trials.


Assuntos
Retinite Pigmentosa , Testes de Campo Visual , Humanos , Retina/diagnóstico por imagem , Retinite Pigmentosa/diagnóstico , Tomografia de Coerência Óptica , Acuidade Visual
18.
Free Radic Biol Med ; 174: 1-11, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34324978

RESUMO

Retinitis pigmentosa (RP) is a group of inherited diseases in which mutations result in the initial loss of night vision, followed by complete blindness. There is currently no effective therapeutic option for RP patients. Given the extremely heterogeneous nature of RP, any causative gene-specific therapy would be practical in a small fraction of patients with RP. Non-gene-specific therapeutics that is applicable to the majority of RP patients regardless of causative mutations may have an enormous impact on RP treatment. Several theories including apoptosis, oxidative stress and neuroinflammation have been proposed as possible underlying mechanisms for photoreceptor death in RP. We have designed and synthesized a series of iron-chelating compounds that possess diverse pharmacological properties and can act in a non-gene-specific manner on multiple pathological features ascribed to Alzheimer's disease, Parkinson's disease and RP. In this review, we discuss the multiple effects of several brain-permeable multi target iron-chelating compounds on photoreceptor degeneration in a mouse model of human RP. Specifically, we focus on the anti-apototic, neuroprotective and neurorescue effects of the compound VK28, M30 and VAR10303 on the histologic and functional preservation of photoreceptors in a mouse model of RP. We consider such drugs as potential therapeutic agents for RP patients.


Assuntos
Degeneração Retiniana , Retinite Pigmentosa , Animais , Modelos Animais de Doenças , Humanos , Quelantes de Ferro/uso terapêutico , Camundongos , Células Fotorreceptoras , Retinite Pigmentosa/tratamento farmacológico , Retinite Pigmentosa/genética
19.
Stem Cell Res ; 54: 102449, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34216980

RESUMO

Induced pluripotent stem cell (iPSC) lines were generated from two patients with RDH12 variants. UCLi014-A is from a patient with heterozygous frameshift mutation c.759del p.(Phe254Leufs*24), associated with autosomal dominant retinitis pigmentosa. UCLi015-A is from a patient with homozygous missense mutation c.619A > G p.(Asn207Asp), associated with Leber congenital amaurosis. Fibroblasts were derived from skin biopsies and reprogrammed using integration free episomal reprogramming plasmids. The iPSC lines expressed pluripotency markers, exhibited differentiation potential in vitro and displayed normal karyotypes. These cell lines will act as a tool for disease modelling, enabling comparison of disease mechanisms, identification of therapeutic targets and drug screening.


Assuntos
Células-Tronco Pluripotentes Induzidas , Amaurose Congênita de Leber , Retinite Pigmentosa , Oxirredutases do Álcool/genética , Linhagem Celular , Heterozigoto , Humanos , Amaurose Congênita de Leber/genética , Mutação , Retinite Pigmentosa/genética
20.
Int J Mol Sci ; 22(12)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203967

RESUMO

A substantial proportion of subjects with autosomal recessive retinitis pigmentosa (arRP) or Usher syndrome type II (USH2) lacks a genetic diagnosis due to incomplete USH2A screening in the early days of genetic testing. These cases lack eligibility for optimal genetic counseling and future therapy. USH2A defects are the most frequent cause of USH2 and are also causative in individuals with arRP. Therefore, USH2A is an important target for genetic screening. The aim of this study was to assess unscreened or incompletely screened and unexplained USH2 and arRP cases for (likely) pathogenic USH2A variants. Molecular inversion probe (MIP)-based sequencing was performed for the USH2A exons and their flanking regions, as well as published deep-intronic variants. This was done to identify single nucleotide variants (SNVs) and copy number variants (CNVs) in 29 unscreened or partially pre-screened USH2 and 11 partially pre-screened arRP subjects. In 29 out of these 40 cases, two (likely) pathogenic variants were successfully identified. Four of the identified SNVs and one CNV were novel. One previously identified synonymous variant was demonstrated to affect pre-mRNA splicing. In conclusion, genetic diagnoses were obtained for a majority of cases, which confirms that MIP-based sequencing is an effective screening tool for USH2A. Seven unexplained cases were selected for future analysis with whole genome sequencing.


Assuntos
Análise Custo-Benefício , Éxons/genética , Proteínas da Matriz Extracelular/genética , Sondas Moleculares/metabolismo , Sítios de Splice de RNA/genética , Retinite Pigmentosa/genética , Análise de Sequência de DNA , Síndromes de Usher/genética , Sequência de Bases , Variações do Número de Cópias de DNA/genética , Deleção de Genes , Humanos , Polimorfismo de Nucleotídeo Único/genética , Retinite Pigmentosa/economia , Síndromes de Usher/economia
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