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Membrane frizzled-related protein gene-related ophthalmological syndrome: 30-month follow-up of a sporadic case and review of genotype-phenotype correlation in the literature.

ABSTRACT: PURPOSE: To report a new sporadic case of membrane frizzled-related protein gene (MFRP)-related syndrome with a 30-month follow-up, and to review the literature for genotype-phenotype correlation in MFRP mutations. METHODS: A complete ophthalmological evaluation was performed at presentation and 30 months later, including best-corrected visual acuity test, slit lamp examination, fundoscopy, kinetic perimetry, electroretinography, fundus imaging (color, red-free, and autofluorescence), and morphologic-biometric analysis of the eye structures with an optical biometer, anterior-segment optical coherence tomography, retinal optical coherence tomography, and a confocal scanning laser for optic nerve head study. Polymerase chain reaction amplification of DNA obtained from peripheral blood lymphocytes and nucleotide sequencing of the complete MFRP gene were performed. The literature on cases of posterior microphthalmos and retinitis pigmentosa associated with MFRP mutations was reviewed. RESULTS: A 33-year-old female patient presented with posterior microphthalmos, retinitis pigmentosa with patches of retinal pigmented epithelium atrophy and scarce pigment mobilization, foveoschisis, and optic nerve drusen. After 30 months, progression of rod-cone retinal degeneration was detected. One obligate carrier showed a normal eye phenotype. A homozygote mutation in the MFRP gene (c.492delC), predicting a truncated protein (P166fsX190), was identified with genetic analysis. To our knowledge, 17 cases of MFRP-related syndrome have been reported in the literature, including the patient described herein. The phenotype of the syndrome, expressivity, and age of onset varied among and within the affected families. However, all patients sharing homozygous mutation c.492delC (alternatively named c.498delC) showed a complete phenotype (including foveoschisis and optic nerve head drusen), and similar fundus characteristics. CONCLUSIONS: A new sporadic case of MFRP-related syndrome is reported. Review of the literature showed variability in the phenotype, but initial elements of genotype-phenotype correlation have been identified in patients sharing the mutation of the present case.

SUBMITTER: Neri A

PROVIDER: S-EPMC3482175 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Membrane frizzled-related protein gene-related ophthalmological syndrome: 30-month follow-up of a sporadic case and review of genotype-phenotype correlation in the literature.

Neri Alberto A Leaci Rosachiara R Zenteno Juan C JC Casubolo Cristina C Delfini Elisabetta E Macaluso Claudio C

Molecular vision 20121026

<h4>Purpose</h4>To report a new sporadic case of membrane frizzled-related protein gene (MFRP)-related syndrome with a 30-month follow-up, and to review the literature for genotype-phenotype correlation in MFRP mutations.<h4>Methods</h4>A complete ophthalmological evaluation was performed at presentation and 30 months later, including best-corrected visual acuity test, slit lamp examination, fundoscopy, kinetic perimetry, electroretinography, fundus imaging (color, red-free, and autofluorescence ...[more]

PMID: 23112574

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Project description:PurposeJoubert syndrome (JS) is caused by mutations in >34 genes that encode proteins involved with primary (nonmotile) cilia and the cilium basal body. This study describes the varying ocular phenotypes in JS patients, with correlation to systemic findings and genotype.DesignPatients were systematically and prospectively examined at the National Institutes of Health (NIH) Clinical Center in the setting of a dedicated natural history clinical trial.ParticipantsNinety-nine patients with JS examined at a single center.MethodsAll patients underwent genotyping for JS, followed by complete age-appropriate ophthalmic examinations at the NIH Clinical Center, including visual acuity (VA), fixation behavior, lid position, motility assessment, slit-lamp biomicroscopy, dilated fundus examination with an indirect ophthalmoscope, and retinoscopy. Color and fundus autofluorescence imaging, Optos wide-field photography (Dunfermline, Scotland, UK), and electroretinography (ERG) were performed when possible.Main outcome measuresThe VA (with longitudinal follow-up where possible), ptosis, extraocular muscle function, retinal and optic nerve status, and retinal function as measured by ERG.ResultsAmong patients with JS with quantifiable VA (68/99), values ranged from 0 logarithm of the minimum angle of resolution (logMAR) (Snellen 20/20) to 1.5 logMAR (Snellen 20/632). Strabismus (71/98), nystagmus (66/99), oculomotor apraxia (60/77), ptosis (30/98), coloboma (28/99), retinal degeneration (20/83), and optic nerve atrophy (8/86) were identified.ConclusionsWe recommend regular monitoring for ophthalmological manifestations of JS beginning soon after birth or diagnosis. We demonstrate delayed visual development and note that the amblyogenic time frame may last significantly longer in JS than is typical. In general, patients with coloboma were less likely to display retinal degeneration, and those with retinal degeneration did not have coloboma. Severe retinal degeneration that is early and aggressive is seen in disease caused by specific genes, such as CEP290- and AHI1-associated JS. Retinal degeneration in INPP5E-, MKS1-, and NPHP1-associated JS was generally milder. Finally, ptosis surgery can be helpful in a subset of patients with JS; decisions as to timing and benefit/risk ratio need to be made on an individual basis according to expert consultation.

Project description:Obesity is associated with an increase in ?-cell mass in response to the rising demand for insulin. ?-cell plasticity is essential to maintaining glucose homeostasis, however, the cellular and molecular mechanisms by which ?-cell mass is regulated remain poorly understood. Recently, we described the existence of a crosstalk between the peripancreatic adipose tissue and ?-cells as a novel mechanism that participates in the regulation of ?-cell plasticity. Here, we identify the secreted frizzled-related protein (Sfrp) 5 as down-regulated in the pancreatic islets of obese rats as well as in the pancreatic islets of human obese patients. Our results demonstrate that the silencing of Sfrp5 induces an increase in ?-cell proliferation, which we correlate with the activation of Wnt signaling and of the MAPK and PI3 kinase pathways. Together, these findings expand our understanding of the mechanisms underlying ?-cell proliferation under conditions of obesity. Furthermore, this study opens new insights into the specific targeting of Sfrp5 as a novel therapeutic strategy for balancing ?-cell mass. Adult male Wistar rats (Charles River Laboratories, Wilmington, MA), 7 wk old (weighing 225–250 g), were caged individually in a 12-h light, 12-h dark cycle in a temperature- and humidity-controlled environment. Animals were divided into two dietary sets for 30 days. One group was fed with standard chow diet (supplying 8% of calories as fat; type AO4 from Panlab, Barcelona, Spain). The second group was fed with a cafeteria diet (66% of calories as fat), as previously described (Endocrinology 2012;153:177-87). Pancreatic islets were isolated through collagenase perfusion of the pancreas, Histopaque gradient and hand-picking under microscopic guidance. Ten micrograms of total RNA from islets were converted into cRNA, biotinylated, fragmented, and hybridized to GeneChip Rat Genome 230 2.0 (Affymetrix, Santa Clara, CA). Ten microarrays were hybridized, five with independent samples coming from rats fed with standard chow (lean group) and five with independent samples coming from rats fed with the cafeteria diet (obese group).

Dataset Information

Membrane frizzled-related protein gene-related ophthalmological syndrome: 30-month follow-up of a sporadic case and review of genotype-phenotype correlation in the literature.

Publications

Membrane frizzled-related protein gene-related ophthalmological syndrome: 30-month follow-up of a sporadic case and review of genotype-phenotype correlation in the literature.

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