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1.
Genes (Basel) ; 15(6)2024 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-38927702

RESUMO

Inherited retinal diseases (IRDs) represent a frequent cause of blindness in children and adults. As a consequence of the phenotype and genotype heterogeneity of the disease, it is difficult to have a specific diagnosis without molecular testing. To date, over 340 genes and loci have been associated with IRDs. We present the molecular finding of 191 individuals with IRD, analyzed by targeted next-generation sequencing (NGS). For 67 of them, we performed a family segregation study, considering a total of 126 relatives. A total of 359 variants were identified, 44 of which were novel. Genetic diagnostic yield was 41%. However, after stratifying the patients according to their clinical suspicion, diagnostic yield was higher for well-characterized diseases such as Stargardt disease (STGD), at 65%, and for congenital stationary night blindness 2 (CSNB2), at 64%. Diagnostic yield was higher in the patient group where family segregation analysis was possible (68%) and it was higher in younger (55%) than in older patients (33%). The results of this analysis demonstrated that targeted NGS is an effective method for establishing a molecular genetic diagnosis of IRDs. Furthermore, this study underlines the importance of segregation studies to understand the role of genetic variants with unknow pathogenic role.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Distrofias Retinianas , Doença de Stargardt , Humanos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Masculino , Feminino , Distrofias Retinianas/genética , Distrofias Retinianas/diagnóstico , Adulto , Doença de Stargardt/genética , Linhagem , Criança , Pessoa de Meia-Idade , Cegueira Noturna/genética , Oftalmopatias Hereditárias/genética , Adolescente , Mutação , Degeneração Macular/genética , Miopia/genética , Pré-Escolar , Fenótipo , Adulto Jovem , Idoso , Doenças Genéticas Ligadas ao Cromossomo X
2.
Invest Ophthalmol Vis Sci ; 65(6): 35, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38916884

RESUMO

Purpose: To investigate the characteristics of microperimetry and optical coherence tomography (OCT) in congenital stationary night blindness (CSNB), as well as their structure-function association. Methods: This cross-sectional study included 32 eyes from 32 participants with CSNB, comprising 18 with complete CSNB and 14 with incomplete CSNB, along with 36 eyes from 36 CSNB-unaffected controls matched for age, sex, and spherical equivalent. Using MP-3 microperimetry, central retinal sensitivity was assessed within a 20° field, distributed across six concentric rings (0°, 2°, 4°, 6°, 8°, and 10°). OCT was used to analyze retinal and choroidal thickness. The study aimed to assess the overall and ring-wise retinal sensitivity, as well as choroidal and retinal thickness in CSNB and CSNB-unaffected controls, with a secondary focus on the relationship between retinal sensitivity and microstructural features on OCT. Results: In comparison with CSNB-unaffected subjects, the overall and ring-wise retinal sensitivity as well as choroidal thickness were reduced in patients with CSNB (P < 0.001). Moreover, the central sensitivity in incomplete CSNB group was lower than in complete CSNB group (25.72 ± 3.93 dB vs. 21.92 ± 4.10 dB; P < 0.001). The retinal thickness in the CSNB group was thinner outside the fovea compared with the CSNB-unaffected group. Multiple mixed regression analyses revealed that point-to-point retinal sensitivity was significantly correlated with BCVA (P = 0.002) and the corresponding retinal thickness (P = 0.004). Conclusions: Examination of retinal sensitivity and OCT revealed different spatial distribution profiles in CSNB and its subtypes. In CSNB eyes, retinal sensitivity on microperimetry was associated with retinal thickness on OCT.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Miopia , Cegueira Noturna , Retina , Tomografia de Coerência Óptica , Testes de Campo Visual , Campos Visuais , Humanos , Tomografia de Coerência Óptica/métodos , Feminino , Masculino , Estudos Transversais , Cegueira Noturna/fisiopatologia , Cegueira Noturna/diagnóstico , Testes de Campo Visual/métodos , Campos Visuais/fisiologia , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Retina/fisiopatologia , Retina/diagnóstico por imagem , Adulto , Miopia/fisiopatologia , Miopia/diagnóstico , Adulto Jovem , Oftalmopatias Hereditárias/fisiopatologia , Oftalmopatias Hereditárias/diagnóstico , Acuidade Visual/fisiologia , Adolescente , Miopia Degenerativa/fisiopatologia , Miopia Degenerativa/complicações , Miopia Degenerativa/diagnóstico , Criança , Corioide/patologia , Corioide/diagnóstico por imagem , Corioide/fisiopatologia
3.
Proc Natl Acad Sci U S A ; 121(22): e2408254121, 2024 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-38768361
4.
Proc Natl Acad Sci U S A ; 121(21): e2404763121, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38743626

RESUMO

Congenital stationary night blindness (CSNB) is an inherited retinal disease that causes a profound loss of rod sensitivity without severe retinal degeneration. One well-studied rhodopsin point mutant, G90D-Rho, is thought to cause CSNB because of its constitutive activity in darkness causing rod desensitization. However, the nature of this constitutive activity and its precise molecular source have not been resolved for almost 30 y. In this study, we made a knock-in (KI) mouse line with a very low expression of G90D-Rho (equal in amount to ~0.1% of normal rhodopsin, WT-Rho, in WT rods), with the remaining WT-Rho replaced by REY-Rho, a mutant with a very low efficiency of activating transducin due to a charge reversal of the highly conserved ERY motif to REY. We observed two kinds of constitutive noise: one being spontaneous isomerization (R*) of G90D-Rho at a molecular rate (R* s-1) 175-fold higher than WT-Rho and the other being G90D-Rho-generated dark continuous noise comprising low-amplitude unitary events occurring at a very high molecular rate equivalent in effect to ~40,000-fold of R* s-1 from WT-Rho. Neither noise type originated from G90D-Opsin because exogenous 11-cis-retinal had no effect. Extrapolating the above observations at low (0.1%) expression of G90D-Rho to normal disease exhibited by a KI mouse model with RhoG90D/WTand RhoG90D/G90D genotypes predicts the disease condition very well quantitatively. Overall, the continuous noise from G90D-Rho therefore predominates, constituting the major equivalent background light causing rod desensitization in CSNB.


Assuntos
Oftalmopatias Hereditárias , Doenças Genéticas Ligadas ao Cromossomo X , Miopia , Cegueira Noturna , Rodopsina , Animais , Cegueira Noturna/genética , Cegueira Noturna/metabolismo , Oftalmopatias Hereditárias/genética , Oftalmopatias Hereditárias/metabolismo , Camundongos , Rodopsina/genética , Rodopsina/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Miopia/genética , Miopia/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/patologia , Escuridão , Transducina/genética , Transducina/metabolismo , Técnicas de Introdução de Genes , Modelos Animais de Doenças
6.
Orphanet J Rare Dis ; 19(1): 101, 2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38448886

RESUMO

BACKGROUND: Congenital stationary night blindness (CSNB) is an inherited retinal disorder. Most of patients have myopia. This study aims to describe the clinical and genetic characteristics of fifty-nine patients with CSNB and investigate myopic progression under genetic cause. RESULTS: Sixty-five variants were detected in the 59 CSNB patients, including 32 novel and 33 reported variants. The most frequently involved genes were NYX, CACNA1F, and TRPM1. Myopia (96.61%, 57/59) was the most common clinical finding, followed by nystagmus (62.71%, 37/59), strabismus (52.54%, 31/59), and nyctalopia (49.15%, 29/59). An average SE of -7.73 ± 3.37 D progressed to -9.14 ± 2.09 D in NYX patients with myopia, from - 2.24 ± 1.53 D to -4.42 ± 1.43 D in those with CACNA1F, and from - 5.21 ± 2.89 D to -9.24 ± 3.16 D in those with TRPM1 during the 3-year follow-up; the TRPM1 group showed the most rapid progression. CONCLUSIONS: High myopia and strabismus are distinct clinical features of CSNB that are helpful for diagnosis. The novel variants identified in this study will further expand the knowledge of variants in CSNB and help explore the molecular mechanisms of CSNB.


Assuntos
Oftalmopatias Hereditárias , Doenças Genéticas Ligadas ao Cromossomo X , Miopia , Cegueira Noturna , Estrabismo , Canais de Cátion TRPM , Humanos , Cegueira Noturna/genética , Miopia/genética , Retina , Canais de Cátion TRPM/genética
7.
Klin Monbl Augenheilkd ; 241(3): 259-265, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38508214

RESUMO

Retinal dystrophies linked to the RPE65 gene are mostly fast-progressing retinal diseases, with childhood onset of night blindness and progressive visual loss up to the middle adult age. Rare phenotypes linked to this gene are known with congenital stationary night blindness or slowly progressing retinitis pigmentosa, as well as an autosomal dominant c.1430A>G (p.Asp477Gly) variant. This review gives an overview of the current knowledge of the clinical phenotypes, as well as experience with the efficacy and safety of the approved gene augmentation therapy voretigene neparvovec.


Assuntos
Cegueira Noturna , Distrofias Retinianas , Retinose Pigmentar , Adulto , Criança , Humanos , cis-trans-Isomerases/genética , Terapia Genética , Mutação , Cegueira Noturna/terapia , Fenótipo , Distrofias Retinianas/diagnóstico , Distrofias Retinianas/genética , Distrofias Retinianas/terapia , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Retinose Pigmentar/terapia
8.
Int J Mol Sci ; 25(5)2024 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-38474172

RESUMO

Aland island eye disease (AIED), an incomplete form of X-linked congenital stationary night blindness (CSNB2A), and X-linked cone-rod dystrophy type 3 (CORDX3) display many overlapping clinical findings. They result from mutations in the CACNA1F gene encoding the α1F subunit of the Cav1.4 channel, which plays a key role in neurotransmission from rod and cone photoreceptors to bipolar cells. Case report: A 57-year-old Caucasian man who had suffered since his early childhood from nystagmus, nyctalopia, low visual acuity and high myopia in both eyes (OU) presented to expand the diagnostic process, because similar symptoms had occurred in his 2-month-old grandson. Additionally, the patient was diagnosed with protanomalous color vision deficiency, diffuse thinning, and moderate hypopigmentation of the retina. Optical coherence tomography of the macula revealed retinoschisis in the right eye and foveal hypoplasia in the left eye. Dark-adapted (DA) 3.0 flash full-field electroretinography (ffERG) amplitudes of a-waves were attenuated, and the amplitudes of b-waves were abolished, which resulted in a negative pattern of the ERG. Moreover, the light-adapted 3.0 and 3.0 flicker ffERG as well as the DA 0.01 ffERG were consistent with severely reduced responses OU. Genetic testing revealed a hemizygous form of a stop-gained mutation (c.4051C>T) in exon 35 of the CACNA1F gene. This pathogenic variant has so far been described in combination with a phenotype corresponding to CSNB2A and CORDX3. This report contributes to expanding the knowledge of the clinical spectrum of CACNA1F-related disease. Wide variability and the overlapping clinical manifestations observed within AIED and its allelic disorders may not be explained solely by the consequences of different mutations on proteins. The lack of distinct genotype-phenotype correlations indicates the presence of additional, not yet identified, disease-modifying factors.


Assuntos
Albinismo Ocular , Oftalmopatias Hereditárias , Doenças Genéticas Ligadas ao Cromossomo X , Miopia , Cegueira Noturna , Doenças Retinianas , Retinose Pigmentar , Retinosquise , Masculino , Humanos , Pré-Escolar , Lactente , Pessoa de Meia-Idade , Canais de Cálcio Tipo L/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/genética , Retina/metabolismo , Mutação
9.
Doc Ophthalmol ; 148(2): 115-120, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38206458

RESUMO

PURPOSE: Bi-allelic variants in CABP4 are associated with congenital cone-rod synaptic disorder, which has also been classified, electrophysiologically, as incomplete congenital stationary night blindness (iCSNB). We describe clinical findings in a patient who demonstrated an unusual macular optical coherence tomography (OCT) phenotype, not previously reported in this condition. METHODS: Our patient underwent multimodal retinal imaging, international standard full-field ERG testing and whole genome sequencing. RESULTS: The patient was a 60-year-old woman with non-progressive visual impairment since birth, nystagmus and preference for dim lighting. Clinical fundus examination was unremarkable. OCT imaging revealed a hypo-reflective zone under an elevated fovea in both eyes. ERGs showed an electronegative DA10 response, with severely abnormal light-adapted responses. Whole genome sequencing revealed homozygosity for a known pathogenic variant in CABP4. No variants were found in other genes that could explain the patient's phenotype. CONCLUSIONS: OCT findings of foveal elevation and an underlying hypo-reflective zone are novel in this condition. Whilst the clinical history was similar to achromatopsia and other cone dysfunction syndromes, ERG findings suggested disease associated with CACNA1F or CABP4. As CACNA1F is X-linked, CABP4 was more likely, and confirmed on genetic testing. The patient saw better in dim light, confirming that night blindness is not a feature of CABP4-associated disease. Our case highlights the value of ERGs in discriminating between causes of cone dysfunction, and extends the range of retinal imaging phenotypes reported in this disorder.


Assuntos
Cegueira Noturna , Tomografia de Coerência Óptica , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia de Coerência Óptica/métodos , Eletrorretinografia , Retina , Cegueira Noturna/diagnóstico , Cegueira Noturna/genética , Células Fotorreceptoras de Vertebrados/patologia , Mutação , Proteínas de Ligação ao Cálcio/genética
11.
CNS Neurosci Ther ; 30(3): e14474, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-37721401

RESUMO

BACKGROUND AND AIMS: Sleep is predicted as a key modulator of cognition, but the underlying mechanisms are poorly understood. In this study, we investigated the effects of melatonin on chronic rapid eye movement sleep deprivation (CRSD)-induced cognitive impairment and circadian dysfunction in rat models. METHODS: Thirty-six Sprague-Dawley male rats were divided into three groups: CRSD with saline treatment, CRSD with chronic melatonin injection (20 mg/kg/day), and non-sleep-deprived control. The cognitive behavioral tests as well as the expression of clocks and HDAC3 were evaluated in all groups. RESULTS: CRSD significantly reduced recognition index in novel object location, increased escape latency and distance traveling in Morris water maze while melatonin treatment attenuated CRSD-induced hippocampal-dependent spatial learning and memory deficits. Furthermore, the mRNAs of brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1(Bmal1) and circadian locomotor output cycles kaput (Clock) were globally down-regulated by CRSD with constant intrinsic oscillation in both hippocampus and peripheral blood. The protein levels of hippocampal Bmal1, Clock, and HDAC3 were also remarkably down-regulated following CRSD. Melatonin treatment reversed CRSD-induced alterations of Bmal1/Clock and HDAC3 on both mRNA levels and protein levels. CONCLUSIONS: Our data indicate that melatonin treatment attenuates CRSD-induced cognitive impairment via regulating HDAC3-Bmal1/Clock interaction. These findings explore a broader understanding of the relationship between sleep and cognition and provide a potential new therapeutic target for cognitive impairment.


Assuntos
Disfunção Cognitiva , Oftalmopatias Hereditárias , Doenças Genéticas Ligadas ao Cromossomo X , Melatonina , Miopia , Cegueira Noturna , Masculino , Ratos , Animais , Melatonina/farmacologia , Melatonina/uso terapêutico , Privação do Sono/complicações , Privação do Sono/tratamento farmacológico , Ratos Sprague-Dawley , Cognição , Ritmo Circadiano/genética
12.
J Physiol ; 601(23): 5317-5340, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37864560

RESUMO

In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), synchronous oscillating retinal ganglion cells (RGCs) lead to oscillatory eye movements, i.e. nystagmus. Given the specific expression of mGluR6 and Cav 1.4 in the photoreceptor to bipolar cell synapses, as well as their clinical association with CSNB, we hypothesize that Grm6nob3 and Cav 1.4-KO mutants show, like the Nyxnob mouse, oscillations in both their RGC activity and eye movements. Using multi-electrode array recordings of RGCs and measurements of the eye movements, we demonstrate that Grm6nob3 and Cav 1.4-KO mice also show oscillations of their RGCs as well as a nystagmus. Interestingly, the preferred frequencies of RGC activity as well as the eye movement oscillations of the Grm6nob3 , Cav 1.4-KO and Nyxnob mice differ among mutants, but the neuronal activity and eye movement behaviour within a strain remain aligned in the same frequency domain. Model simulations indicate that mutations affecting the photoreceptor-bipolar cell synapse can form a common cause of the nystagmus of CSNB by driving oscillations in RGCs via AII amacrine cells. KEY POINTS: In Nyxnob mice, a model for congenital nystagmus associated with congenital stationary night blindness (CSNB), their oscillatory eye movements (i.e. nystagmus) are caused by synchronous oscillating retinal ganglion cells. Here we show that the same mechanism applies for two other CSNB mouse models - Grm6nob3 and Cav 1.4-KO mice. We propose that the retinal ganglion cell oscillations originate in the AII amacrine cells. Model simulations show that by only changing the input to ON-bipolar cells, all phenotypical differences between the various genetic mouse models can be reproduced.


Assuntos
Miopia , Cegueira Noturna , Nistagmo Congênito , Camundongos , Animais , Cegueira Noturna/genética , Cegueira Noturna/metabolismo , Miopia/genética , Miopia/metabolismo , Células Ganglionares da Retina/fisiologia , Mutação , Eletrorretinografia
13.
Int J Mol Sci ; 24(18)2023 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-37762657

RESUMO

Choroideremia is an X-linked retinal degeneration resulting from the progressive, centripetal loss of photoreceptors and choriocapillaris, secondary to the degeneration of the retinal pigment epithelium. Affected individuals present in late childhood or early teenage years with nyctalopia and progressive peripheral visual loss. Typically, by the fourth decade, the macula and fovea also degenerate, resulting in advanced sight loss. Currently, there are no approved treatments for this condition. Gene therapy offers the most promising therapeutic modality for halting or regressing functional loss. The aims of the current review are to highlight the lessons learnt from clinical trials in choroideremia, review endpoints, and propose a future strategy for clinical trials.


Assuntos
Coroideremia , Cegueira Noturna , Criança , Adolescente , Humanos , Coroideremia/genética , Coroideremia/terapia , Corioide , Fóvea Central , Terapia Genética
14.
Am J Ophthalmol ; 254: 87-103, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37327959

RESUMO

PURPOSE: To describe the genetic and clinical spectrum of GUCY2D-associated retinopathies and to accurately establish their prevalence in a large cohort of patients. DESIGN: Retrospective case series. METHODS: Institutional study of 47 patients from 27 unrelated families with retinal dystrophies carrying disease-causing GUCY2D variants from the Fundación Jiménez Díaz hospital dataset of 8000 patients. Patients underwent ophthalmological examination and molecular testing by Sanger or exome sequencing approaches. Statistical and principal component analyses were performed to determine genotype-phenotype correlations. RESULTS: Four clinically different associated phenotypes were identified: 66.7% of families with cone/cone-rod dystrophy, 22.2% with Leber congenital amaurosis, 7.4% with early-onset retinitis pigmentosa, and 3.7% with congenital night blindness. Twenty-three disease-causing GUCY2D variants were identified, including 6 novel variants. Biallelic variants accounted for 28% of patients, whereas most carried dominant alleles associated with cone/cone-rod dystrophy. The disease onset had statistically significant differences according to the functional variant effect. Patients carrying GUCY2D variants were projected into 3 subgroups by allelic combination, disease onset, and presence of nystagmus or night blindness. In contrast to patients with the most severe phenotype of Leber congenital amaurosis, 7 patients with biallelic GUCY2D had a later and milder rod form with night blindness in infancy as the first symptom. CONCLUSIONS: This study represents the largest GUCY2D cohort in which 4 distinctly different phenotypes were identified, including rare intermediate presentations of rod-dominated retinopathies. We established that GUCY2D is linked to about 1% of approximately 3000 molecularly characterized families of our cohort. All of these findings are critical for defining cohorts for inclusion in future clinical trials.


Assuntos
Distrofias de Cones e Bastonetes , Amaurose Congênita de Leber , Cegueira Noturna , Humanos , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/genética , Genótipo , Amaurose Congênita de Leber/diagnóstico , Amaurose Congênita de Leber/genética , Mutação , Cegueira Noturna/diagnóstico , Cegueira Noturna/genética , Linhagem , Fenótipo , Estudos Retrospectivos
15.
Stem Cell Res ; 69: 103101, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37126974

RESUMO

Biallelic variants in the USH2A gene cause Usher syndrome type 2 (USH2), in which patients' symptoms are progressive night blindness, reduced visual field, decreased central vision and sensorineural hearing impairment. There is currently no effective drug for USH2. In this study, we isolated peripheral blood mononuclear cells from a patient with USH2. The pluripotency of induced cells was verified by the presence of cell surface markers, the expression of pluripotent genes, and the formation of teratomas. The generation of this induced pluripotent stem cell line provides an effective way to study USH2, such as disease modeling and drug screening. Usher syndrome type 2 (USH2) is a genetic disease mainly caused by biallelic variants in the USH2A gene. Patients usually present with progressive night blindness, reduced visual field, and then reduced central vision. Patients with USH2 also have sensorineural hearing impairment. There is currently no effective treatment for USH2, and the pathogenesis is still unclear. Therefore, it is of great significance to study the pathogenic mechanism of USH2A gene variants for the study of therapeutic targets. In this study, we obtained induced pluripotent stem cell (iPSC) line containing USH2A gene variants. We isolated mononuclear cells from the peripheral blood of patient and established iPSCs by reprogramming with nonintegrating vectors. We then confirmed the pluripotency of our generated iPSCs through the detection of multiple cell surface markers, the expression of pluripotency-related genes, and the ability to form teratomas with three germ layer structures in vivo. The generation of this cell line will facilitate research on USH2 disease and will play a role that cannot be underestimated in future organoid generation, drug screening, and research on drug targets as well as mechanisms.


Assuntos
Células-Tronco Pluripotentes Induzidas , Cegueira Noturna , Síndromes de Usher , Humanos , Síndromes de Usher/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Mutação , Proteínas da Matriz Extracelular/genética , Proteínas da Matriz Extracelular/metabolismo
16.
Vision Res ; 209: 108260, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37220680

RESUMO

Congenital stationary night blindness (CSNB) is a group of inherited retinal diseases in which either rod-to-ON-bipolar cell (ON-BC) signaling, or rod function is affected leading to impaired vision under low light conditions. One type of CSNB is associated with defects in genes (NYX, GRM6, TRPM1, GPR179, and LRIT3) involved in the mGluR6 signaling cascade at the ON-BC dendritic tips. We have previously characterized a canine model of LRIT3-CSNB and demonstrated short-term safety and efficacy of an ON-BC targeting AAV-LRIT3 (AAVK9#4-shGRM6-cLRIT3-WPRE) gene therapy. Herein, we demonstrate long-term functional recovery and molecular restoration following subretinal injection of the ON-BC targeting AAV-LRIT3 vector in all eight treated eyes for up to 32 months. Following subretinal administration of the therapeutic vector, expression of the LRIT3 transgene, as well as restoration of mGluR6 signaling cascade member TRPM1, were confirmed in the outer plexiform layer (OPL) of the treated area. However, further investigation of the transgene LRIT3 transcript expression by RNA in situ hybridization (RNA-ISH) revealed off-target expression in non-BCs including the photoreceptors, inner nuclear, and ganglion cell layers, despite the use of a mutant AAVK9#4 capsid and an improved mGluR6 promoter designed to specifically transduce and promote expression in ON-BCs. While the long-term therapeutic potential of AAVK9#4-shGRM6-cLRIT3-WPRE is promising, we highlight the necessity for further optimization of AAV-LRIT3 therapy in the canine CSNB model prior to its clinical application.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Miopia , Cegueira Noturna , Animais , Cães , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Cegueira Noturna/genética , Cegueira Noturna/terapia , Cegueira Noturna/metabolismo , Retina , Miopia/genética , Miopia/terapia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Eletrorretinografia
17.
Int J Mol Sci ; 24(8)2023 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-37108642

RESUMO

Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies characterized by the degeneration of rod photoreceptors, followed by the degeneration of cone photoreceptors. As a result of photoreceptor degeneration, affected individuals experience gradual loss of visual function, with primary symptoms of progressive nyctalopia, constricted visual fields and, ultimately, central vision loss. The onset, severity and clinical course of RP shows great variability and unpredictability, with most patients already experiencing some degree of visual disability in childhood. While RP is currently untreatable for the majority of patients, significant efforts have been made in the development of genetic therapies, which offer new hope for treatment for patients affected by inherited retinal dystrophies. In this exciting era of emerging gene therapies, it remains imperative to continue supporting patients with RP using all available options to manage their condition. Patients with RP experience a wide variety of physical, mental and social-emotional difficulties during their lifetime, of which some require timely intervention. This review aims to familiarize readers with clinical management options that are currently available for patients with RP.


Assuntos
Cegueira Noturna , Distrofias Retinianas , Retinose Pigmentar , Humanos , Retinose Pigmentar/genética , Células Fotorreceptoras Retinianas Cones , Células Fotorreceptoras Retinianas Bastonetes
18.
Channels (Austin) ; 17(1): 2192360, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-36943941

RESUMO

Cav1.4 L-type calcium channels are predominantly expressed at the photoreceptor terminals and in bipolar cells, mediating neurotransmitter release. Mutations in its gene, CACNA1F, can cause congenital stationary night-blindness type 2 (CSNB2). Due to phenotypic variability in CSNB2, characterization of pathological variants is necessary to better determine pathological mechanism at the site of action. A set of known mutations affects conserved gating charges in the S4 voltage sensor, two of which have been found in male CSNB2 patients. Here, we describe two disease-causing Cav1.4 mutations with gating charge neutralization, exchanging an arginine 964 with glycine (RG) or arginine 1288 with leucine (RL). In both, charge neutralization was associated with a reduction channel expression also reflected in smaller ON gating currents. In RL channels, the strong decrease in whole-cell current densities might additionally be explained by a reduction of single-channel currents. We further identified alterations in their biophysical properties, such as a hyperpolarizing shift of the activation threshold and an increase in slope factor of activation and inactivation. Molecular dynamic simulations in RL substituted channels indicated water wires in both, resting and active, channel states, suggesting the development of omega (ω)currents as a new pathological mechanism in CSNB2. This sum of the respective channel property alterations might add to the differential symptoms in patients beside other factors, such as genomic and environmental deviations.


Assuntos
Oftalmopatias Hereditárias , Miopia , Cegueira Noturna , Humanos , Masculino , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Cegueira Noturna/metabolismo , Oftalmopatias Hereditárias/metabolismo , Miopia/metabolismo , Cálcio/metabolismo
19.
BMC Ophthalmol ; 23(1): 116, 2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-36959549

RESUMO

BACKGROUND: Retinitis pigmentosa (RP) is one of the most frequent hereditary retinal diseases that often starts with night blindness and eventually leads to legal blindness. Our study aimed to identify the underlying genetic cause of autosomal recessive retinitis pigmentosa (arRP) in a consanguineous Pakistani family. METHODS: Following a detailed ophthalmological examination of the patients by an ophthalmologist, whole-exome sequencing was performed on the proband's DNA to delineate the genetic cause of RP in the family. In-depth computational methods, in-silico analysis, and familial co-segregation study were performed for variant detection and validation. RESULTS: We studied an inbred Pakistani family with two siblings affected by retinitis pigmentosa. The proband, a 32 years old female, was clinically diagnosed with RP at the age of 6 years. A classical night blindness symptom was reported in the proband since her early childhood. OCT report showed a major reduction in the outer nuclear layer and the ellipsoid zone width, leading to the progression of the disease. Exome sequencing revealed a novel homozygous missense mutation (c.938C > T;p.Thr313Ile) in exon 12 of the PDE6B gene. The mutation p.Thr313Ile co-segregated with RP phenotype in the family. The altered residue (p.Thr313) was super conserved evolutionarily across different vertebrate species, and all available in silico tools classified the mutation as highly pathogenic. CONCLUSION: We present a novel homozygous pathogenic mutation in the PDE6B gene as the underlying cause of arRP in a consanguineous Pakistani family. Our findings highlight the importance of missense mutations in the PDE6B gene and expand the known mutational repertoire of PDE6B-related RP.


Assuntos
Cegueira Noturna , Retinose Pigmentar , Pré-Escolar , Feminino , Humanos , Consanguinidade , Nucleotídeo Cíclico Fosfodiesterase do Tipo 6/genética , Análise Mutacional de DNA , Proteínas do Olho/genética , Mutação , Cegueira Noturna/genética , Paquistão , Linhagem , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Homozigoto
20.
Optom Vis Sci ; 100(2): 174-177, 2023 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-36728650

RESUMO

SIGNIFICANCE: Vitamin A is a micronutrient critical for retinal function. Patients with a deficiency may notice a progressive decline in night vision as rod photoreceptors become unable to regenerate rhodopsin. Although uncommon in developed nations, vitamin A deficiency should be considered in symptomatic patients with chronic, severe liver disease. PURPOSE: This report presents a rare case of night blindness secondary to poor vitamin A metabolism due to severe liver cirrhosis. CASE REPORT: A 62-year-old White woman presented with progressively worsening vision in dim lighting over the past 6 to 8 months. She was asymptomatic in daylight but "blind in the dark" to the extent that she was afraid to go outside at night. She had no personal or family history of night blindness or retinal disorders. Ocular health was unremarkable with dilation. Given her medical history of severe nonalcoholic liver cirrhosis, malabsorption of vitamin A was suspected and subsequently confirmed by the very low vitamin A level in her serum analysis. The patient was sent to endocrinology for evaluation, and appropriate repletion therapy was implemented. Subjective improvement in symptoms, along with better performance on visual field testing, was noted after initiating oral vitamin A supplementation for 5 months. CONCLUSIONS: Although vitamin A deficiency is a relatively rare disorder in the United States, it should be suspected in patients with severe liver disease or other conditions causing malabsorption who experience a loss of night vision.


Assuntos
Cegueira Noturna , Deficiência de Vitamina A , Humanos , Feminino , Pessoa de Meia-Idade , Cegueira Noturna/diagnóstico , Deficiência de Vitamina A/diagnóstico , Vitamina A , Retina , Cirrose Hepática/complicações
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