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At least 451 records · Page 25Linked to original sources
PubMed2004

Improvement of neuronal visual responses in the superior colliculus in Prph2(Rd2/Rd2) mice following gene therapy.

Inherited retinal degenerations are a major cause of blindness for which there are currently no effective therapies. Significant progress concerning in vivo gene transfer has allowed retardation of degeneration or retinal functional improvement in different animal models. To date, there has been no evaluation of the impact of these treatments on higher visual function, a critical step for validating gene therapy treatment strategies. Here, we have used adeno-associated (AAV2)-mediated gene transfer of Prph2 in the Prph2(Rd2/Rd2) mouse model. We then assessed higher visual function by recording from central visually responsive neurons in the superior colliculus and improvements were correlated in individual animals with retinal function (ERG) and histological and biochemical changes. Although gene replacement therapy only partially restores photoreceptor morphology, it results in a 300% increase of the visual cycle protein rhodopsin, leading to retinal function improvement (250% increase of b-wave amplitude) and significantly higher central visual responses (166% increase at 24 cd/m(2)). These findings suggest that gene replacement therapy leading to even relatively modest structural improvement may result in improved central visual function.

Action Potentials↗
PubMed2005

Identification of lynx2, a novel member of the ly-6/neurotoxin superfamily, expressed in neuronal subpopulations during mouse development.

We isolated a new gene which shares all the features of the Ly-6/neurotoxin superfamily, from gene organization to predicted 3D structure. As it is preferentially expressed in the nervous system, we called this gene lynx2, by analogy with lynx1, a nAChR modulator. In embryonic and postnatal mouse, lynx2 is expressed in postmitotic central and peripheral neurons. These include subpopulations of motor neurons, sensory neurons, interneurons and neurons of the autonomous nervous system. In addition, lynx2 is transiently expressed around the growing nerves in the limb bud. Comparison of its spatio-temporal expression pattern with that of two other members of this family, lynx1 and ly-6h, shows that these genes are detected both in distinct and overlapping neuron populations.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Localization of mechanosensitive channel TRPV4 in mouse skin.

A transient receptor potential (TRP) family, TRPV4, is a calcium-permeable swell-activated channel, playing a role in cutaneous mechanosensation. To elucidate the localization in the mechanosensitive endings, we found with immunohistochemistry in mice that TRPV4 was expressed both by small (low threshold) and large (high threshold) dorsal root ganglia neurons. In addition to free nerve endings, TRPV4 was specifically located at cutaneous mechanosensory terminals co-localized with neurofilament 200, including Meissner, Merkel, penicillate and intraepidermal terminals but not including hair follicle palisades. The distribution suggests that the sensation of pressure by mechanosensitive TRPV4 channel is transmitted through A- as well as C-fiber.

Animals↗
PubMed2005

Expression of aquaporin-1 immunoreactivity by photoreceptor cells in the mouse retina.

Aquaporin water channels play a crucial role in the maintenance of ionic and osmotic homeostasis in the neural tissue. In the sensory retina, aquaporin-4 is expressed by Müller glial cells, predominantly in the inner retina, while aquaporin-1 is expressed mainly in the outer retina. However, it is unknown whether aquaporin-1 expression occurs in Müller cells or photoreceptor cells. By using immunohistochemical staining of retinal slices from rds mice, we show that the immunoreactivity for aquaporin-1 disappears along with the photoreceptor cell degeneration. In suspensions of dissociated retinal cells from control mice, photoreceptor cells expressed aquaporin-1 immunoreactivity while Müller cells were largely devoid of staining. The data suggest that photoreceptor cells, but not Müller cells, express aquaporin-1 in the murine retina.

Animals↗
PubMed2004

The contribution of autophosphorylated alpha-calcium-calmodulin kinase II to injury-induced persistent pain.

Increases in neuronal activity in response to tissue or nerve injury can lead to prolonged functional changes in the spinal cord resulting in an enhancement/sensitization of nociceptive processing. To assess the contribution of alpha-calcium-calmodulin kinase II (alpha-CaMKII) to injury-induced inflammation and pain, we evaluated nociceptive responses in mice that carry a point mutation in the alpha-CaMKII gene at position 286 (threonine to alanine). The mutated protein is unable to autophosphorylate and thus cannot function independently of calcium and calmodulin. Responses to acute noxious stimuli did not differ between alpha-CaMKII T286A mutant and wild type mice. However, the ongoing pain produced by formalin injury was significantly reduced in the mutant mice, as was formalin-evoked spinal Fos-immunoreactivity. In contrast, the decreased mechanical and thermal thresholds associated with nerve injury, Complete Freund's Adjuvant-induced inflammation or formalin-evoked tissue injury were manifest equally in wild-type and mutant mice. Double-labeling immunofluorescence studies revealed that in the mouse alpha-CaMKII is expressed in the superficial dorsal horn as well as in a population of small diameter primary afferent neurons. In summary, our results suggest that alpha-CaMKII, perhaps secondary to an N-methyl-D-aspartate-mediated calcium increase in postsynaptic dorsal horn nociresponsive neurons, is a critical contributor to the spontaneous/ongoing component of tissue-injury evoked persistent pain.

Animals↗
PubMed2005

Cone-rod dystrophy, intrafamilial variability, and incomplete penetrance associated with the R172W mutation in the peripherin/RDS gene.

PURPOSE: To determine the underlying molecular genetic basis of a retinal dystrophy identified in a 5-generation family, and to examine the phenotype and degree of intrafamilial variability. DESIGN: Family genetic study. PARTICIPANTS: Nine affected individuals from a nonconsanguineous British family. METHODS: Ophthalmologic examination, color vision testing, fundus photography, autofluorescence imaging, and electrophysiological assessment were performed. The clinical notes of 2 additional deceased affected family members were also reviewed. Blood samples were taken for DNA extraction, with linkage analysis being performed, and subsequent mutation screening of the peripherin/RDS gene. RESULTS: Linkage analysis established a disease interval on chromosome 6p, which harbored the retinal candidate gene, peripherin/RDS. The 3 coding exons of the peripherin/RDS gene were subsequently screened for mutations in affected and unaffected family members. A nonconservative missense substitution, Arg172Trp (R172W), segregated uniquely in all affected subjects. The majority of subjects carrying the R172W peripherin/RDS mutation complained of reduced central vision starting in the second or third decade, with subsequent gradual deterioration of visual acuity and color vision. Three affected individuals complained of nyctalopia. A range of macular appearances were seen, varying from a typical granular appearance to extensive macular atrophy. Autofluorescence imaging in the majority of individuals identified a highly characteristic speckled macular appearance. All affected subjects had abnormal pattern electroretinograms (ERGs) consistent with macular dysfunction and 4 subjects showed additional full-field ERG abnormalities, providing evidence of generalized retinal dysfunction. There was marked variation in the clinical phenotype in those individuals who carried the R172W peripherin/RDS mutation, ranging from severe cone-rod dystrophy to asymptomatic individuals with normal retinal function. CONCLUSIONS: The Arg172Trp (R172W) peripherin/RDS mutation has been previously reported to cause a fully penetrant progressive macular dystrophy with high intrafamilial and interfamilial consistency of phenotype. This is the first report describing marked intrafamilial variation associated with this mutation, including nonpenetrance. These findings are clinically important in relation to advice on prognosis and accurate genetic counseling.

Adolescent↗
PubMed2005

Nociceptor-specific gene deletion using heterozygous NaV1.8-Cre recombinase mice.

NaV1.8 is a voltage-gated sodium channel expressed only in a subset of sensory neurons of which more than 85% are nociceptors. In order to delete genes in nociceptive neurons, we generated heterozygous transgenic mice expressing Cre recombinase under the control of the NaV1.8 promoter. Functional Cre recombinase expression replicated precisely the expression pattern of NaV1.8. Cre expression began at embryonic day 14 in small diameter neurons in dorsal root, trigeminal and nodose ganglia, but was absent in non-neuronal or CNS tissues into adulthood. Sodium channel subtypes were normal in isolated DRG neurons. Pain behaviour in response to mechanical or thermal stimuli, and in acute, inflammatory and neuropathic pain was also normal. These data demonstrate that the heterozygous NaV1.8-Cre mouse line is a useful tool to analyse the effects of deleting floxed genes on pain behaviour.

Animals↗
PubMed2004

Systemic but not intraocular Epo gene transfer protects the retina from light-and genetic-induced degeneration.

Molecules with neurotrophic activity are being evaluated for treatment of retinitis pigmentosa in animal models. In particular, great interest has been focused recently on erythropoietin (Epo). Evidence of its neurotrophic activity comes mainly from data demonstrating photoreceptor protection in a rodent light-damage model through systemic administration of a recombinant form of this hormone. Our goal was to test whether Epo retinal gene transfer can rescue or delay photoreceptor cell death. We delivered adeno-associated viral vectors encoding Epo intraocularly and, for comparison, intramuscularly to one light-induced and two genetic models of retinal degeneration. Intraocular Epo gene transfer resulted in sustained hormone expression in the eye, which was undetectable systemically. In contrast, Epo intramuscular gene transfer resulted in hormone secretion in the circulation, which was not detected in ocular fluids. The protein secreted from muscle and retina is of the same molecular weight as a commercial recombinant human Epo. Interestingly, following systemic but not intraocular Epo delivery, morphological photoreceptor protection was observed in the light-damage and rds/peripherin (Prph2) models of retinal degeneration. In the light-damage model, the morphological rescue was accompanied by a significant electrophysiological improvement of photoreceptor function. In contrast, no photoreceptor rescue was observed following Epo gene transfer in the rd10 model. This suggests that different apoptotic mechanisms, with varying sensitivities to Epo, occur in different retinal degeneration models. In conclusion, our data support Epo as a neuroprotective agent in some, but not all, retinal degenerations. Further, rescue is observed in specific models after systemic but not intraocular Epo gene transfer.

Animals↗
PubMed2006

In contrast to AAV-mediated Cntf expression, AAV-mediated Gdnf expression enhances gene replacement therapy in rodent models of retinal degeneration.

While AAV- and lentivirus-mediated gene replacement therapy can produce structural and functional improvements in various animal models of inherited retinal degeneration, this approach often has very limited effects on the rate of photoreceptor cell loss. Neurotrophic factors such as ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) have been shown to prolong photoreceptor survival in rodent models of retinal degeneration, but AAV-mediated Cntf expression also results in suppression of electrophysiological responses from the retina. In this study using mice, we show that while the deleterious effects mediated by CNTF are dose-dependent, administering a dose of CNTF that does not adversely affect retinal function precludes its ability to delay photoreceptor cell death. In evaluating GDNF as a neuroprotective agent, we show that AAV-mediated Gdnf expression does not produce adverse effects similar to those of CNTF. In addition, we demonstrate the ability of AAV-mediated delivery of Gdnf to slow cell death in two rodent models of retinitis pigmentosa and to enhance retinal function in combination with the relevant gene replacement therapy. These data show for the first time that a combination of these approaches can provide enhanced rescue over gene replacement or growth factor therapy alone.

Animals↗
PubMed2001

Splice site mutation in the peripherin/RDS gene associated with pattern dystrophy of the retina.

PURPOSE: To report the phenotype and genotype of a splice site mutation at intron 2 of the peripherin/RDS gene in four half-siblings with pattern dystrophy of the retina. DESIGN: Experimental study. METHODS: In four siblings with a common mother and three separate fathers, complete ophthalmic examination, pedigree, electrophysiologic testing, and fluorescein angiography studies were obtained. Genomic DNA from serum lymphocytes was isolated and used as a template for primers specific for the cone homeobox gene (CRX), rhodopsin (RHO), and peripherin/RDS genes to conduct single stranded conformational analysis and cycle sequencing. RESULTS: The pedigree of four affected siblings suggested probable autosomal dominance transmission of pattern dystrophy. In the four siblings, best corrected visual acuity ranged from 20/20 to 20/80 by Snellen chart. Clinical findings included discrete, localized degenerative changes of the macular retinal pigment epithelium in all patients, with subclassification foveal. One patient exhibited pigment clumping within the atrophic areas. Another patient exhibited yellow flecks diffusely in the macula. Fluorescein angiographic findings included central hypofluorescence with a surrounding rim of hyperfluorescence that corresponded to the observed fundus lesions and window defects. There was a range of electroretinography (ERG) and electrooculography (EOG) findings. One patient demonstrated both cone and rod dysfunction on ERG testing and another demonstrated decreased rod function. EOG testing was normal in two patients and mildly diminished in one patient. DNA sequencing identified a point mutation in intron 2 of the peripherin/RDS gene, consisting of an A to T change at 1068+3, present in all four affected patients. CONCLUSIONS: Four siblings with pattern dystrophy of the retina presented a splice site mutation in the peripherin/RDS gene.

Adult↗
PubMed2003

A novel mutation in the RDS/Peripherin gene causes adult-onset foveomacular dystrophy.

PURPOSE: To describe a novel mutation in the RDS/Peripherin gene that results in a moderately severe form of adult-onset foveomacular dystrophy. DESIGN: Observational case series. METHODS: Selected members of a family with adult-onset foveomacular dystrophy underwent complete ophthalmic evaluation, including fundus photography and fluorescein angiography, in a tertiary care referral center. The study population consisted of 12 members of a Caucasian kindred. After providing informed consent, patients donated blood for genomic DNA extraction and mutational screening using standard techniques. The main outcome measure were the presence of a RDS/Peripherin gene mutation in a patient with the disease and its absence in unaffected family members and controls. RESULTS: Eight affected family members and no unaffected family members demonstrated a single guanine base deletion at nucleotide 112 that led to premature termination at amino acid 38 of RDS/Peripherin polypeptide. This frameshift mutation results in truncation of nearly 90% of the gene product, thus probably representing a null allele. That results in a relatively severe phenotype, with choroidal neovascularization developing in two patients and geographic atrophy involving the macula in three patients. CONCLUSIONS: We describe a frameshift null mutation in the RDS/Peripherin gene associated with a relatively severe manifestation of adult-onset foveomacular dystrophy in affected family members.

Adult↗
PubMed1996

Retinitis punctata albescens associated with the Arg135Trp mutation in the rhodopsin gene.

PURPOSE: To screen for mutations in the rhodopsin, peripherin/RDS, and ROM1 genes in a family affected with retinitis punctata albescens. Because clinical heterogeneity was observed in this family, with some members affected with retinitis punctata albescens and one member affected with features typical of retinitis pigmentosa, we analyzed the apolipoprotein E gene to elucidate this unusual intrafamilial heterogeneity. METHODS: The coding sequences of these genes were analyzed with a combination of single-strand conformation polymorphism and direct sequence analysis. Haplotypes of the apolipoprotein E gene were analyzed by polymerase chain reaction and enzymatic digestion. RESULTS: The Arg135Trp mutation in the rhodopsin gene was observed in all affected members of this family, but no mutation was detected in the peripherin/RDS or ROM1 genes. The e4 allele of the apolipoprotein E gene apparently cosegregated with the albescens phenotype in this family. CONCLUSIONS: The albescent phenotype in retinal dystrophy appears to not be caused exclusively by a peripherin/RDS gene mutation, and we suggest that the apolipoprotein E gene may play a role in the albescent phenotype.

Adolescent↗
PubMed1996

Autosomal dominant central areolar choroidal dystrophy caused by a mutation in codon 142 in the peripherin/RDS gene.

PURPOSE: Because several macular dystrophies are caused by mutations in the peripherin/RDS gene, we examined autosomal dominant and sporadic cases of central areolar choroidal dystrophy for mutations in the peripherin/RDS gene. METHODS: DNA sequence analysis of the peripherin/RDS gene was performed in four sporadic cases and in ten affected and nine unaffected individuals from seven families with autosomal dominant central areolar choroidal dystrophy. RESULTS: An Arg-142-Trp mutation in the peripherin/RDS gene was found in ten affected family members in seven families. Among these, a 69-year-old man with the Arg-142-Trp mutation, who was unaffected six years before blood sample analysis, showed a parafoveal area of chorioretinal atrophy. The 65-year-old sister of this family had the Arg-142-Trp mutation with no macular abnormalities, but she might still develop central areolar choroidal dystrophy at an older age. No mutation was found in the four sporadic cases. CONCLUSION: Autosomal dominant central areolar choroidal dystrophy, studied in seven families, is caused by an Arg-142-Trp mutation in the peripherin/RDS gene.

Adult↗
PubMed1995

Retinitis pigmentosa associated with a dominant mutation in codon 46 of the peripherin/RDS gene (arginine-46-stop).

PURPOSE: We identified genetic mutations and characterized their associated phenotypes in patients with retinitis pigmentosa. METHODS: Patients with retinitis pigmentosa were prospectively examined and screened for genetic mutations. RESULTS: A 46-year-old man with retinitis pigmentosa was found to have a heterozygous mutation in the peripherin/RDS gene (arginine-46-stop). He had late onset of symptoms and demarcated peripheral retinal atrophy. All five first-degree relatives including his parents had no detectable mutations or retinitis pigmentosa. Genotypic data were consistent with reported family structure. CONCLUSIONS: This study shows that new dominant mutations are a rare cause of isolated, or simplex, cases of retinitis pigmentosa. Identification of these mutations is helpful for genetic counseling.

Adult↗
PubMed2000

A peptide analogue to a fusion domain within photoreceptor peripherin/rds promotes membrane adhesion and depolarization.

Photoreceptor peripherin/rds promotes membrane fusion, through a putative fusion domain located within the C-terminus (Boesze-Battaglia et al., Biochemistry 37 (1998) 9477-9487). A peptide analogue to this region, PP-5, competitively inhibits peripherin/rds mediated fusion in a cell free assay system. To characterize how this region is involved in the fusion process we investigated two of the individual steps in membrane fusion, membrane adhesion and membrane destabilization inferred from depolarization studies. Membrane depolarization was measured as the collapse of a valinomycin induced K(+) diffusion potential in model membranes, using a potential sensitive fluorescent probe, diS-C(2)-5. PP-5 induced membrane depolarization in a concentration dependent manner. PP-5 has been shown by Fourier transform infrared spectroscopy to be an amphiphilic alpha-helix. Therefore, the requirement for an amphiphilic alpha-helix to promote depolarization was tested using two mutant peptides designed to disrupt either the amphiphilic nature of PP-5 (PP-5AB) or the alpha-helical structure (PP-5HB). PP-5AB inhibited PP-5 induced depolarization when added in an equimolar ratio to PP-5. Neither mutant peptide alone or in combination with PP-5 had any effect on calcium dependent vesicle aggregation. Using non-denaturing gel electrophoresis and size exclusion chromatography techniques PP-5 was shown to form a tetrameric complex. Equimolar mixtures of PP-5 and PP-5AB formed a heterotetramer which was unable to promote membrane depolarization. The hypothesis that PP-5 tetramers promote membrane depolarization is consistent with the calculated Hill coefficient of 3.725, determined from a Hill analysis of the depolarization data.

Amino Acid Sequence↗
PubMed2000

Diurnal metabolism of dopamine in dystrophic retinas of homozygous and heterozygous retinal degeneration slow (rds) mice.

Dopamine metabolism was studied in dystrophic retinal degeneration slow (rds) mice which carry a mutation in the rds/peripherin gene. RDS mutations in humans cause several forms of retinal degeneration. Dopamine synthesis and utilization were analyzed at various time points in the diurnal cycle in homozygous rds/rds retinas which lack photoreceptor outer segments and heterozygous rds/+ retinas which have short malformed outer segments. Homozygous retinas exhibited depressed dopamine synthesis and utilization while the heterozygous retina retained a considerable level of activity which was, nevertheless, significantly lower than that of normal retinas. By one year, heterozygous rds/+ retinas which had lost half of the photoreceptors still maintained significant levels of dopamine metabolism. Normal characteristics of dopamine metabolism such as a spike in dopamine utilization at light onset were observed in mutant retinas. However, light intensity-dependent changes in dopamine utilization were observed in normal but not rds/+ retinas. The findings of this study suggest that human patients with peripherin/rds mutations, or other mutations that result in abnormal outer segments that can still capture light, might maintain light-evoked dopamine metabolism and dopamine-dependent retinal functions during the progression of the disease, proportional to remaining levels of light capture capabilities. However, visual deficits due to reduced light-evoked dopamine metabolism and abnormal patterns of dopamine utilization could be expected in such diseased retinas.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2003

Autosomal dominant macular dystrophy in a large Canadian family.

BACKGROUND: We studied a large Canadian family (178 total family members) spanning seven generations with autosomal dominant macular dystrophy. We performed a study to identify the gene mutation responsible for the disease in the family. METHODS: Participating family members were evaluated clinically. Genetic linkage, genotyping, mutation screening and an extensive genealogic investigation were performed. RESULTS: The common clinical findings in affected family members included progressive early- to mid-onset visual loss and extensive areas of central chorioretinal atrophy. Two-point linkage analysis indicated linkage to chromosome 6p. Direct DNA sequencing showed a C/T transition in codon 172 of the retinal degeneration slow (RDS) gene creating an amino acid change to Arg172Trp. Haplotype analysis of affected family members using microsatellite markers distributed around the RDS gene locus revealed that the markers were not conserved when compared to members of British families with the Arg172Trp mutation. Genealogic studies indicated the family immigrated to Canada from Ireland in 1843. INTERPRETATION: A newly identified large family with autosomal dominant macular dystrophy is described. The phenotypic appearance of the fundus is similar to that of previously described patients with an Arg172Trp mutation in the RDS gene. Haplotype analysis of markers spanning the disease locus identified a new founder for this mutation. The identification of the disease-causing gene in this family allows for better genetic counselling for patients with this condition and provides a basis to distinguish clinically similar types of macular dystrophy based on the clinical phenotype.

Adult↗