174delG Mutation in Mouse MFRP Causes Photoreceptor Degeneration and RPE Atrophy

Fogerty, Joseph; Besharse, Joseph C.

doi:10.1167/iovs.11-8112

Cited by 44 publications

(87 citation statements)

References 25 publications

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“…3F). The MFRP immunoreactive band migrated at about 120 kDa, a much larger size than the predicted molecular mass of 65 kDa of wild-type protein, but consistent with results of previous studies (Won et al, 2008;Fogerty and Besharse, 2011). This high molecular weight band suggests that MFRP may exist as a dimer in RPE cells.…”

Section: Retinal Function and Morphology In Aav Vector-treated Rd6 Micesupporting

confidence: 89%

“…C1q is a key component of the classical pathway of complement activation, and is known to be involved in many critical processes including innate and adaptive immunity, inflammation, apoptosis, cell adhesion, and monocyte chemotaxis (Kishore et al, 2004;Lu et al, 2008). Interestingly, a study describing a murine Mfrp null mutant has shown that CTRP5 is upregulated in both rd6 and Mfrp 174delG (Fogerty and Besharse, 2011). Thus, the lack of MFRP protein might lead to uncontrolled signaling by CTRP5, triggering the migration of phagocytic cells from the choroid into the subretinal space, as seen in rd6 mice.…”

Section: Gene Therapy In the Rd6 Mouse Model Of Mfrp Diseasementioning

confidence: 99%

“…CTRP5 also has a human disease association; specifically, a Ser163Arg mutation causes an autosomal dominant late-onset retina-wide degeneration, which can feature neovascular macular degeneration (Milam et al, 2000;Jacobson et al, 2001;Hayward et al, 2003). The functional relationship between the two proteins remains under investigation (Fogerty and Besharse, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Gene Therapy for Retinitis Pigmentosa Caused by MFRP Mutations: Human Phenotype and Preliminary Proof of Concept

et al. 2012

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Autosomal recessive retinitis pigmentosa (RP), a heterogeneous group of degenerations of the retina, can be due to mutations in the MFRP (membrane-type frizzled-related protein) gene. A patient with RP with MFRP mutations, one of which is novel and the first splice site mutation reported, was characterized by noninvasive retinal and visual studies. The phenotype, albeit complex, suggested that this retinal degeneration may be a candidate for gene-based therapy. Proof-of-concept studies were performed in the rd6 Mfrp mutant mouse model. The fast-acting tyrosine-capsid mutant AAV8 (Y733F) vector containing the small chicken β-actin promoter driving the wild-type mouse Mfrp gene was used. Subretinal vector delivery on postnatal day 14 prevented retinal degeneration. Treatment rescued rod and cone photoreceptors, as assessed by electroretinography and retinal histology at 2 months of age. This AAV-mediated gene delivery also resulted in robust MFRP expression predominantly in its normal location within the retinal pigment epithelium apical membrane and its microvilli. The clinical features of MFRP-RP and our preliminary data indicating a response to gene therapy in the rd6 mouse suggest that this form of RP is a potential target for gene-based therapy.

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Section: Retinal Function and Morphology In Aav Vector-treated Rd6 Micesupporting

confidence: 89%

Section: Gene Therapy In the Rd6 Mouse Model Of Mfrp Diseasementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gene Therapy for Retinitis Pigmentosa Caused by MFRP Mutations: Human Phenotype and Preliminary Proof of Concept

et al. 2012

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“…A similar phenotype has been described in homozygous Mfrp rdx mice (Fogerty and Besharse, 2011). In humans, MFRP mutations are associated with RP in an ocular syndrome that also includes posterior microphthalmos, foveoschisis and optic nerve head drusen (Ayala-Ramírez et al, 2006; Crespí et al, 2008; Mukhopadhyay et al, 2010; Neri et al, 2012; Zenteno et al, 2009).…”

Section: Introductionsupporting

confidence: 78%

Genetic modifier loci of mouse Mfrprd6 identified by quantitative trait locus analysis

Jung

Charette

Philip

et al. 2014

Experimental Eye Research

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The identification of genes that modify pathological ocular phenotypes in mouse models may improve our understanding of disease mechanisms and lead to new treatment strategies. Here, we identify modifier loci affecting photoreceptor cell loss in homozygous Mfrprd6 mice, which exhibit a slowly progressive photoreceptor degeneration. A cohort of 63 F2 homozygous Mfrprd6 mice from a (B6.C3Ga-Mfrprd6/J × CAST/EiJ) F1 intercross exhibited a variable number of cell bodies in the retinal outer nuclear layer at 20 weeks of age. Mice were genotyped with a panel of single nucleotide polymorphism markers, and genotypes were correlated with phenotype by quantitative trait locus (QTL) analysis to map modifier loci. A genome-wide scan revealed a statistically significant, protective candidate locus on CAST/EiJ Chromosome 1 and suggestive modifier loci on Chromosomes 6 and 11. Multiple regression analysis of a three-QTL model indicated that the modifier loci on Chromosomes 1 and 6 together account for 26% of the observed phenotypic variation, while the modifier locus on Chromosome 11 explains only an additional 4%. Our findings indicate that the severity of the Mfrprd6 retinal degenerative phenotype in mice depends on the strain genetic background and that a significant modifier locus on CAST/EiJ Chromosome 1 protects against Mfrprd6-associated photoreceptor loss.

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“…Compared to wild-type control iPS-RPE cells, patient iPS-RPE containing a mutation in the Mfrp gene exhibited the loss of apical microvilli as observed by electron microscopy. This result was in stark contrast to the phenotype Mfrp rd6 /Mfrp rd6 mice RPE, which showed higher densities of apical microvilli (Fogerty and Besharse 2011). Because differences in phenotypic expression can be observed among species with the same genetic mutation, it is important to study patient-specific cell lines as a complement to mouse models.…”

Section: Progress Of Retinal Disease Modelingmentioning

confidence: 83%

Personalized Medicine: Cell and Gene Therapy Based on Patient-Specific iPSC-Derived Retinal Pigment Epithelium Cells

Chan

Nguyen

et al. 2015

Retinal Degenerative Diseases

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Interest in generating human induced pluripotent stem (iPS) cells for stem cell modeling of diseases has overtaken that of patient-specific human embryonic stem cells due to the ethical, technical, and political concerns associated with the latter. In ophthalmology, researchers are currently using iPS cells to explore various applications, including: (1) modeling of retinal diseases using patient-specific iPS cells; (2) autologous transplantation of differentiated retinal cells that undergo gene correction at the iPS cell stage via gene editing tools (e.g., CRISPR/Cas9, TALENs and ZFNs); and (3) autologous transplantation of patient-specific iPS-derived retinal cells treated with gene therapy. In this review, we will discuss the uses of patient-specific iPS cells for differentiating into retinal pigment epithelium (RPE) cells, uncovering disease pathophysiology, and developing new treatments such as gene therapy and cell replacement therapy via autologous transplantation.

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174delG Mutation in Mouse MFRP Causes Photoreceptor Degeneration and RPE Atrophy

Cited by 44 publications

References 25 publications

Gene Therapy for Retinitis Pigmentosa Caused by MFRP Mutations: Human Phenotype and Preliminary Proof of Concept

Gene Therapy for Retinitis Pigmentosa Caused by MFRP Mutations: Human Phenotype and Preliminary Proof of Concept

Genetic modifier loci of mouse Mfrprd6 identified by quantitative trait locus analysis

Personalized Medicine: Cell and Gene Therapy Based on Patient-Specific iPSC-Derived Retinal Pigment Epithelium Cells

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