Neuronal intermediate filament overexpression and neurodegeneration in transgenic mice.
Explore the source record for details and available documents.
Animals↗
SEARCH · Search PubMed
Results for “Peripherins”
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Peripherin/RDS gene mutation (Pro210Leu) and polymorphisms in Japanese patients with retinal dystrophies.
PURPOSE: To determine the frequency of peripherin/RDS (retinal degeneration slow) gene mutations in Japanese patients with retinal dystrophies. METHODS: We analyzed the peripherin/RDS gene in 54 unrelated Japanese patients with retinal dystrophies. Genomic DNA was amplified by polymerase chain reaction (PCR) and the PCR products were sequenced. We also examined 100 healthy subjects, seeking mutations or variations of the peripherin/RDS gene. RESULTS: Of the 54 Japanese patients, one with retinitis pigmentosa had a heterozygous C to T change at the second nucleotide at codon 210 of exon 2 (CCT to CTT/Pro210Leu) of the peripherin/RDS gene. None of the 100 individuals with normal fundi had the Pro210Leu mutation of the peripherin/RDS gene. Three variants of the peripherin/RDS gene (GTC to GTT/Val106Val, Glu304Gln, and Gly338Asp) were also found. The first variation (GTC to GTT/Val106Val) was silent. Two concurrent missense variations (Glu304Gln and Gly338Asp) were seen in 25.9% of the affected patients and in 29% of the healthy individuals. CONCLUSION: A novel mutation (Pro210Leu) of the peripherin/RDS gene has been found in one Japanese patient with retinitis pigmentosa. The alterations of Val106Val, Glu304Gln, and Gly338Asp may be polymorphic variants in the Japanese population.
DNA Mutational Analysis↗
Analysis of peripherin/RDS gene for Japanese retinal dystrophies.
We studied 133 Japanese patients with retinal dystrophies to detect peripherin/RDS (retinal degeneration slow) gene defects. The patients analyzed included 52 with autosomal dominant retinitis pigmentosa, 36 with autosomal recessive retinitis pigmentosa, 3 with simplex retinitis pigmentosa, 12 with cone-rod dystrophy, 5 with rod-cone dystrophy, 3 with vitelliform macular dystrophy (Best's disease), 4 with macular dystrophy, 2 with cone dystrophy, 2 with fundus flavimaculatus, 2 with fundus albipunctatus, and 12 with retinitis pigmentosa with macular degeneration as well as 40 unrelated normal persons. Three exons of the peripherin/RDS gene cut into 150-200 base-pair fragments were amplified by polymerase chain reaction and screened by single-strand conformation polymorphism. The DNA fragments with any suspected variations were directly sequenced. Eight point mutations were detected. Among them, two missense mutations at codons 304 and 338 result in an amino acid substitution of glutamine for glutamic acid and aspartic acid for glycine, respectively. However, they were not cosegregated with the diseases, and these mutations were also commonly found in normal controls. For these controls, the proportion of transversion from G to C at codon 304 (GAG-->CAG) and transition from G to A at codon 338 (GGC-->GAC) were 0.192 +/- 0.045 and 0.173 +/- 0.053, respectively. Our results suggest that a peripherin/RDS gene mutation might be rare in Japanese patients.
DNA↗
Photoreceptor renewal: a role for peripherin/rds.
Visual transduction begins with the detection of light within the photoreceptor cell layer of the retina. Within this layer, specialized cells, termed rods and cones, contain the proteins responsible for light capture and its transduction to nerve impulses. The phototransductive proteins reside within an outer segment region that is connected to an inner segment by a thin stalk rich in cytoskeletal elements. A unique property of the outer segments is the presence of an elaborate intracellular membrane system that holds the phototransduction proteins and provides the requisite lipid environment. The maintenance of normal physiological function requires that these postmitotic cells retain the unique structure of the outer segment regions--stacks of membrane saccules in the case of rods and a continuous infolding of membrane in the case of cones. Both photoreceptor rod and cone cells achieve this through a series of coordinated steps. As new membranous material is synthesized, transported, and incorporated into newly forming outer segment membranes, a compensatory shedding of older membranous material occurs, thereby maintaining the segment at a constant length. These processes are collectively referred to as ROS (rod outer segment) or COS (cone outer segment) renewal. We review the cellular and molecular events responsible for these renewal processes and present the recent but compelling evidence, drawn from molecular genetic, biochemical, and biophysical approaches, pointing to an essential role for a unique tetraspanning membrane protein, called peripherin/rds, in the processes of disk morphogenesis.
Animals↗
Role of peripherin/rds in vertebrate photoreceptor architecture and inherited retinal degenerations.
The vertebrate photoreceptor outer segment (OS) is a highly structured and dynamic organelle specialized to transduce light signals. The elaborate membranous architecture of the OS requires peripherin/rds (P/rds), an integral membrane protein and tetraspanin protein family member. Gene-level defects in P/rds cause a broad variety of late-onset progressive retinal degenerations in humans and dysmorphic photoreceptors in murine and Xenopus models. Although proposed to fulfill numerous roles related to OS structural stability and renewal, P/rds molecular function remains uncertain. An increasingly resolved model of this protein's oligomeric structure can account for disease inheritance patterns and severity in some instances. Nonetheless, the pathogenic mechanisms underlying the uniquely broad spectrum of retinal diseases associated with P/rds defects are not currently well understood. Recent findings point to the possibility that P/rds acts as a multifunctional scaffolding protein for OS architecture and that partial-loss-of-function mutations contribute to the hallmark phenotypic heterogeneity associated with inherited defects in RDS.
Amino Acid Sequence↗
Fusion between retinal rod outer segment membranes and model membranes: functional assays and role for peripherin/rds.
Explore the source record for details and available documents.
Amino Acid Sequence↗
In vivo assessment of photoreceptor function in human diseases caused by photoreceptor-specific gene mutations.
Explore the source record for details and available documents.
Electroretinography↗
Expression and characterization of peripherin/rds-rom-1 complexes and mutants implicated in retinal degenerative diseases.
Nearly 40 disease-linked mutations have been reported for peripherin/rds to date; heterologous expression in tissue culture cells offers a valuable means of efficiently characterizing the biochemical properties of the various mutants. Peripherin/rds is proposed to act as an essential structural element in outer segment disk morphogenesis, and a present transgenic mice offer the sole tractable system in which recombinant peripherin/rds may be examined functionally in situ. Because the generation and characterization of transgenic animals are both expensive and time consuming, heterologous expression in cultured cells offers an important and complementary means of addressing protein structure and function. The immunopurification and detection of the peripherin/rds-rom-1 complex are performed using specific immunochemical reagents, monoclonal and polyclonal antibodies, that are not commonly available. Several laboratories have developed antibodies to peripherin/rds and rom-1 in rabbits and mice, using a variety of immunogens: purified ROS membranes, purified E. coli fusion proteins, and synthetic peptides coupled to proteins. The C-terminal regions appear to be most highly antigenic, although antibodies have been generated to other regions as well. Regardless of their source, antibodies must be thoroughly characterized; specificity is often a function of solution conditions and must be determined empirically. The approach as described here has provided explanations for several instances of peripherin/rds-associated disease, including digenic RP linked to as L185P mutation, and adRP associated with C118/119del and C214S mutations. In addition, the R172W mutation, linked to macular dystrophy and preferential loss in cone function, is shown to behave normally with respect to biosynthesis and subunit assembly; it likely involves a more subtle functional defect that remains to be described. Finally, the methodology reported here has suggested the existence of a novel (homotetrameric) form of peripherin/rds in individuals lacking rom-1; this hypothesis has been confirmed in rom-1 knockout mice. The information obtained thus far demonstrates the utility of using heterologously expressed peripherin/rds and rom-1 to investigate the consequences of disease-linked mutations in these polypeptides. Heterologous cell expression coupled with transgenic mouse methodologies should continue to provide a more detailed understanding of molecular mechanisms underlying inherited retinal degenerative diseases.
Animals↗
Atypical presentation of pattern dystrophy in two families with peripherin/RDS mutations.
PURPOSE: To describe the atypical clinical presentations of pattern dystrophy (PD) in two unrelated families with novel peripherin/RDS mutations. DESIGN: Observational case reports and family genetic study with review of peripherin/RDS mutations. PARTICIPANTS: Affected and unaffected members of two families with PD. METHODS: The probands of two families, as well as other family members, underwent an ophthalmologic assessment including slit-lamp biomicroscopy, applanation tonometry, and a dilated fundus examination. Goldmann visual fields and fluorescein angiography were performed, wherever appropriate. Blood samples were obtained from affected and selected unaffected members of the families for DNA analysis. RESULTS: The proband of family 1 had an acute onset of decreased vision and a yellowish lesion in both maculae that appeared inflammatory. However, resolution of the acute lesion ultimately resulted in fundus changes more typical for PD. Moreover, the proband's sister showed more classic-appearing PD lesions. Screening of the peripherin/RDS gene for sequence variations showed a 2-bp deletion, resulting in a translational frameshift at codon 290 in affected members of the family. The proband's father, who showed this sequence variation, did not have a macular lesion. The proband of family 2 was asymptomatic and showed a fundus phenotype similar to fundus flavimaculatus. The patient had normal visual acuity and did not demonstrate a "dark choroid" on fluorescein angiography. Molecular screening showed a Gln331stop variation in the peripherin/RDS gene. CONCLUSIONS: We describe two novel mutations in the peripherin/RDS gene in two unrelated families with PD. Clinicians should recognize the atypical features that may occur in patients with PD. A suspected diagnosis of PD may be confirmed by the identification of a mutation in the peripherin/RDS gene. In isolated family members with PD, a mutation in this gene may occur even in the absence of a clinically discernible macular lesion.
Adult↗
Clinical features of a previously undescribed codon 216 (proline to serine) mutation in the peripherin/retinal degeneration slow gene in autosomal dominant retinitis pigmentosa.
BACKGROUND: Mutations in the human peripherin/retinal degeneration slow (rds) gene have been found in patients with macular dystrophies as well as in those with autosomal dominant retinitis pigmentosa. The authors studied the clinical features in members of two families with autosomal dominant retinitis pigmentosa and a previously unreported mutation in the peripherin/rds gene. METHODS: Affected family members underwent a clinical ophthalmic examination and electrophysiologic and psychophysical testing. Available family members were evaluated for a mutation in the peripherin/rds gene. RESULTS: A mutation in codon 216 of the peripherin/rds gene, resulting in a substitution of the amino acid serine for proline, was found to segregate with retinitis pigmentosa in these two families. Ocular features of this mutation include a later onset of more notable ophthalmoscopic, electrophysiologic, and psychophysical abnormalities of the retina, an atrophic-appearing foveal lesion, and extrafoveal atrophic and hyperpigmented degenerative retinal changes, which were found more posteriorly than usually seen in patients with retinitis pigmentosa. Visual field testing showed a partial ring scotoma or pear-shaped configuration of the remaining portions of the peripheral fields. CONCLUSION: A previously undescribed mutation in the peripherin/rds gene is responsible for an autosomal dominant retinitis pigmentosa phenotype. This phenotype tends to be associated with the development of an atrophic-appearing foveal lesion, more posterior distribution of pigmentary changes involving the vascular arcades, the presence of a partial ring scotoma or a pear-shaped configuration of the peripheral visual field, and a later onset of more extensive retinal structural and functional impairment.
Adolescent↗
A peripherin/retinal degeneration slow mutation (Pro-210-Arg) associated with macular and peripheral retinal degeneration.
BACKGROUND: Mutations in the peripherin/retinal degeneration slow (RDS) gene have been identified in patients with retinitis pigmentosa and pattern macular dystrophy. The authors initially examined a large family affected with both peripheral and macular degeneration, inherited as an autosomal dominant trait. Screening for peripherin/RDS mutations identified a previously unreported nucleotide alteration in all of the affected individuals. Two additional families later were found to have this same mutation. METHODS: DNA samples from the members of three unrelated families were screened for peripherin/RDS mutations by denaturing gradient gel electrophoresis of the polymerase chain reaction-amplified peripherin/RDS coding sequences. The sequence change that was detected was further characterized by DNA sequencing. Family members were examined and evaluated with psychophysical and electrophysiologic methods. RESULTS: A proline to arginine mutation in codon 210 of peripherin/RDS was found in all clinically affected individuals. Macular changes included extensive geographic atrophy, pigment epithelial changes, and/or drusen. The proline to arginine mutation was not found among 100 healthy individuals, making it unlikely to be a nondisease-causing polymorphism. CONCLUSIONS: The authors identified a novel peripherin/RDS gene mutation associated with autosomal dominant retinal degeneration in patients from three different families. The largest family showed a broad variability in the expressivity of the mutation. The overlap of clinical features with those of age-related maculopathy highlights the need to consider photoreceptor-specific genes as potential factors in the etiology of the latter condition.
Adolescent↗
Looking slim: peripherin/rds and photoreceptor cell morphology.
Explore the source record for details and available documents.
Humans↗
Upregulation of CD44 expression in the retina during the rds degeneration.
In adult mouse retinas the standard form of the cell surface adhesion/receptor molecule CD44 is localized to Müller cell apical microvilli. In the rds (retinal degeneration slow) mouse, however, CD44 immunolabel is increased and distributed throughout the retina by 3 months postnatal. At present, it is unclear if this labeling pattern is due to the increased expression of standard CD44, the expression of variant CD44 isoforms, or an unmasking of CD44 antigenic sites. To further characterize this response, we have studied the expression of CD44 mRNA and protein in rds retinas of different ages. RT-PCR analysis demonstrated one product which represented the message for standard CD44 in adult BALB/c mouse retina and in all ages of rds retinas studied. Upon Southern blotting, this major product was detected along with two minor bands of larger size in all samples. Northern blot analysis demonstrated a major transcript of approximately 4.0 kb and a minor one of 3.0 kb in all BALB/c and rds retinas. By 3 months postnatal in rds retinas, the expression of CD44 message was increased by at least two-fold. Western blot analysis demonstrated the presence of only the standard form of CD44 protein in all BALB/c and rds retinas. An increased amount of this standard CD44 protein was observed in 2, 3, and 6 month rds retinas. Thus, this study demonstrates that the inherited retinal degeneration exhibited by the rds mouse does not cause an altered expression of retinal CD44 isoforms, but does lead to an upregulation in the expression of mRNA and protein for standard CD44.
Aging↗
Sodium channel Na(v)1.6 is expressed along nonmyelinated axons and it contributes to conduction.
Nodes of Ranvier in myelinated fibers exhibit a complex architecture in which specific molecules organize in distinct nodal, paranodal and juxtaparanodal domains to support saltatory conduction. The clustering of sodium channel Na(v)1.6 within the nodal membrane has led to its identification as the major nodal sodium channel in myelinated axons. In contrast, much less is known about the molecular architecture of nonmyelinated fibers. In the present study, Na(v)1.6 is shown to be a significant component of nonmyelinated PNS axons. In DRG C-fibers, Na(v)1.6 is distributed continuously from terminal receptor fields in the skin to the dorsal root entry zone in the spinal cord. Na(v)1.6 is also present in the nerve endings of corneal C-fibers. Analysis of compound action potential recordings from wildtype and med mice, which lack Na(v)1.6, indicates that Na(v)1.6 plays a functional role in nonmyelinated fibers where it contributes to action potential conduction. These observations indicate that Na(v)1.6 functions not only in saltatory conduction in myelinated axons but also in continuous conduction in nonmyelinated axons.
Animals↗
[Hereditary macular dystrophies].
Hereditary macular dystrophies are degenerative diseases of the central area of the retina associating primary anomalies of the retinal pigment epithelium and sensory retina. These conditions, whose hallmark is a loss of visual acuity, are a major cause of blindness and affect patients at all ages. Macular dystrophies group diseases that are heterogenous at the genetic level, as well as at the clinical, histological and physiopathological levels. Monogenic macular dystrophies are rare autosomal dominant conditions, with the exception of Stargardt disease in its typical form, which is not only relatively frequent but is also inherited as an autosomal recessive trait. During the last few years, the molecular bases of these conditions have begun to be elucidated with the identification of several responsible genes. For some macular dystrophies, this new information has confirmed pre-existing hypotheses on their pathophysiology, but for others, the discovery of the disease gene has added further complexity to the disease process. Two contradictory concepts were particularly highlighted by these genetic studies. Several phenotypes previously described as different clinical entities were brought together by the identification of mutations in the same gene, and converselyome conditions that were clinically assigned the same name, often heterogeneous at the clinical level, appeared genetically and physiopathologically heterogeneous. In addition, it is worth noting that the monogenic macular dystrophy genes were often regarded as potential factors for susceptibility to age-related macular degenerations. However, to date, only ABCA4 mutations have been associated with a minority of this frequent multifactorial condition. The aim of this article is to give a progress report on the monogenic macular dystrophy genes and to review current knowledge concerning the pathophysiology of these conditions.
Humans↗
Xenopus laevis red cone opsin and Prph2 promoters allow transgene expression in amphibian cones, or both rods and cones.
We have cloned the promoter regions of two Xenopus laevis genes, Prph2 (also called RDS) and red cone opsin (RCO) using a polymerase chain reaction-based gene-walking method. The proteins coded by these genes are expressed exclusively in retinal photoreceptors. Although these promoter sequences are evolutionarily distant from previously described homologues, potentially informative similarities were noted that suggest conserved binding sites of the transcription factors Crx and Rx. The promoters were tested for function in transgenic X. laevis. RCO-driven expression was restricted to cones and pinealocytes, while the Prph2 promoter drove expression of a reporter green fluorescent protein transgene in both rod and cone photoreceptors, as well as low levels of expression in muscle tissue. This is the first description of transgene expression driven by a Prph2 promoter homologue from any species. In combination with the previously reported X. laevis opsin and arrestin promoters, these sequences will facilitate the development and analysis of X. laevis models of inherited retinal degeneration.
Animals↗
Autosomal dominant retinitis pigmentosa: a novel mutation at the peripherin/RDS locus in the original 6p-linked pedigree.
Using single-strand conformation polymorphism electrophoresis, heteroduplex analysis, and direct sequencing, we have searched for possible disease-causing mutations in the adRP family in which we originally found tight linkage of the disease to 6p. We have now identified a single base change in exon 2, which results in the replacement of a serine residue at codon 212 for a glycine residue. The mutation cosegregates with the disease with a lod score of 12.1 at theta = 0.0.
Amino Acid Sequence↗
Evidence for nonallelic genetic heterogeneity in autosomal recessive retinitis pigmentosa.
Recent evidence suggesting the involvement of mutant rhodopsin proteins in the pathogenesis of autosomal recessive retinitis pigmentosa has prompted us to investigate whether this form of the disease shows non-allelic genetic heterogeneity, as has previously been shown to be the case in autosomal dominant retinitis pigmentosa. The availability of a unique inbred Dutch pedigree has enabled us to address this question. We have used an intragenic polymorphism to exclude the possibility that a mutation in the rhodopsin gene is responsible for the disease in this patient population. These data provide evidence for the involvement of at least two loci in autosomal recessively inherited retinitis pigmentosa.
Base Sequence↗