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INTRODUCTION: Adult-onset vitelliform macular dystrophy (AVMD) is an inherited maculopathy characterized by metamorphopsias and decrease in visual acuity occurring between the fourth and the sixth decade. It is characterized by an 'egg yolk' macular lesion eventually evolving towards foveal atrophy and fibrosis. It is usually an autosomal dominant inherited disorder with variable penetrance, mainly related to variants in BEST1, PRPH2, IMPG1, and IMPG2 genes. CASE DESCRIPTION: A 47-year-old woman complaining of "wavy" vision was referred to our clinic. Her past medical history and reported family history did not reveal any ocular disease. Complete ophthalmological evaluation was performed. Funduscopic examination and multimodal imaging revealed a round vitelliform lesion in both eyes, leading to a diagnosis of AVMD. Genetic analysis revealed a novel, likely pathogenetic, heterozygous c.478G > T (p.Glu160Ter), (NM_016247) variant in the IMPG2 gene. DISCUSSION: Our patient exhibits a novel pathogenetic variant in a gene associated with AVMD. Heterozygous variants in the IMPG2 gene have been reported in multiple individuals with vitelliform macular dystrophy, with an autosomal dominant mode of inheritance. Genetic screening is essential to characterize patients, to predict vision loss in patients with a positive family history and to characterize eligible patients for new potential emerging therapies. Genotype-phenotype correlation studies are needed to have a clearer picture of pathogenetic mechanisms. Our study characterizes the phenotype related to a novel IMPG2 pathogenic variant through multimodal imaging.
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Distrofia Macular Viteliforme , Femenino , Humanos , Persona de Mediana Edad , Bestrofinas/genética , Proteínas de la Matriz Extracelular/genética , Proteínas del Ojo/genética , Pruebas Genéticas , Mutación , Fenotipo , Proteoglicanos/genética , Retina/patología , Tomografía de Coherencia Óptica , Trastornos de la Visión , Distrofia Macular Viteliforme/diagnóstico , Distrofia Macular Viteliforme/genéticaRESUMEN
Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) in humans cause retinitis pigmentosa (RP) with early macular involvement, albeit the disease progression varies widely due to genetic heterogeneity and IMPG2 mutation type. There are currently no treatments for IMPG2-RP. To aid preclinical studies toward eventual treatments, there is a need to better understand the progression of disease pathology in appropriate animal models. Toward this goal, we developed mouse models with patient mimicking homozygous frameshift (T807Ter) or missense (Y250C) Impg2 mutations, as well as mice with a homozygous frameshift mutation (Q244Ter) designed to completely prevent IMPG2 protein expression, and characterized the trajectory of their retinal pathologies across postnatal development until late adulthood. We found that the Impg2T807Ter/T807Ter and Impg2Q244Ter/Q244Ter mice exhibited early onset gliosis, impaired photoreceptor outer segment maintenance, appearance of subretinal deposits near the optic disc, disruption of the outer retina, and neurosensorial detachment, whereas the Impg2Y250C/Y250C mice exhibited minimal retinal pathology. These results demonstrate the importance of mutation type in disease progression in IMPG2-RP and provide a toolkit and preclinical data for advancing therapeutic approaches.
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Proteoglicanos , Retinitis Pigmentosa , Humanos , Animales , Ratones , Adulto , Proteoglicanos/genética , Retina , Mutación , Retinitis Pigmentosa/genética , Progresión de la EnfermedadRESUMEN
The interphotoreceptor matrix (IPM) is the extracellular matrix between the photoreceptors and the retinal pigment epithelium (RPE). The IPM has two proteoglycans: the IPM proteoglycans 1 and 2 (IMPG1 and IMPG2, respectively). Patients with mutations on IMPG2 develop subretinal vitelliform lesions that affect vision. We previously created an IMPG2 knockout (KO) mice model that generates subretinal lesions similar to those found in humans. These subretinal lesions in IMPG2 KO mice retinas are, in part, composed of mislocalized IMPG1. In addition, IMPG2 KO mice show microscopic IMPG1 material accumulation between the RPE and the photoreceptor outer segments. In this work we discuss the possibility that material accumulation on IMPG2 KO mice retinas affects photoreceptor metabolism. To further investigate this idea, we used targeted metabolomics to profile retinal metabolome on IMPG2 KO mice. The metabolite set enrichment analysis showed reduced glutamate metabolism, urea cycle, and galactose metabolism suggesting affected energy metabolism in mice retinas of IMPG2 KO mice with subretinal lesion.
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Proteínas del Ojo , Retina , Animales , Ratones , Proteínas de la Matriz Extracelular/metabolismo , Proteínas del Ojo/genética , Proteínas del Ojo/metabolismo , Metaboloma , Ratones Noqueados , Proteoglicanos , Retina/metabolismoRESUMEN
Interphotoreceptor matrix proteoglycan 2 (IMPG2) mutations cause a severe form of early-onset retinitis pigmentosa (RP) with macular involvement. IMPG2 is expressed by photoreceptors and incorporated into the matrix that surrounds the inner and outer segments (OS) of rods and cones, but the mechanism of IMPG2-RP remains unclear. Loss of Impg2 function in mice produces a mild, late-onset photoreceptor phenotype without the characteristic OS loss that occurs in human patients. We generated retinal organoids (ROs) from patient-derived induced pluripotent stem (iPS) cells and gene-edited embryonic stem cells to model human IMPG2-RP in vitro. All ROs harboring IMPG2 mutations lacked an OS layer, in contrast to isogenic controls. Subsequent protein analyses revealed that this phenotype arises due to a loss of IMPG2 expression or its inability to undergo normal post-translational modifications. We hypothesized that loss of IMPG2 function destabilizes the interphotoreceptor matrix and renders the OS vulnerable to physical stressors, which is accentuated in the tissue culture environment. In support of this mechanism, transplantation of IMPG2 mutant ROs into the protected subretinal space of immunocompromised rodents restored OS production. Beyond providing a robust platform to study IMPG2-RP, this human RO model system may serve a broader role in honing strategies to treat advanced photoreceptor-based diseases.
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Organoides , Retinitis Pigmentosa , Humanos , Ratones , Animales , Organoides/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Proteínas del Ojo/genética , Proteoglicanos/genética , Retinitis Pigmentosa/genética , Retina/metabolismo , Mutación , Células Fotorreceptoras Retinianas Conos/metabolismo , FenotipoRESUMEN
Several pathogenic variants have been reported in the IMPG1 gene associated with the inherited retinal disorders vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). IMPG1 and its paralog IMPG2 encode for two proteoglycans, SPACR and SPACRCAN, respectively, which are the main components of the interphotoreceptor matrix (IPM), the extracellular matrix surrounding the photoreceptor cells. To determine the role of SPACR in the pathological mechanisms leading to RP and VMD, we generated a knockout mouse model lacking Impg1, the mouse ortholog. Impg1-deficient mice show abnormal accumulation of autofluorescent deposits visible by fundus imaging and spectral-domain optical coherence tomography (SD-OCT) and attenuated electroretinogram responses from 9 months of age. Furthermore, SD-OCT of Impg1-/- mice shows a degeneration of the photoreceptor layer, and transmission electron microscopy shows a disruption of the IPM and the retinal pigment epithelial cells. The decrease in the concentration of the chromophore 11-cis-retinal supports this loss of photoreceptors. In conclusion, our results demonstrate the essential role of SPACR in maintaining photoreceptors. Impg1-/- mice provide a novel model for mechanistic investigations and the development of therapies for VMD and RP caused by IMPG1 pathogenic variants.
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Proteínas de la Matriz Extracelular , Proteínas del Ojo , Proteoglicanos , Retinitis Pigmentosa , Distrofia Macular Viteliforme , Animales , Matriz Extracelular/genética , Matriz Extracelular/patología , Proteínas de la Matriz Extracelular/genética , Proteínas del Ojo/genética , Ratones , Células Fotorreceptoras/patología , Proteoglicanos/genética , Epitelio Pigmentado de la Retina/patología , Pigmentos Retinianos , Retinaldehído , Retinitis Pigmentosa/genética , Retinitis Pigmentosa/patología , Distrofia Macular Viteliforme/genéticaRESUMEN
Purpose: To present a case of unilateral IMPG2-associated adult onset vitelliform macular dystrophy (AVMD). Observations: A 68 year-old female presented with best corrected visual acuity (BCVA) of 20/20 and 20/40 for the right and left eye respectively. The patient had a left subfoveal yellow lesion on dilated fundus examination. Optical coherence tomography showed hyper-reflective material accumulation below the fovea in the left eye only. The patient was followed for 10 years with stable BCVA, and evolution of the subretinal vitelliform lesion to a "vitelliruptive" stage. The right eye did not develop vitelliform lesion. Genetic testing identified a heterozygous likely disease-causing variant in IMPG2; c.3423-7_3423-4del. Conclusions and importance: This is the first report of unilateral AVMD associated with IMPG2, expanding the phenotypic spectrum of IMPG2 retinopathy. We provide further evidence that IMPG2 variants can cause both autosomal recessive rod-cone dystrophy and autosomal dominant AVMD, with implications for patient counselling.
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We report on the genetic analysis of a north Indian family affected with Stargardt-like juvenile macular dystrophy. Considering an autosomal recessive inheritance of macular dystrophy in the recruited family, whole exome sequencing was employed in two affected siblings and their mother. We have identified a novel splice-site variant NC_000003.11(NM_016247.3):c.1239 + 1G > T, co-segregating in the affected siblings, in the Interphotoreceptor Matrix Proteoglycan 2 (IMPG2) gene. The identified variant is present immediately after exon 11, and is predicted to disrupt the wild-type donor splice-site of IMPG2 transcripts. We confirmed the splice-site changes in the IMPG2 transcripts using minigene functional assay. Although a number of studies on IMPG2 have demonstrated its involvement in retinitis pigmentosa and vitelliform macular dystrophy, this is the first report of a splice-site variant in IMPG2 that is responsible for Stargardt-like juvenile macular dystrophy.
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Proteoglicanos/genética , Sitios de Empalme de ARN/genética , Enfermedad de Stargardt/genética , Adolescente , Adulto , Niño , Biología Computacional , Femenino , Pruebas Genéticas , Humanos , Masculino , Mutación , Linaje , Secuenciación del Exoma , Adulto JovenRESUMEN
BACKGROUND: Canine progressive retinal atrophies are a group of hereditary retinal degenerations in dogs characterised by depletion of photoreceptor cells in the retina, which ultimately leads to blindness. PRA in the Lhasa Apso (LA) dog has not previously been clinically characterised or described in the literature, but owners in the UK are advised to have their dog examined through the British Veterinary Association/ Kennel Club/ International Sheep Dog Society (BVA/KC/ISDS) eye scheme annually, and similar schemes that are in operation in other countries. After the exclusion of 25 previously reported canine retinal mutations in LA PRA-affected dogs, we sought to identify the genetic cause of PRA in this breed. RESULTS: Analysis of whole-exome sequencing data of three PRA-affected LA and three LA without signs of PRA did not identify any exonic or splice site variants, suggesting the causal variant was non-exonic. We subsequently undertook a genome-wide association study (GWAS), which identified a 1.3 Mb disease-associated region on canine chromosome 33, followed by whole-genome sequencing analysis that revealed a long interspersed element-1 (LINE-1) insertion upstream of the IMPG2 gene. IMPG2 has previously been implicated in human retinal disease; however, until now no canine PRAs have been associated with this gene. The identification of this PRA-associated variant has enabled the development of a DNA test for this form of PRA in the breed, here termed PRA4 to distinguish it from other forms of PRA described in other breeds. This test has been used to determine the genotypes of over 900 LA dogs. A large cohort of genotyped dogs was used to estimate the allele frequency as between 0.07-0.1 in the UK LA population. CONCLUSIONS: Through the use of GWAS and subsequent sequencing of a PRA case, we have identified a LINE-1 insertion in the retinal candidate gene IMPG2 that is associated with a form of PRA in the LA dog. Validation of this variant in 447 dogs of 123 breeds determined it was private to LA dogs. We envisage that, over time, the developed DNA test will offer breeders the opportunity to avoid producing dogs affected with this form of PRA.
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Enfermedades de los Perros/genética , Elementos de Nucleótido Esparcido Largo , Regiones Promotoras Genéticas , Proteoglicanos/genética , Degeneración Retiniana/veterinaria , Animales , Atrofia/genética , Atrofia/veterinaria , Cruzamiento , Perros/genética , Frecuencia de los Genes , Estudios de Asociación Genética/veterinaria , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/veterinaria , Mutagénesis Insercional , Retina/patología , Degeneración Retiniana/genética , Secuenciación del Exoma/veterinariaRESUMEN
Introduction: Biallelic mutations in interphotoreceptor matrix proteoglycan 2 (IMPG2) have been shown to underlie recessive childhood-onset rod-cone dystrophy with early macular involvement in several families. In other families, heterozygous IMPG2 mutations have been associated with dominant vitelliform macular dystrophy. To date, the retinal phenotype of heterozygotes from families with recessive IMPG2-related retinal dystrophy has not been assessed. This study documents the genotypes and phenotypes observed in both homozygotes and available heterozygotes from additional families with IMPG2-related recessive rod-cone dystrophy. Methods: Retrospective case series (2016-2018). Results: Four families were identified. All were first-cousin marriages and had no known relation to each other. Individuals with biallelic pathogenic variants (7 individuals) had childhood-onset rod-cone dystrophy. Families 1 and 2 harboured the same novel homozygous mutation c.189dup;p.Gln64Thrfs*9 (5 individuals, 4-17 years old). Family 3 harboured the novel homozygous mutation c.533 + 4_533 + 7del;p.? (1 individual, 17 years old), and Family 4 harboured the previously reported homozygous mutation c.3262C>T;p.Arg1088* (1 individual, 45 years old). The 3 available carriers were genetically confirmed (both parents from Family 1 and the father from Family 3) and had macular focal retinal pigment epithelium thickening by optical coherence tomography (OCT). The father from Family 3 also had unilateral sectoral pigmentary retinopathy. Conclusions: Childhood-onset recessive rod-cone dystrophy with early macular involvement should prompt examination of the parents for macular focal retinal pigment epithelium thickening on OCT. If present the possibility of biallelic IMPG2 mutations in the proband should be considered. Young affected relatives of the proband can show multimodal imaging abnormalities before they are overtly symptomatic.
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Heterocigoto , Homocigoto , Mutación , Proteoglicanos/genética , Distrofias Retinianas/genética , Distrofias Retinianas/patología , Adolescente , Niño , Preescolar , Femenino , Genes Recesivos , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Pronóstico , Estudios RetrospectivosRESUMEN
A significant portion of patients diagnosed with vitelliform macular dystrophy (VMD) do not carry causative mutations in the classic VMD genes BEST1 or PRPH2. We therefore performed a mutational screen in a cohort of 106 BEST1/PRPH2-negative VMD patients in two genes encoding secreted interphotoreceptor matrix proteoglycans-1 and -2 (IMPG1 and IMPG2). We identified two novel mutations in IMPG1 in two simplex VMD cases with disease onset in their early childhood, a heterozygous p.(Leu238Pro) missense mutation and a homozygous c.807 + 5G > A splice site mutation. The latter induced partial skipping of exon 7 of IMPG1 in an in vitro splicing assay. Furthermore, we found heterozygous mutations including three stop [p.(Glu226*), p.(Ser522*), p.(Gln856*)] and five missense mutations [p.(Ala243Pro), p.(Gly1008Asp), p.(Phe1016Ser), p.(Tyr1042Cys), p.(Cys1077Phe)] in the IMPG2 gene, one of them, p.(Cys1077Phe), previously associated with VMD. Asymptomatic carriers of the p.(Ala243Pro) and p.(Cys1077Phe) mutations show subtle foveal irregularities that could characterize a subclinical stage of disease. Taken together, our results provide further evidence for an involvement of dominant and recessive mutations in IMPG1 and IMPG2 in VMD pathology. There is a remarkable similarity in the clinical appearance of mutation carriers, presenting with bilateral, central, dome-shaped foveal accumulation of yellowish material with preserved integrity of the retinal pigment epithelium (RPE). Clinical symptoms tend to be more severe for IMPG1 mutations.
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PURPOSE: To provide the first detailed clinical description in patients with RP caused by recessive mutations in IMPG2. METHODS: This international collaborative study includes 17 RP patients with inherited retinal disease caused by mutations in IMPG2. The patients were clinically (re-)examined, including extensive medical history taking, slit-lamp biomicroscopy, ophthalmoscopy, perimetry, ERG, optical coherence tomography (OCT), fundus autofluorescence (FAF) imaging, fundus photography, and color vision tests. The main outcome measures included mean age at onset, initial symptom, best-corrected visual acuity, fundus appearance, perimetry results, ERG responses, OCT images, FAF imaging, color vision test reports and DNA sequence variants. RESULTS: The mean age at onset was 10.5 years (range, 4-20 years). Initial symptoms included night blindness in 59% of patients, a decreased visual acuity in 35%, and visual field loss in 6%. Fundus abnormalities were typical of RP: optic disc pallor, attenuated vessels, bone spicules, and generalized atrophy of the retina and choriocapillaris. Additionally, we observed macular abnormalities in all patients, ranging from subtle mottling of the macular pigment epithelium (two patients) and a bull's eye maculopathy (seven patients) to macular chorioretinal atrophy (seven patients). CONCLUSIONS: Mutations in IMPG2 cause a severe form of RP with symptoms manifesting in the first 2 decades of life. IMPG2-associated RP is frequently accompanied by macular involvement, ranging from mild pigment alterations to profound chorioretinal atrophy. The resulting decrease in central vision in combination with the severe tunnel vision leads to severe visual impairment in patients with IMPG2-associated RP.