RESUMO
PRPH2, one of the most frequently inherited retinal dystrophy (IRD)-causing genes, implies a high phenotypic variability. This study aims to analyze the PRPH2 mutational spectrum in one of the largest cohorts worldwide, and to describe novel pathogenic variants and genotype-phenotype correlations. A study of 220 patients from 103 families recruited from a database of 5000 families. A molecular diagnosis was performed using classical molecular approaches and next-generation sequencing. Common haplotypes were ascertained by analyzing single-nucleotide polymorphisms. We identified 56 variants, including 11 novel variants. Most of them were missense variants (64%) and were located in the D2-loop protein domain (77%). The most frequently occurring variants were p.Gly167Ser, p.Gly208Asp and p.Pro221_Cys222del. Haplotype analysis revealed a shared region in families carrying p.Leu41Pro or p.Pro221_Cys222del. Patients with retinitis pigmentosa presented an earlier disease onset. We describe the largest cohort of IRD families associated with PRPH2 from a single center. Most variants were located in the D2-loop domain, highlighting its importance in interacting with other proteins. Our work suggests a likely founder effect for the variants p.Leu41Pro and p.Pro221_Cys222del in our Spanish cohort. Phenotypes with a primary rod alteration presented more severe affectation. Finally, the high phenotypic variability in PRPH2 hinders the possibility of drawing genotype-phenotype correlations.
Assuntos
Distrofias Retinianas , Retinose Pigmentar , Humanos , Análise Mutacional de DNA , Mutação , Mutação de Sentido Incorreto , Fenótipo , Distrofias Retinianas/genética , Retinose Pigmentar/genéticaRESUMO
Prph2 is a photoreceptor-specific tetraspanin with an essential role in the structure and function of photoreceptor outer segments. PRPH2 mutations cause a multitude of retinal diseases characterized by the degeneration of photoreceptors as well as defects in neighboring tissues such as the RPE. While extensive research has analyzed photoreceptors, less attention has been paid to these secondary defects. Here, we use different Prph2 disease models to evaluate the damage of the RPE arising from photoreceptor defects. In Prph2 disease models, the RPE exhibits structural abnormalities and cell loss. Furthermore, RPE functional defects are observed, including impaired clearance of phagocytosed outer segment material and increased microglia activation. The severity of RPE damage is different between models, suggesting that the different abnormal outer segment structures caused by Prph2 disease mutations lead to varying degrees of RPE stress and thus influence the clinical phenotype observed in patients.
Assuntos
Periferinas , Doenças Retinianas , Tetraspaninas , Humanos , Mutação , Periferinas/genética , Células Fotorreceptoras , Doenças Retinianas/genética , Epitélio Pigmentado da Retina , Tetraspaninas/genéticaRESUMO
INTRODUCTION: Mutations in the peripherin-2 gene (PRPH2) are a common cause of inherited retinal dystrophies well known for their phenotypic diversity. We describe a novel presentation of the c.623G > A; p.(Gly208Asp) variant in association with cone-rod dystrophy and reduced penetrance. CASE DESCRIPTION: A 39-year-old man presents with a history of decreased visual acuity, photophobia, and dyschromatopsia. Fundus examination was largely unremarkable while spectral-domain optical coherence tomography (SD-OCT) demonstrated diffuse granularity at the ellipsoid zone. Full-field electroretinogram (ffERG) revealed a cone-rod dystrophy. Genetic testing revealed a heterozygous pathogenic variant, c.623G > A; p.(Gly208Asp), in the PRPH2 gene, also found in an unaffected brother. The 50-year-old brother had no visual symptoms and no findings on fundus examination. SD-OCT showed normal retinal architecture and ffERG was within normal limits bilaterally. CONCLUSION: This case report broadens the known phenotypic presentations of PRPH2-associated retinopathy and suggests that the PRPH2 variant c.623G > A; p.(Gly208Asp) may be associated with reduced penetrance.
Assuntos
Distrofias de Cones e Bastonetes , Retinose Pigmentar , Masculino , Humanos , Adulto , Pessoa de Meia-Idade , Distrofias de Cones e Bastonetes/diagnóstico , Distrofias de Cones e Bastonetes/genética , Penetrância , Eletrorretinografia , Retinose Pigmentar/diagnóstico , Retinose Pigmentar/genética , Mutação , Variação Biológica da População , Tomografia de Coerência Óptica , FenótipoRESUMO
Mutations in peripherin 2 (PRPH2) are associated with a spectrum of inherited retinal diseases (IRDs) including retinitis pigmentosa (RP) and macular degeneration. As PRPH2 is localized to cone and rod outer segments, mutations in PRPH2 lead the disorganization or absence of photoreceptor outer segments. Here, we report on a patient with PRPH2-linked RP who exhibited widespread RPE atrophy with a central area of macular atrophy sparing the fovea. In future studies, we plan to model the pathobiology of PRPH2-based RP using induced pluripotent stem cell (iPSC)-derived retinal organoids. To effectively model rare mutations using iPSC-derived retinal organoids, we first require a strategy that can install the desired mutation in healthy wild-type iPSC, which can efficiently generate well-laminated retinal organoids. In this study, we developed an efficient prime editing strategy for the installation of the pathogenic PRPH2 c.828+1 G>A splice-site mutation underlying our patient's disease.
Assuntos
Degeneração Macular , Degeneração Retiniana , Retinose Pigmentar , Humanos , Periferinas/genética , Degeneração Retiniana/genética , Degeneração Retiniana/terapia , Degeneração Retiniana/patologia , Retinose Pigmentar/genética , Retinose Pigmentar/patologia , Degeneração Macular/genética , Degeneração Macular/patologia , Mutação , AtrofiaRESUMO
Prime editing (PE) is a novel, double-strand break (DSB)-independent gene editing technology that represents an exciting avenue for the treatment of inherited retinal diseases (IRDs). Given the extensive and heterogenous nature of the 280 genes associated with IRDs, genome editing has presented countless complications. However, recent advances in genome editing technologies have identified PE to have tremendous potential, with the capability to ameliorate small deletions and insertions in addition to all twelve possible transition and transversion mutations. The current PE system is based on the fusion of the Streptococcus pyogenes Cas9 (SpCas9) nickase H840A mutant and an optimized Moloney murine leukemia virus (MMLV) reverse-transcriptase (RT) in conjunction with a PE guide RNA (pegRNA). In this study, we developed a prime editor based on the avian myeloblastosis virus (AMV)-RT and showed its applicability for the installation of the PRPH2 c.828+1G>A mutation in HEK293 cells.
Assuntos
Vírus da Mieloblastose Aviária , DNA Polimerase Dirigida por RNA , Humanos , Animais , Camundongos , DNA Polimerase Dirigida por RNA/genética , DNA Polimerase Dirigida por RNA/metabolismo , Vírus da Mieloblastose Aviária/genética , Vírus da Mieloblastose Aviária/metabolismo , Células HEK293 , Edição de Genes , Vírus da Leucemia Murina de Moloney/genética , Vírus da Leucemia Murina de Moloney/metabolismo , Sistemas CRISPR-CasRESUMO
The light-sensitive outer segment organelle of photoreceptor cells contains a stack of hundreds of flat, disc-shaped membranes called discs. The rims of these discs contain a photoreceptor-specific tetraspanin protein peripherin-2 (also known as rds or PRPH2). Mutations in the PRPH2 gene lead to a wide variety of inherited retinal degenerations in humans. The vast majority of these mutations occur within a large, intradiscal loop of peripherin-2, known as the D2 loop. The D2 loop mediates well-established intermolecular interactions of peripherin-2 molecules among themselves and a homologous protein ROM1. These interactions lead to the formation of large, highly ordered oligomers. In this chapter, we discuss the supramolecular organization of peripherin-2/ROM1 complexes and their contribution to the process of outer segment disc morphogenesis and enclosure.
Assuntos
Degeneração Retiniana , Tetraspaninas , Humanos , Periferinas/genética , Tetraspaninas/genética , Degeneração Retiniana/genética , Mutação , Morfogênese , Proteínas do Olho/genéticaRESUMO
Trafficking of photoreceptor membrane proteins from their site of synthesis in the inner segment (IS) to the outer segment (OS) is critical for photoreceptor function and vision. Here we evaluate the role of syntaxin 3 (STX3), in trafficking of OS membrane proteins such as peripherin 2 (PRPH2) and rhodopsin. Photoreceptor-specific Stx3 knockouts [Stx3f/f(iCre75) and Stx3f/f(CRX-Cre) ] exhibited rapid, early-onset photoreceptor degeneration and functional decline characterized by structural defects in IS, OS, and synaptic terminals. Critically, in the absence of STX3, OS proteins such as PRPH2, the PRPH2 binding partner, rod outer segment membrane protein 1 (ROM1), and rhodopsin were mislocalized along the microtubules to the IS, cell body, and synaptic region. We find that the PRPH2 C-terminal domain interacts with STX3 as well as other photoreceptor SNAREs, and our findings indicate that STX3 is an essential part of the trafficking pathway for both disc (rhodopsin) and rim (PRPH2/ROM1) components of the OS.
Assuntos
Periferinas/metabolismo , Proteínas Qa-SNARE/metabolismo , Segmento Interno das Células Fotorreceptoras da Retina/metabolismo , Segmento Externo das Células Fotorreceptoras da Retina/metabolismo , Rodopsina/metabolismo , Animais , Técnicas de Silenciamento de Genes , Camundongos , Células Fotorreceptoras de Vertebrados/fisiologia , Transporte Proteico , Proteínas Qa-SNARE/genética , Segmento Interno das Células Fotorreceptoras da Retina/ultraestrutura , Segmento Externo das Células Fotorreceptoras da Retina/ultraestrutura , Proteínas SNARE/metabolismoRESUMO
Variants in PRPH2 are a common cause of inherited retinal dystrophies with high genetic and phenotypic heterogeneity. In this study, variants in PRPH2 were selected from in-house exome sequencing data, and all reported PRPH2 variants were evaluated with the assistance of online prediction tools and the comparative validation of large datasets. All variants were classified based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. Individuals with pathogenic or likely pathogenic variants of PRPH2 were confirmed by Sanger sequencing. Clinical characteristics were summarized. Ten pathogenic or likely pathogenic variants of PRPH2 were identified in 14 families. In our cohort, the most frequent variant was p.G305Afs*19, accounting for 33.3% (5/15) of alleles, in contrast to the literature, where p.R172G (11.6%, 119/1028) was the most common variant. Nine in-house families (63.8%) were diagnosed with retinitis pigmentosa (RP), distinct from the phenotypic spectrum in the literature, which shows that RP accounts for 27.9% (283/1013) and macular degeneration is more common (45.2%, 458/1013). Patients carrying missense variants predicted as damaging by all seven prediction tools and absent in the gnomAD database were more likely to develop RP compared to those carrying missense variants predicted as damaging with fewer tools or with more than one allele number in the gnomAD database (p = 0.001). The population-specific genetic and phenotypic spectra of PRPH2 were explored, and novel insight into the genotype-phenotype correlation of PRPH2 was proposed. These findings demonstrated the importance of assessing PRPH2 variants in distinct populations and the value of providing practical suggestions for the genetic interpretation of PRPH2 variants.
Assuntos
Degeneração Macular , Retinose Pigmentar , Humanos , Alelos , Estudos de Coortes , População do Leste Asiático/genética , Exoma , Estudos de Associação Genética , Genótipo , Degeneração Macular/genética , Mutação , Linhagem , Fenótipo , Distrofias Retinianas/genética , Retinose Pigmentar/patologiaRESUMO
Both PRPF31 and PRPH2 are the causative genes for retinitis pigmentosa. And both of them are associated with the balance of rhodopsin. In this study, we aim to investigate the co-expression and interaction of PRPF31 and PRPH2. We used PRPF31-eGFP, PRPF31-3xFlag and PRPH2-mCherry vectors were transfected into HEK293T and APRE-19 cells. Immunoblotting and co-immunoprecipitation (Co-IP) were used for gene expression validation and protein interaction. Immunofluorescence staining assay was used to test the co-localization analysis of PRPF31 and PRPH2. Co-IP experiments showed that PRPF31 could be pulled down with an anti-PRPH2 antibody. There was co-localization between PRPF31 and PRPH2 in HEK293T, APRE-19 and mouse retina. The Co-IP and co-localization experiments suggest that PRPF31 interacted with PRPH2.
Assuntos
Retinose Pigmentar , Rodopsina , Animais , Proteínas do Olho/genética , Células HEK293 , Humanos , Imunoprecipitação , Camundongos , Mutação , Linhagem , Periferinas , Retinose Pigmentar/genética , Rodopsina/genéticaRESUMO
Mutations in PRPH2, encoding peripherin-2, are associated with the development of a wide variety of inherited retinal diseases (IRDs). To determine the causality of the many PRPH2 variants that have been discovered over the last decades, we surveyed all published PRPH2 variants up to July 2020, describing 720 index patients that in total carried 245 unique variants. In addition, we identified seven novel PRPH2 variants in eight additional index patients. The pathogenicity of all variants was determined using the ACMG guidelines. With this, 107 variants were classified as pathogenic, 92 as likely pathogenic, one as benign, and two as likely benign. The remaining 50 variants were classified as variants of uncertain significance. Interestingly, of the total 252 PRPH2 variants, more than half (n = 137) were missense variants. All variants were uploaded into the Leiden Open source Variation and ClinVar databases. Our study underscores the need for experimental assays for variants of unknown significance to improve pathogenicity classification, which would allow us to better understand genotype-phenotype correlations, and in the long-term, hopefully also support the development of therapeutic strategies for patients with PRPH2-associated IRD.
Assuntos
Periferinas/genética , Doenças Retinianas , Estudos de Associação Genética , Humanos , Mutação , Mutação de Sentido Incorreto , Doenças Retinianas/genéticaRESUMO
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 , Retinose Pigmentar , Idoso , China , Glaucoma de Ângulo Fechado/genética , Humanos , Masculino , Mutação , Linhagem , Periferinas , Retinose Pigmentar/genéticaRESUMO
BACKGROUND: Retinitis pigmentosa punctata albescens (RPA) is a particular form of retinitis pigmentosa characterized by childhood onset night blindness and areas of peripheral retinal atrophy. We investigated the genetic cause of RPA in a family consisting of two affected Egyptian brothers with healthy consanguineous parents. METHODS: Mutational analysis of four RPA causative genes was realized by Sanger sequencing on both probands, and detected variants were subsequently genotyped in their parents. Afterwards, found variants were deeply, statistically, and in silico characterized to determine their possible effects and association with RPA. RESULTS: Both brothers carry three missense PRPH2 variants in a homozygous condition (c.910C > A, c.929G > A, and c.1013A > C) and two promoter variants in RHO (c.-26A > G) and RLBP1 (c.-70G > A) genes, respectively. Haplotype analyses highlighted a PRPH2 rare haplotype variant (GAG), determining a possible alteration of PRPH2 binding with melanoregulin and other outer segment proteins, followed by photoreceptor outer segment instability. Furthermore, an altered balance of transcription factor binding sites, due to the presence of RHO and RLBP1 promoter variants, might determine a comprehensive downregulation of both genes, possibly altering the PRPH2 shared visual-related pathway. CONCLUSIONS: Despite several limitations, the study might be a relevant step towards detection of novel scenarios in RPA etiopathogenesis.
Assuntos
Variação Genética , Haplótipos , Periferinas/genética , Segmento Externo das Células Fotorreceptoras da Retina/metabolismo , Retinose Pigmentar/metabolismo , Sítios de Ligação , Proteínas de Transporte/genética , Pré-Escolar , Simulação por Computador , Análise Mutacional de DNA , Egito , Saúde da Família , Humanos , Transdução de Sinal Luminoso , Masculino , Mutação , Mutação de Sentido Incorreto , Doenças do Sistema Nervoso Periférico/metabolismo , Dobramento de Proteína , Degeneração Retiniana/metabolismo , Proteínas rho de Ligação ao GTP/genéticaRESUMO
The purpose of this study was to develop a flexible, cost-efficient, next-generation sequencing (NGS) protocol for genetic testing. Long-range polymerase chain reaction (PCR) amplicons of up to 20 kb in size were designed to amplify entire genomic regions for a panel (n = 35) of inherited retinal disease (IRD)-associated loci. Amplicons were pooled and sequenced by NGS. The analysis was applied to 227 probands diagnosed with IRD: (A) 108 previously molecularly diagnosed, (B) 94 without previous genetic testing, and (C) 25 undiagnosed after whole-exome sequencing (WES). The method was validated with 100% sensitivity on cohort A. Long-range PCR-based sequencing revealed likely causative variant(s) in 51% and 24% of proband from cohorts B and C, respectively. Breakpoints of 3 copy number variants (CNVs) could be characterized. Long-range PCR libraries spike-in extended coverage of WES. Read phasing confirmed compound heterozygosity in 5 probands. The proposed sequencing protocol provided deep coverage of the entire gene, including intronic and promoter regions. Our method can be used (i) as a first-tier assay to reduce genetic testing costs, (ii) to elucidate missing heritability cases, (iii) to characterize breakpoints of CNVs at nucleotide resolution, (iv) to extend WES data to non-coding regions by spiking-in long-range PCR libraries, and (v) to help with phasing of candidate variants.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Bestrofinas/genética , Sequenciamento de Nucleotídeos em Larga Escala , Periferinas/genética , Doenças Retinianas/genética , Análise de Sequência de DNA , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Canais de Cátion Regulados por Nucleotídeos Cíclicos/genética , Variações do Número de Cópias de DNA , Proteínas do Olho/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Mutação , Proteínas do Tecido Nervoso/genética , Reação em Cadeia da Polimerase , Doenças Retinianas/congênito , Doenças Retinianas/diagnóstico , Adulto JovemRESUMO
Molecular variant interpretation lacks disease gene-specific cohorts for determining variant enrichment in disease versus healthy populations. To address the molecular etiology of retinal degeneration, specifically the PRPH2-related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE® participants from 161 families. Clinical details were provided by referring clinicians participating in the eyeGENE® Network. The cohort was sequenced for variants in PRPH2. Variant complementary DNA clusters and cohort frequency were compared to variants in public databases to help us to determine pathogenicity by current American College of Medical Genetics and Genomics/Association for Molecular Pathology interpretation criteria. The most frequent variant was c.828+3A>T, which affected 28 families (17.4%), and 25 of 79 (31.64%) variants were novel. The majority of missense variants clustered in the D2 intracellular loop of the peripherin-2 protein, constituting a hotspot. Disease enrichment was noted for 23 (29.1%) of the variants. Hotspot and disease-enrichment evidence modified variant classification for 16.5% of variants. The missense allele p.Arg172Trp was associated with a younger age of onset. To the best of our knowledge, this is the largest patient cohort review of PRPH2-related retinopathy. Large disease gene-specific cohorts permit gene modeling for hotspot and disease-enrichment analysis, providing novel variant classification evidence, including for novel missense variants.
Assuntos
Estudos de Associação Genética , Periferinas/genética , Doenças Retinianas/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Linhagem , Sistema de Registros , Adulto JovemRESUMO
Mutations in human prominin 1 (PROM1), encoding a transmembrane glycoprotein localized mainly to plasma membrane protrusions, have been reported to cause retinitis pigmentosa, macular degeneration, and cone-rod dystrophy. Although the structural role of PROM1 in outer-segment (OS) morphogenesis has been demonstrated in Prom1-knockout mouse, the mechanisms underlying these complex disease phenotypes remain unclear. Here, we utilized a zebrafish model to further investigate PROM1's role in the retina. The Prom1 orthologs in zebrafish include prom1a and prom1b, and our results showed that prom1b, rather than prom1a, plays an important role in zebrafish photoreceptors. Loss of prom1b disrupted OS morphogenesis, with rods and cones exhibiting differences in impairment: cones degenerated at an early age, whereas rods remained viable but with an abnormal OS, even at 9 months postfertilization. Immunofluorescence experiments with WT zebrafish revealed that Prph2, an ortholog of the human transmembrane protein peripherin 2 and also associated with OS formation, is localized to the edge of OS and is more highly expressed in the cone OS than in the rod OS. Moreover, we found that Prom1b deletion causes mislocalization of Prph2 and disrupts its oligomerization. We conclude that the variation in Prph2 levels between cones and rods was one of the reasons for the different PROM1 mutation-induced phenotypes of these retinal structures. These findings expand our understanding of the phenotypes caused by PROM1 mutations and provide critical insights into its function.
Assuntos
Antígeno AC133/metabolismo , Células Fotorreceptoras/metabolismo , Segmento Externo da Célula Bastonete/metabolismo , Antígeno AC133/genética , Animais , Distrofias de Cones e Bastonetes/genética , Modelos Animais de Doenças , Células HeLa , Humanos , Degeneração Macular/metabolismo , Proteínas de Membrana/metabolismo , Morfogênese , Mutação , Periferinas/genética , Retina/metabolismo , Retina/fisiologia , Células Fotorreceptoras Retinianas Cones/metabolismo , Degeneração Retiniana/genética , Degeneração Retiniana/fisiopatologia , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Retinose Pigmentar/genética , Deleção de Sequência , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/metabolismoRESUMO
The large number of inherited retinal disease genes (IRD), including the photopigment rhodopsin and the photoreceptor outer segment (OS) structural component peripherin 2 (PRPH2), has prompted interest in identifying common cellular mechanisms involved in degeneration. Although metabolic dysregulation has been shown to play an important role in the progression of the disease etiology, identifying a common regulator that can preserve the metabolic ecosystem is needed for future development of neuroprotective treatments. Here, we investigated whether retbindin (RTBDN), a rod-specific protein with riboflavin binding capability, and a regulator of riboflavin-derived cofactors flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), is protective to the retina in different IRD models; one carrying the P23H mutation in rhodopsin (which causes retinitis pigmentosa) and one carrying the Y141C mutation in Prph2 (which causes a blended cone-rod dystrophy). RTBDN levels are significantly upregulated in both the rhodopsin (Rho)P23H/+ and Prph2Y141C/+ retinas. Rod and cone structural and functional degeneration worsened in models lacking RTBDN. In addition, removing Rtbdn worsened other phenotypes, such as fundus flecking. Retinal flavin levels were reduced in RhoP23H/+/Rtbdn-/- and Prph2Y141C/+/Rtbdn-/- retinas. Overall, these findings suggest that RTBDN may play a protective role during retinal degenerations that occur at varying rates and due to varying disease mechanisms.
Assuntos
Proteínas do Olho/fisiologia , Mutação , Periferinas/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/patologia , Degeneração Retiniana/patologia , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Periferinas/genética , Retina/metabolismo , Degeneração Retiniana/genética , Degeneração Retiniana/metabolismo , Proteínas rho de Ligação ao GTP/genéticaRESUMO
Peripherin 2 (also known as RDS/Prph2) is localized to the rims of rod and cone outer segment (OS) discs. The C-terminus of Prph2 is a critical functional domain, but its exact role is still unknown. In this mini review, we describe work on the Prph2 C-terminus, highlighting its role as a regulator of protein trafficking, membrane curvature, ectosome secretion, and membrane fusion. Evidence supports a role for the Prph2 C-terminus in these processes and demonstrates that it is necessary for the initiation of OS morphogenesis.
Assuntos
Periferinas/fisiologia , Segmento Externo das Células Fotorreceptoras da Retina/fisiologia , Segmento Externo da Célula Bastonete/fisiologia , Humanos , Morfogênese , Transporte Proteico , Retina/crescimento & desenvolvimentoRESUMO
It can be clinically challenging to distinguish dry age-related macular degeneration (AMD) from AMD-mimicking dystrophies, and sometimes misdiagnosis occurs. With upcoming therapies for dry AMD it is important to exclude patients with a different retinal disease from clinical trials. In this study we evaluated the occurrence of AMD-mimicking dystrophies in an AMD cohort. Whole-exome sequencing (WES) was performed in 218 patients with intermediate AMD or geographic atrophy secondary to AMD and 133 control individuals. WES data was analyzed for rare variants in 19 genes associated with autosomal dominant and recessive macular dystrophies mimicking AMD. In three (1.4%) of 218 cases we identified a pathogenic heterozygous variant (PRPH2 c.424C > T; p.R142W) causal for autosomal dominant central areolar choroidal dystrophy (CACD). Phenotypically, these patients all presented with geographic atrophy. In 12 (5.5%) of 218 cases we identified a heterozygous variant of unknown clinical significance, but predicted to be highly deleterious, in genes previously associated with autosomal dominant macular dystrophies. The distinction between AMD and AMD-mimicking dystrophies, such as CACD, can be challenging based on fundus examination alone. Genetic screening for genes associated with macular dystrophies, especially PRPH2, can be beneficial to help identify AMD-mimicking dystrophies.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Degeneração Macular/diagnóstico , Degeneração Macular/genética , Fenótipo , Idoso , Idoso de 80 Anos ou mais , Alelos , Substituição de Aminoácidos , Estudos de Casos e Controles , Feminino , Genes Dominantes , Estudos de Associação Genética/métodos , Testes Genéticos , Genótipo , Atrofia Geográfica/diagnóstico , Atrofia Geográfica/genética , Humanos , Masculino , Sequenciamento do ExomaRESUMO
BACKGROUND: Retinitis pigmentosa (RP), a neurodegenerative disease, is occasionally accompanied by choroidal neovascularization (CNV) and cystoid macular oedema. It is presently treated with repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents. However, there are concerns regarding long-term inhibition of VEGF by the use of these agents, especially in cases involving neurodegenerative diseases, since VEGFs have a neuroprotective effect. Currently, there are no reports on the long-term safety of anti-VEGF therapy in patients with RP. CASE PRESENTATION: In this report, we describe the case of a 56-year-old female patient with CNV associated with RP who was treated with anti-VEGF therapy for 8 years. She had autosomal dominant RP with a heterozygous PRPH2 mutation (c.410G > A) and complained of metamorphopsia in her left eye. Examinations revealed CNV with serous retinal detachment. She was treated with as-needed injections for 2 years; however, she experienced a recurrence. Therefore, we switched to a bimonthly regimen that was continued for 6 years. In total, the patient received 34 injections of various types of anti-VEGFs over 8 years. No recurrences were noted during that time, and we have not detected any negative effects concerning the progression of visual field loss in comparison with the fellow eye. CONCLUSIONS: No negative effects related to the progression of visual field loss were observed during continuous treatment with anti-VEGF agents for 8 years in our patient.
Assuntos
Bevacizumab/administração & dosagem , Ranibizumab/administração & dosagem , Retinose Pigmentar/tratamento farmacológico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Acuidade Visual , Inibidores da Angiogênese/administração & dosagem , Feminino , Seguimentos , Humanos , Injeções Intravítreas , Pessoa de Meia-Idade , Retinose Pigmentar/diagnóstico , Fatores de Tempo , Tomografia de Coerência ÓpticaRESUMO
PURPOSE: To report on a patient with spinocerebellar ataxia type 14 (SCA14) and macular dystrophy with identification of a novel PRPH2 variant. METHODS: Case report. RESULTS: A 63-year-old female with molecularly confirmed SCA14 presented with symmetric pigmentary disturbances in a perifoveal distribution resembling a pattern macular dystrophy. She had no history of using medications with recognized toxic macular effects. Subsequent genetic testing confirmed a novel heterozygous missense variant of unknown significance in PRPH2 (PRPH2: c.694 G>A, p.(Ala232Thr)). CONCLUSIONS: To our knowledge, this is the first case of macular dystrophy identified in a patient with SCA14. While it is possible that the macular dystrophy observed in this patient might be an under-reported phenotype associated with SCA14, the pattern of macular changes is consistent with PRPH2-related disorders. The identified missense variant is predicted to be damaging by most in silico models, and the residue is highly conserved, adding support to a dual genetic diagnosis in this case.