Alternative titles; symbols
HGNC Approved Gene Symbol: PRPH2
SNOMEDCT: 232049001;
Cytogenetic location: 6p21.1 Genomic coordinates (GRCh38): 6:42,696,598-42,722,597 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p21.1 | Choroidal dystrophy, central areolar 2 | 613105 | Autosomal dominant | 3 |
| Leber congenital amaurosis 18 | 608133 | Autosomal dominant; Autosomal recessive; Digenic dominant | 3 | |
| Macular dystrophy, patterned, 1 | 169150 | Autosomal dominant | 3 | |
| Macular dystrophy, vitelliform, 3 | 608161 | Autosomal dominant | 3 | |
| Retinitis pigmentosa 7 and digenic form | 608133 | Autosomal dominant; Autosomal recessive; Digenic dominant | 3 | |
| Retinitis punctata albescens | 136880 | Autosomal dominant; Autosomal recessive | 3 |
PRPH2 and ROM1 (180721) are tetraspanning membrane proteins that assemble into noncovalent tetramers and higher order disulfide-linked oligomers and are involved in photoreceptor disc morphogenesis (Loewen et al., 2001).
Human Gene
Using a probe derived from the coding region of the mouse rds cDNA to screen a human retina cDNA library, Travis et al. (1991) isolated a human RDS cDNA clone that encodes a putative 346-amino acid protein with 92% homology to the mouse protein. Four hydrophobic domains of 22 to 26 residues, as well as 2 possible sites for N-linked glycosylation, were conserved between the human and mouse proteins. Northern blot analysis detected 2 RDS transcripts of 3.0 and 5.5 kb in human retina. Dryja et al. (1989) also determined that the human RDS protein shares 92% homology to its murine analog.
Mouse Gene
Mouse 'retinal degeneration, slow' (rds) is a phenotype characterized by abnormal development of photoreceptor outer segments in the retina followed by a slow degeneration of rods and cones, resembling the abnormalities seen in human retinopathies. Using a subtractive cDNA cloning strategy based on the hypothesis that the rds gene is normally expressed in photoreceptors, Travis et al. (1989) isolated and cloned the putative mouse gene for the disorder. The gene encodes a 346-amino acid specific retinal protein with homology to the rod outer segment protein-1 (ROM1; 180721). An insertion of 10 kb of foreign DNA into an rds exon appeared to be responsible for the murine rds defect. The peripherin that is mutant in rds of the mouse is a different protein from the peripherin (Prph) encoded on mouse chromosome 15 (Pendleton et al., 1991); see 170710.
Connell et al. (1991) reported that the amino acid sequence of the bovine photoreceptor cell protein peripherin is 92.5% identical to the sequence of the mouse protein encoded by the normal rds gene.
Demant et al. (1979) localized the rds mutation to mouse chromosome 17, which was confirmed by Travis et al. (1989).
By analysis of DNA from a panel of human/hamster somatic cell hybrids and by direct in situ hybridization, Travis et al. (1991) showed that the human PRPH2 gene is located on the proximal portion of chromosome 6p.
Bascom et al. (1990) presented the results of experiments designed to characterize the RDS gene product at molecular and ultrastructural levels. Preliminary evidence showed that the RDS and ROM1 gene products form a heterodimer in vivo using disulfide bonds. Using antibodies against a synthetic peptide derived from the predicted protein sequence, Travis et al. (1991) showed that the rds protein is a membrane-associated glycoprotein restricted to photoreceptor outer segment discs. It may function as an adhesion molecule involved in stabilization and compaction of outer segment discs.
Connell et al. (1991) used monoclonal antibodies with Western blot analysis to show that the peripherin protein deficient in the rds mutant is normally localized to the rod outer segments and that it exists as 2 subunits linked by one or more disulfide bonds.
In a large Irish pedigree with autosomal dominant retinitis pigmentosa-7 (RP7; 608133), Farrar et al. (1991) identified a 3-bp deletion in the RDS gene (179605.0001), resulting in loss of one of a pair of highly conserved cysteine residues in the predicted third transmembrane domain of peripherin (codon 118 or 119). The deletion segregated with the disease phenotype in the family. Wells et al. (1993) found the same mutation in another family with autosomal dominant retinitis pigmentosa.
In 4 unrelated patients with RP, Kajiwara et al. (1991) identified heterozygous mutations in the RDS gene (179605.0002-179605.0004).
Wells et al. (1993) analyzed the PRPH2 gene in 13 probands with various macular dystrophies and identified 2 heterozygous missense mutations at codon 172 (R172Q, 179605.0006; R172W, 179605.0007) in affected members of 3 families with macular dystrophy involving the central retina, or central areolar choroidal dystrophy-2 (CACD2; 613105); the authors also identified a heterozygous nonsense mutation (179605.0008) in a woman with adult-onset vitelliform macular dystrophy (VMD3; 608161).
Travis and Hepler (1993) commented on the variety of phenotypically different retinal disorders caused by mutation in the RDS gene. The mutations seem to affect both rods and cones. Although some mutations are accompanied by autosomal dominant retinitis pigmentosa (RP7; 608133), others have the phenotype of macular dystrophy, retinitis punctata albescens (136880), or patterned pigment dystrophy of the fovea (MDPT1; 169150).
In 4 affected members from a family exhibiting various eye phenotypes, Weleber et al. (1993) identified heterozygosity for a 3-bp deletion in the RDS gene (179605.0017). The affected individuals had been diagnosed with RP and patterned macular dystrophy as well as a progressive form of macular degeneration that was consistent with fundus flavimaculatus (see 248200).
Kajiwara et al. (1994) demonstrated that retinitis pigmentosa can be caused by digenic mutations (double heterozygosity) by showing that the L185P mutation in the RDS gene (179605.0004) causes RP only when combined with a null mutation of the ROM1 gene (180721.0001). Two-locus hypotheses had been proposed as the mechanism for a number of disorders; this was one of the first examples of molecular documentation. Nadeau (2001) reviewed modifier genes in mice and humans. He considered the digenic inheritance of RP in this instance to be an example of dominance modification, ROM1 being the modifier gene and RDS the target modifier gene. He cited classic examples of dominance modification in mouse mutants.
In patients with patterned macular dystrophy, Nichols et al. (1993, 1993) and Kim et al. (1995) identified mutations in the RDS gene (see 179605.0009, 179605.0010, and 179605.0013).
In a Spanish family with central areolar choroidal dystrophy (CACD2), Reig et al. (1995) identified the R172W mutation in the PRPH2 gene.
Hoyng et al. (1996) analyzed exon 1 of the PRPH2 gene in 7 families with CACD2 and identified heterozygosity for an arg142-to-trp (R142W; 179605.0022) mutation in affected individuals from each family; in contrast, no mutations were detected in 4 sporadic CACD patients after complete screening of the PRPH2 gene.
Piguet et al. (1996) analyzed the PRPH2, rhodopsin (180380), and TIMP3 (188826) genes in a large Swiss pedigree segregating autosomal dominant progressive macular dystrophy and identified heterozygosity for the PRPH2 R172W mutation in affected individuals.
To assess the frequency of peripherin/RDS mutations in the clinically heterogeneous group of adult vitelliform macular dystrophy (AVMD), Felbor et al. (1997) analyzed the entire coding region of the gene in 28 unrelated patients. They identified 5 novel mutations, including 2 presumed null mutations (see, e.g., 179605.0014 and 179605.0015). Thus, 18% of AVMD patients carried point mutations in the RDS gene, suggesting that it is frequently involved in the pathogenesis of this macular disorder.
Payne et al. (1998) analyzed the PRPH2 gene in 300 British patients with autosomal dominant macular dystrophies and identified mutations in 7.3% of patients. The R172W mutation was found in 11 families, including 2 previously reported families (Wells et al., 1993 and Chopdar, 1993, respectively). Payne et al. (1998) demonstrated a shared haplotype consistent with a founder effect in the 11 R172W families, and noted that although the families had been referred separately with various diagnoses, including cone dystrophy, macular dystrophy, and CACD, review of the clinical data indicated a common phenotype involving significant loss of central vision, with a distinctive retinal appearance.
In 3 affected members of a Japanese family with sharply demarcated progressive chorioretinal atrophy in the macular area, compatible with CACD, Yanagihashi et al. (2003) identified heterozygosity for a novel missense mutation in the PRPH2 gene (R195L; 179605.0021).
In affected individuals from 3 unrelated families, 2 with adult-onset foveomacular dystrophy (AOFMD) and 1 with patterned macular dystrophy (MDPT1), Yang et al. (2004) identified heterozygosity for a missense mutation in the RDS gene (Y141C; 179605.0024). Haplotype analysis was consistent with an ancestral founder mutation in all 3 families. The authors stated that it was unclear why the Y141C mutation caused MDPT1 in 1 family and AOFMD in the other 2, and suggested that genetic modifiers or environmental influences may play a role in these phenotypic differences.
Boon et al. (2009) analyzed the PRPH2 gene in 103 Dutch CACD patients and identified the R142W mutation in 98 patients from 45 different families and the R172Q mutation in 5 affected family members from 1 family. The great majority of R142W-carrying CACD patients originated from the southeast region of the Netherlands, and haplotype analysis suggested a common founder mutation.
In affected individuals from a Swiss family with patterned macular dystrophy who exhibited marked intrafamilial and even intraindividual phenotypic variability, Vaclavik et al. (2012) identified heterozygosity for the Y141C mutation in the RDS gene.
In 3 unrelated patients with early-onset retinal dystrophy who were negative for mutation in known LCA or juvenile RP genes, Wang et al. (2013) identified homozygosity for mutations in the PRPH2 gene: 2 of the patients, 1 diagnosed with Leber congenital amaurosis (LCA18; see 608133) and 1 with juvenile RP (see 608133), were homozygous for the L185P mutation previously detected in patients with digenic RP7 (179605.0004), whereas the third patient, diagnosed with LCA, was homozygous for another missense mutation in PRPH2 (C213R; 179605.0023).
In a cohort of 310 families, originating mainly from France, with a diagnosis of autosomal dominant RP, Manes et al. (2015) screened for mutations in the PRPH2 gene and identified 15 different mutations in 32 probands, accounting for a prevalence of 10.3% in this population. Manes et al. (2015) then studied the clinical findings in 27 to 67 patients (depending on the examinations performed) from these families and identified variable phenotypes. Some patients had macular involvement with either normal, moderately reduced, or severely decreased visual acuity; some had mild RP with a few spots of atrophy in the retinal periphery and macular sparing. In other cases, typical pigment deposits and widespread atrophy in the midperipheral retina were present. Some patients showed pericentral localization of the retinal lesions, while other family members had a widespread form of RP. In a few cases, the presence of yellow deposits was observed. In 1 family, a mother had typical RP and her son had a vitelliform foveal deposit without signs of RP.
Keen and Inglehearn (1996) reported that a total of 43 sequence variants had been described in the human RDS gene, including 30 missense mutations, 2 single-base substitutions producing termination codons, 7 small in-frame deletions, and 4 insertion/deletion events that break the reading frame. Of these, 39 were associated with retinal phenotypes that could be grouped into 4 broad categories: dominant retinitis pigmentosa, progressive macular degeneration, digenic RP, and pattern dystrophies. The mutations underlying dominant RP and severe macular degeneration were largely missense or small in-frame deletions in a large intradiscal loop between the third and fourth transmembrane domains. In contrast, the mutations associated with the milder patterned phenotypes or with digenic RP were scattered more evenly through the gene and were often nonsense mutations. Keen and Inglehearn (1996) stated that this distinction supported the hypothesis that the large loop is an important site of interaction between RDS molecules and other protein components in the disc.
Kohl et al. (1997) screened 76 independent families with various forms of mostly central retinal dystrophies for mutations in the RDS gene. Two nonsense mutations, 5 missense mutations, and 1 single-base insertion were detected. All of these were in heterozygous state. Kohl et al. (1997) commented on the remarkable variation in phenotype and disease expression between and within families.
Anand et al. (2009) analyzed total area of geographic atrophy and age-related visual acuity data in patients with the R172Q, R172W, and R142W mutations in the PRPH2 gene and observed a trend toward earlier age at onset and worse visual acuity with the R172W mutation compared to R142W or R172Q. Linear regression analysis showed that up to 60 years of age, visual acuity with the R172W mutation was significantly worse than that with the R142W (p less than 0.001) or R172Q (p = 0.04) mutations. Anand et al. (2009) suggested that the visual prognosis associated with variation in the PRPH2 gene may be mutation-specific and may be worse with the R172W mutation compared to R142W or R172Q mutations.
Ma et al. (1995) showed that the rds phenotype in mice is caused by an insertion mutation of a 9.2-kb repetitive genomic element into exon 2 of the rds gene that is very similar to the haplotype-specific element in the H-2 complex. The entire element is included in the RNA products of the mutant locus. Ma et al. (1995) presented evidence that rds in mice represents a null allele.
A common feature of peripherin-related retinitis pigmentosa and macular dystrophy in the human and the rds mutation in mouse is the loss of photoreceptor function. It is characterized by complete failure to develop photoreceptor discs and outer segments, downregulation of rhodopsin (180380), and apoptotic loss of photoreceptor cells. Ali et al. (2000) demonstrated that subretinal injection of recombinant adeno-associated virus encoding a Prph2 transgene resulted in stable generation of outer segment structures and formation of new stacks of discs containing both peripherin-2 and rhodopsin, which in many cases were morphologically similar to normal outer segments. Moreover, the reestablishment of the structural integrity of the photoreceptor layer resulted in electrophysiologic correction. These studies demonstrated for the first time that a complex ultrastructural by in vivo gene transfer. Sarra et al. (2001) extended the analysis and demonstrated that the potential for ultrastructural improvement is dependent upon the age at which animals are treated, but the effect of a single injection on photoreceptor ultrastructure may be long-term. However, there was no significant effect on photoreceptor cell loss, irrespective of the date of administration, despite the improvements in morphology and function. These findings suggested that successful gene therapy in patients with photoreceptor defects may ultimately depend upon intervention in early stages of disease and upon accurate control of transgene expression.
Kedzierski et al. (2001) conducted a series of transgenic/knockout mouse experiments to determine whether the clinical observation of digenic RP in humans could be corroborated in the mouse model; how the pathogenic L185P (179605.0004) and P216L (179605.0003) D2-loop substitutions in RDS affect the abundance of RDS protein; and what the correlation is between disorganization of outer segment discs and photoreceptor degeneration in the different mutant RDS alleles. Photoreceptor degeneration in the mouse model of digenic RP was faster than in the wildtype and monogenic controls by histologic, electroretinographic, and biochemical analysis. A simple deficiency of RDS and ROM1 protein appeared to be the cause of the photoreceptor degeneration in RDS-mediated RP. The critical threshold for the combined abundance of RDS and ROM1 was approximately 60% of wildtype. Below this value, the extent of outer segment disorganization resulted in clinically significant photoreceptor degeneration.
McNally et al. (2002) introduced a targeted single-base deletion at codon 307 of the rds-peripherin gene in mice, similar to a human mutation reported by Apfelstedt-Sylla et al. (1995) (179605.0019). Histopathologic and electroretinographic analysis indicated that the retinopathy in mice heterozygous and homozygous for the codon 307 mutation appeared more severe than that in rds +/- and rds -/- mice, suggesting that the rds-307 mutation may exert a dominant-negative effect on the phenotype.
Li et al. (2003) identified the skate ortholog of mammalian peripherin/rds. Conservation of most of the residues associated with human retinal diseases indicated that these residues serve important functional roles.
Ding et al. (2004) created transgenic mice bearing the R172W (179605.0007) mutation in Rds. While mutant Rds was appropriately localized, a direct correlation existed between transgene expression levels and the onset/severity of the phenotype. In the wildtype background, both structure and function of cone and rod photoreceptors were significantly diminished, suggesting a dominant-negative cone-rod defect. Whereas Rds heterozygous mice maintained normal cone function at early ages, cone responses in R172W/Rds double-heterozygous mice were diminished to 40% of the wildtype level, signifying a preferential damaging effect of the mutation on cones. Conversely, R172W/Rds double heterozygotes showed a significant rescue of rod function and improvement of rod outer segment structure. Although Rds-null mice have no detectable rod or cone responses, R172W-homozygous/Rds-null animals retained 30% of wildtype structure and rod function, but no significant rescue of cone function was detected at 1 month of age. Biochemical abnormalities were not observed in complex formation and association with ROM1 (180721); however, R172W protein was more sensitive to tryptic digestion, indicative of a change in protein conformation, possibly contributing to the cone-dominated phenotype.
Lee et al. (2006) studied trafficking of peripherin/rds and Rom1 (180721) in several knockout and transgenic animal models. Peripherin/rds transport and localization were polarized to the site of outer segment morphogenesis before disc formation in developing photoreceptors. Peripherin/rds and Rom1 trafficking was maintained in rhodopsin-knockout mice, suggesting that rim proteins and rhodopsin have separate transport pathways. The presence of truncated peripherin/rds-GFP in the outer segment supported previous evidence that peripherin/rds mice form homotetramers for outer segment targeting. The finding that Rom1 transports to the outer segment domain in rds mice suggested that Rom1 may possess its own sorting and transport signals.
Chakraborty et al. (2009) showed that transgenic mice containing the Rds C150S mutation (C150S-Rds) failed to form higher-order Rds oligomers, although interactions between C150S-Rds and Rom1 occurred in rods, but not in cones. C150S-Rds mice exhibited marked early-onset reductions in cone function and abnormal outer segment structure. In contrast, C150S-Rds expression in rods partly rescued the Rds +/- phenotype. Although C150S-Rds was detected in the outer segments in rods and cones, a substantial percentage of C150S-Rds and cone opsins were mislocalized to different cellular compartments in cones. The apparent outer segment structural differences between rods and cones may cause cones to be more susceptible to the elimination of higher-order Rds/Rom1 oligomers (e.g., as mediated by mutation of the Rds C150 residue).
Only approximately 3% of wildtype mouse photoreceptors are cones. In order to better study cones in transgenic mice bearing the R172W mutation, Conley et al. (2014) used the Nrl (162080) -/- mouse background, in which developing rods adopt a cone-like fate. They found that the R172W mutation caused abnormalities in the ultrastructure of the cone outer segment, as well as formation of abnormally large Rom1 complexes.
In a large Irish pedigree with autosomal dominant retinitis pigmentosa-7 (608133), Farrar et al. (1991) identified a 3-bp deletion in the RDS gene, resulting in loss of one of a pair of highly conserved cysteine residues in the predicted third transmembrane domain of peripherin (codon 118 or 119). The deletion segregated with the disease phenotype but was not present in unaffected individuals. The deletion was absent in 152 unrelated normal individuals and in 59 other autosomal dominant RP families. The mutation was identified by single-strand conformation polymorphism electrophoresis of PCR-amplified DNA. Wells et al. (1993) found the same mutation in another family with autosomal dominant retinitis pigmentosa.
By single-strand conformation polymorphism analysis (SSCP) of PCR-amplified DNA sequences from the RDS gene, Kajiwara et al. (1991) identified 3 mutations in the RDS gene in patients with autosomal dominant retinitis pigmentosa-7 (608133). One mutation, found in a single patient, was a 3-bp deletion that precisely eliminated codon 219, which normally specifies proline.
In a single patient with autosomal dominant retinitis pigmentosa-7 (608133), Kajiwara et al. (1991) identified a C-T transition in the RDS gene, resulting in a pro216-to-leu (P216L) change.
In 2 unrelated patients with autosomal dominant retinitis pigmentosa (RP7; 608133) from a cohort of 139 RP patients who were negative for a rhodopsin mutation, Kajiwara et al. (1991) identified heterozygosity for a T-C transition in the RDS gene, resulting in a leu185-to-pro (L185P) substitution. Electroretinography suggested that mutations in the RDS gene affect both rods and cones.
In 3 unrelated families with RP, 1 of which included a patient who was previously reported by Kajiwara et al. (1991), Kajiwara et al. (1994) demonstrated that the L185P mutation causes retinitis pigmentosa only when combined with a null mutation of the ROM1 gene in double heterozygous state; see 180721.0001.
Loewen et al. (2001) showed that the L185P mutant self-assembled into dimers that further associated through intermolecular disulfide bonds to form tetramers but not higher order oligomers, which are characteristic of wildtype peripherin-2. The L185P mutant, however, could interact with wildtype ROM1 and wildtype peripherin-2 to form core tetramers and higher order disulfide-linked oligomers.
In 2 patients with early-onset retinal dystrophy, including a 66-year-old woman diagnosed with Leber congenital amaurosis (LCA18; see 608133) and an unrelated 30-year-old woman with juvenile retinitis pigmentosa (see 608133), Wang et al. (2013) identified homozygosity for the L185P mutation in the PRPH2 gene. Examination of the 30-year-old woman's asymptomatic 56-year-old father, a heterozygous carrier of L185P with normal visual acuity, revealed patterned macular dystrophy (169150) and foveal changes.
In a 59-year-old man with advanced retinal degeneration involving the macula and with peripheral subretinal flecks (retinitis punctata albescens; see 136880), Kajiwara et al. (1992, 1993) identified a 2-bp deletion in codon 25 of the RDS gene, leading to a premature stop codon 54 bases downstream. The predicted protein product, if expressed, would contain only 42 amino acid residues rather than the normal 346. Of the patient's immediate relatives available for testing, only his 33-year-old daughter carried the mutation. She had no relevant visual symptoms but had funduscopic abnormalities, including attenuated vessels and subretinal flecks, and ERG findings indicating progressive retinal degeneration.
In 4 affected members of a family segregating autosomal dominant macular dystrophy affecting the central retina (CACD2; 613105), Wells et al. (1993) identified a G-to-A transition in the PRPH2 gene resulting in an arg172-to-gln (R172Q). The patients described difficulty passing from light to dark during their third or fourth decades, and visual acuity progressively worsened between the ages of 36 and 56 years. They denied night blindness or peripheral field loss. Ophthalmoscopic changes, identified by 35 years of age, consisted of macular atrophy; the peripheral fundus was normal.
Boon et al. (2009) identified the R172Q mutation in 5 affected members of a Dutch family with CACD.
In affected members of 2 families segregating autosomal dominant macular dystrophy affecting the central retina (CACD2; 613105), Wells et al. (1993) identified heterozygosity for a C-to-T transition in the PRPH2 gene resulting in an arg172-to-trp (R172W) substitution. Typically, affected persons became symptomatic in the third decade with blurred central vision and photophobia; none complained of night blindness or restricted peripheral visual fields. By 40 years of age, visual acuity was less than 6/60, and funduscopic examination showed sharply demarcated atrophy of the central retina, pigment epithelium, and choriocapillaris.
Wroblewski et al. (1994) described in greater detail the clinical, psychophysical, and ERG findings in the 2 families described by Wells et al. (1993). All affected members of these families had a progressive symmetric macular dystrophy. Symptoms of progressive central visual loss developed in the third or fourth decade of life, accompanied by central scotoma and well-demarcated atrophy of the retinal pigment epithelium and choriocapillaris of the macula. Studies revealed evidence of primary cone dysfunction and preservation of peripheral rod function.
Reig et al. (1995) identified the R172W mutation in a Spanish family with central areolar choroidal dystrophy. The mutation was also detected in 2 asymptomatic family members who showed irregular pigmentation in the retinal pigment epithelium.
Piguet et al. (1996) analyzed the PRPH2, rhodopsin (180380), and TIMP3 (188826) genes in a large Swiss pedigree segregating autosomal dominant progressive macular dystrophy and identified heterozygosity for the PRPH2 R172W mutation in affected individuals.
Payne et al. (1998) identified the R172W mutation in 11 British families segregating autosomal dominant macular dystrophies, including 2 previously reported families (Wells et al., 1993 and Chopdar, 1993, respectively). Analysis of microsatellite markers revealed a shared haplotype that was absent in 50 population-matched controls, suggesting a founder effect. Although the families had been referred separately with a variety of diagnoses, Payne et al. (1998) stated that review of the clinical data indicated a common phenotype involving significant loss of central vision, with a distinctive retinal appearance.
Wells et al. (1993) identified a nonsense mutation involving tyrosine-258 (Y258X) in a woman with adult vitelliform macular dystrophy (VMD3; 608161). Her father was deceased but the disorder was verified in him by fundus photographs. The patient became aware of distorted left eye central vision in her middle thirties. At 44 years of age, her visual acuity was 6/6 with the right eye and 6/12 with the left. Fundus examination was normal except for a small discrete yellow deposit at the level of the retinal pigment epithelium centered in the fovea of each eye.
Nichols et al. (1993) studied a family in which 12 individuals in 3 generations had butterfly dystrophy of the retinal pigment epithelium (169150). An extraordinary feature of the family was the occurrence of 16 sibs in the second generation, all apparently living. In the affected individuals, a G-A transition was found in the RDS gene, resulting in a gly167-to-asp (G167D) substitution.
Nichols et al. (1993) described deletion of 2 basepairs overlapping codons 299 and 300 in the RDS gene in affected members of a family with butterfly-shaped pigment dystrophy of the fovea (169150). The TG deletion began at nucleotide 1137 of their clone. All affected patients demonstrated perifoveal deposits of yellow pigment at the level of the retinal pigment epithelium.
By nonradioisotopic SSCP analysis, Kikawa et al. (1994) identified an asn244-to-lys (N244K) mutation in the RDS gene in a family with a form of autosomal dominant retinitis pigmentosa (608133). The phenotypic expression associated with the N244K mutation showed striking intrafamilial concordance. The features were night blindness, usually noticed by the patient in the early teens; decreased visual acuity, with an onset in the late thirties; diffuse pigmentary retinal degeneration in the midperipheral to peripheral retina; and bull's-eye maculopathy, which also appeared in the late thirties. ERG assessments showed almost extinguished amplitudes of rod-isolated responses and severely reduced amplitudes of cone-isolated responses beginning at about age 9 years, even though the patient had no complaint of difficulty with night vision.
In a man with adult-onset foveomacular dystrophy and choroidal neovascularization (VMD3; 608161), Feist et al. (1994) identified heterozygosity for a pro210-to-arg (P210R) mutation in the PRPH2 gene.
In a large 4-generation family with both peripheral retinal and macular degeneration, in which 12 individuals exhibited a wide variety of eye features, including diffuse fine hard drusen in the macula, butterfly pattern, extensive retinal atrophy, diffuse pigment epithelial disturbances, and severe atrophic macular degeneration, Gorin et al. (1995) identified heterozygosity for the P210R mutation in PRPH2 in all affected members, as well as in one 39-year-old man who had no visual symptoms or electrophysiologic or fundus abnormalities. Heterozygosity for the P210R mutation was also detected in 3 affected members of the family with foveomacular dystrophy that was originally reported by Gass (1974), as well as in a mother and son with decreased visual acuity and bilateral yellowish subfoveal lesions. None of the patients studied by Gorin et al. (1995) exhibited choroidal neovascularization. The mutation was not found in 100 controls.
Kim et al. (1995) studied a kindred with patterned dystrophy of the retina (169150) with probable autosomal dominant inheritance, although no male-to-male transmission was observed. They demonstrated a 4-bp insertion at codon 140 of the peripherin/RDS gene.
In a 67-year-old German patient with adult-onset vitelliform macular dystrophy (VMD3; 608161), Felbor et al. (1997) identified a met1-to-thr (M1T) amino acid substitution in the PRPH2 gene.
In a German patient, aged 55 years, with adult vitelliform macular dystrophy (VMD3; 608161), Felbor et al. (1997) identified a trp316-to-ter (W316X) nonsense mutation in the RDS gene.
Yang et al. (2003) reported a family in which all 8 members affected with adult-onset foveomacular dystrophy with choroidal neovascularization (VMD3; 608161) had a frameshift null mutation, a 1-bp deletion at nucleotide 112 (112delG), in the RDS gene that was associated with relatively severe manifestations. Choroidal neovascularization developed in 2 patients, and geographic atrophy involved the macula in 3 patients.
Weleber et al. (1993) reported the occurrence of 3 separate phenotypes within a single family with a 3-bp deletion of codon 153 or 154 of the RDS gene. The mother presented at age 63 with adult-onset retinitis pigmentosa (608133) that progressed dramatically over 12 years, with marked loss of peripheral visual field. One daughter developed patterned macular dystrophy (169150) at age 31 years. At age 44 years, her ERG was moderately abnormal, but her clinical disease was limited to the macula. Another daughter presented at age 42 years with macular degeneration; over 10 years, she developed a clinical picture of fundus flavimaculatus (see 248200). Her peripheral visual field was preserved but her ERG was moderately abnormal. A son had onset of macular degeneration at age 44 years. Pericentral scotomas were present and ERG was markedly abnormal.
In a 58-year-old German man with retinitis pigmentosa (RP7; 608133), who had previously been given a diagnosis of Stargardt macular dystrophy at 27 years of age, Meins et al. (1993) identified heterozygosity for an arg46-to-ter (R46X) mutation in exon 1 of the RDS gene. Apfelstedt-Sylla et al. (1995) restudied the family and identified the same R46X mutation in the proband's 40-year-old asymptomatic son. Examination of the son revealed multiple yellow-white deposits varying in shape and size within the retinal pigment epithelium layer and abnormal ERG findings. Apfelstedt-Sylla et al. (1995) noted the variation in the phenotypes of the father and son and suggested that their features might represent disparate manifestations of fundus flavimaculatus (see 248200).
Gruning et al. (1994) identified a 1-bp deletion at codon 307 of the RDS gene in a 68-year-old German woman with typical late-onset retinitis pigmentosa (608133). The deletion resulted in a frameshift and a premature stop codon after 16 triplets. The C terminus of the protein is radically altered by this change, and an additional HaeII site is created. The same patient was reported by Apfelstedt-Sylla et al. (1995).
In 10 patients with retinitis pigmentosa-7 (608133) from a large multigenerational Spanish family, Gruning et al. (1994) identified an A-to-T transversion in the RDS gene, resulting in an asp173-to-val (D173V) substitution. The patients ranged in age from 6 to 47 years and showed typical signs of retinitis pigmentosa of variable severity.
In 3 affected members of a Japanese family with sharply demarcated progressive chorioretinal atrophy in the macular area, compatible with central areolar choroidal dystrophy (CACD2; 613105), Yanagihashi et al. (2003) identified heterozygosity for a transversion in the PRPH2 gene, resulting in an arg195-to-leu (R195L) substitution.
In 11 affected members from 7 families with central areolar choroidal dystrophy (CACD2; 613105), Hoyng et al. (1996) identified heterozygosity for a 664C-T transition in exon 1 of the PRPH2 gene, resulting in an arg142-to-trp (R142W) substitution. The mutation was also detected in a 65-year-old female family member who had 20/20 visual acuity bilaterally and no posterior pole abnormalities on ophthalmoscopy or fluorescein angiography. The mutation was not found in 7 other unaffected family members or in 200 control chromosomes.
Boon et al. (2009) identified the R142W mutation in 98 patients with CACD from 45 different Dutch families and noted that 96 (98%) of the patients originated from the southeast region of the Netherlands. Analysis of CA repeat markers and SNPs near the PRPH2 gene in 3 large families carrying the R142W mutation revealed an approximately 519-kb shared chromosomal segment, strongly suggesting that R142W represents a founder mutation. Carrier frequency of R142W was analyzed in 57 asymptomatic controls over 70 years of age from the same region of the Netherlands; the mutation was found in a 76-year-old man who reported no visual disturbances, but who was found to have early stage II CACD on ophthalmoscopic examination and fundus autofluorescence imaging.
In a patient diagnosed with patterned macular dystrophy (169150), Payne et al. (1998) identified heterozygosity for a cys213-to-arg (C213R) substitution in the PRPH2 gene.
In a 29-year-old woman with an early-onset retinal dystrophy diagnosed as Leber congenital amaurosis (LCA18; see 608133), Wang et al. (2013) identified homozygosity for a c.673T-C transition in the PRPH2 gene, resulting in the C213R substitution. The mutation was present in heterozygosity in 2 family members who exhibited patterned macular dystrophy: the proband's asymptomatic 57-year-old mother, who had 20/20 visual acuity, showed florid butterfly-shaped macular pattern dystrophy as well as other retinal flecks; and her 7-year-old son, who had decreased visual acuity due to partial amblyopia, showed a miniature form of foveal butterfly-shaped macular pattern dystrophy. The mutation was not found in the proband's unaffected brother, who had normal visual acuity and no maculopathy on examination.
In affected individuals from 3 unrelated families, 2 with adult-onset foveomacular dystrophy (AOFMD; 608161) and 1 with patterned macular dystrophy (MDPT1; 169150), Yang et al. (2004) identified heterozygosity for a c. 422A-G transition in the RDS gene, resulting in a tyr141-to-cys (Y141C) substitution in the intradiscal space. The mutation, which segregated with disease in each family, was not found in 200 control chromosomes. Haplotype analysis was consistent with an ancestral founder mutation in all 3 families. The authors noted that it was unclear why the Y141C mutation caused MDPT1 in 1 family and AOFMD in the other 2, and suggested that genetic modifiers or environmental influences may play a role in these phenotypic differences.
In affected individuals from a 3-generation Swiss family with patterned macular dystrophy, Vaclavik et al. (2012) identified heterozygosity for the Y141C mutation in the RDS gene. The family exhibited marked intrafamilial and even intraindividual phenotypic variability: the 43-year-old male cousin of the proband had butterfly-pattern dystrophy in the right eye and adult-onset foveomacular dystrophy in the left eye.
Stuck et al. (2014) generated a knockin mouse model expressing the Y141C RDS mutation. Knockin mice exhibited clinical signs similar to those in humans, including late-onset fundus abnormalities (widespread hyperfluorescent yellow flecks) characteristic of RPE and choroidal defects, and both scotopic and photopic electroretinogram defects. Ultrastructural examination indicated that disc formation was initiated by the Y141C mutant, but proper sizing and alignment of discs required wildtype Rds. The biochemical mechanism underlying these abnormalities was associated with defects in the normal process of Rds oligomerization, which is required for proper Rds function. The Y141C mutant and wildtype Rds formed strikingly abnormal disulfide-linked complexes that were localized to the outer segment (OS), where they impaired the formation of proper OS structure. Based on these findings, Stuck et al. (2014) proposed a model of pattern dystrophy wherein a primary molecular defect occurring in all photoreceptors causes secondary sequelae in adjacent tissues, an outcome resulting in macular vision loss.
Ali, R. R., Sarra, G.-M., Stephens, C., de Alwis, M., Bainbridge, J. W. B., Munro, P. M., Fauser, S., Reichell, M. B., Kinnon, C., Hunt, D. M., Bhattacharya, S. S., Thrasher, A. J. Restoration of photoreceptor ultrastructure and function in retinal degeneration slow mice by gene therapy. Nature Genet. 25: 306-310, 2000. [PubMed: 10888879] [Full Text: https://doi.org/10.1038/77068]
Anand, S., Sheridan, E., Cassidy, F., Inglehearn, C., Williams, G., Springell, K., Allgar, V., Kelly, T.-L., McKibbin, M. Macular dystrophy associated with the arg172trp substitution in peripherin/RDS: genotype-phenotype correlation. Retina 29: 682-688, 2009. [PubMed: 19262438] [Full Text: https://doi.org/10.1097/IAE.0b013e318198dbed]
Apfelstedt-Sylla, E., Theischen, M., Ruther, K., Wedemann, H., Gal, A., Zrenner, E. Extensive intrafamilial and interfamilial phenotypic variation among patients with autosomal dominant retinal dystrophy and mutations in the human RDS/peripherin gene. Brit. J. Ophthal. 79: 28-34, 1995. [PubMed: 7880786] [Full Text: https://doi.org/10.1136/bjo.79.1.28]
Bascom, R. A., Connell, G., Garcia-Heras, J., Collins, L., Ledbetter, D., Molday, R. S., Kalnins, V., McInnes, R. R. Molecular and ultrastructural characterization of the products of the human retinopathy candidate genes ROM1 and RDS. (Abstract) Am. J. Hum. Genet. 47 (suppl.): A101 only, 1990.
Boon, C. J. F., Klevering, B. J., Cremers, F. P. M., Zonneveld-Vrieling, M. N., Theelen, T., Den Hollander, A. I., Hoyng, C. B. Central areolar choroidal dystrophy. Ophthalmology 116: 771-782, 2009. [PubMed: 19243827] [Full Text: https://doi.org/10.1016/j.ophtha.2008.12.019]
Chakraborty, D., Ding, X.-Q., Conley, S. M., Fliesler, S. J., Naash, M. I. Differential requirements for retinal degeneration slow intermolecular disulfide-linked oligomerization in rods versus cones. Hum. Molec. Genet. 18: 797-808, 2009. [PubMed: 19050038] [Full Text: https://doi.org/10.1093/hmg/ddn406]
Chopdar, A. A variant of central areolar choroidal dystrophy. Ophthalmic Paediat. Genet. 13: 151-164, 1993.
Conley, S. M., Stuck, M. W., Burnett, J. L., Chakraborty, D., Azadi, S., Fliesler, S. J., Naash, M. I. Insights into the mechanisms of macular degeneration associated with the R172W mutation in RDS. Hum. Molec. Genet. 23: 3102-3114, 2014. [PubMed: 24463884] [Full Text: https://doi.org/10.1093/hmg/ddu014]
Connell, G., Bascom, R., Molday, L., Reid, D., McInnes, R. R., Molday, R. S. Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse. Proc. Nat. Acad. Sci. 88: 723-726, 1991. [PubMed: 1992463] [Full Text: https://doi.org/10.1073/pnas.88.3.723]
Demant, P., Ivanyi, D., van Nie, R. The map position of the rds gene on the 17th chromosome of the mouse. Tissue Antigens 13: 53-55, 1979. [PubMed: 419532] [Full Text: https://doi.org/10.1111/j.1399-0039.1979.tb01136.x]
Ding, X.-Q., Nour, M., Ritter, L. M., Goldberg, A. F. X., Fliesler, S. J., Naash, M. I. The R172W mutation in peripherin/rds causes a cone-rod dystrophy in transgenic mice. Hum. Molec. Genet. 13: 2075-2087, 2004. [PubMed: 15254014] [Full Text: https://doi.org/10.1093/hmg/ddh211]
Dryja, T. P., Grondin, V. J., Ringens, P., Cotran, P., Berson, E. L., Travis, G. Isolation of human retinal cDNA fragments homologous to the murine rds gene transcript. (Abstract) Invest. Ophthal. Vis. Sci. 30 (suppl.): 43 only, 1989.
Farrar, G. J., Kenna, P., Jordan, S. A., Kumar-Singh, R., Humphries, M. M., Sharp, E. M., Sheils, D. M., Humphries, P. A three-base-pair deletion in the peripherin-RDS gene in one form of retinitis pigmentosa. Nature 354: 478-480, 1991. [PubMed: 1749427] [Full Text: https://doi.org/10.1038/354478a0]
Feist, R. M., White, M. F., Jr., Skalka, H., Stone, E. M. Choroidal neovascularization in a patient with adult foveomacular dystrophy and a mutation in the retinal degeneration slow gene (pro210-to-arg). Am. J. Ophthal. 118: 259-260, 1994. [PubMed: 7519821] [Full Text: https://doi.org/10.1016/s0002-9394(14)72913-7]
Felbor, U., Schilling, H., Weber, B. H. F. Adult vitelliform macular dystrophy is frequently associated with mutations in the peripherin/RDS gene. Hum. Mutat. 10: 301-309, 1997. [PubMed: 9338584] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1997)10:4<301::AID-HUMU6>3.0.CO;2-J]
Gass, J. D. M. A clinicopathologic study of a peculiar foveomacular dystrophy. Trans. Am. Ophthal. Soc. 72: 139-155, 1974. [PubMed: 4142662]
Gorin, M. B., Jackson, K. E., Ferrell, R. E. Scheffield, V. C., Jacobson, S. G., Gass, D. M., Mitchell, E., Stone, E. M. A peripherin/retinal degeneration slow mutation (pro-210-arg) associated with macular and peripheral retinal degeneration. Ophthalmology 102: 246-255, 1995. [PubMed: 7862413] [Full Text: https://doi.org/10.1016/s0161-6420(95)31029-9]
Gruning, G., Millan, J. M., Meins, M., Beneyto, M., Caballero, M., Apfelstedt-Sylla, E., Bosch, R., Zrenner, E., Prieto, F., Gal, A. Mutations in the human peripherin/RDS gene associated with autosomal dominant retinitis pigmentosa. Hum. Mutat. 3: 321-323, 1994. [PubMed: 8019570] [Full Text: https://doi.org/10.1002/humu.1380030326]
Hoyng, C. B., Heutink, P., Testers, L., Pinckers, A., Deutman, A. F., Oostra, B. A. Autosomal dominant central areolar choroidal dystrophy caused by a mutation in codon 142 in the peripherin/RDS gene. Am. J. Ophthal. 121: 623-629, 1996. [PubMed: 8644804] [Full Text: https://doi.org/10.1016/s0002-9394(14)70627-0]
Jackson, K. E., Mitchell, E. B., Stone, E. M., Ferrell, R. E., Gorin, M. B. The identification of an exon-2 peripherin mutation in a family with heterogeneous manifestations of a butterfly pattern macular dystrophy. (Abstract) Am. J. Hum. Genet. 53 (suppl.): 1177 only, 1993.
Kajiwara, K., Berson, E. L., Dryja, T. P. Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science 264: 1604-1608, 1994. [PubMed: 8202715] [Full Text: https://doi.org/10.1126/science.8202715]
Kajiwara, K., Hahn, L. B., Mukai, S., Travis, G. H., Berson, E. L., Dryja, T. P. Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa. Nature 354: 480-483, 1991. [PubMed: 1684223] [Full Text: https://doi.org/10.1038/354480a0]
Kajiwara, K., Sandberg, M. A., Berson, E. L., Dryja, T. P. A null mutation in the human RDS/peripherin gene in a family with autosomal dominant retinitis punctata albescens. (Abstract) Am. J. Hum. Genet. 51 (suppl.): A6 only, 1992.
Kajiwara, K., Sandberg, M. A., Berson, E. L., Dryja, T. P. A null mutation in the human peripherin/RDS gene in a family with autosomal dominant retinitis punctata albescens. Nature Genet. 3: 208-212, 1993. [PubMed: 8485575] [Full Text: https://doi.org/10.1038/ng0393-208]
Kedzierski, W., Nusinowitz, S., Birch, D., Clarke, G., McInnes, R. R., Bok, D., Travis, G. H. Deficiency of rds/peripherin causes photoreceptor death in mouse models of digenic and dominant retinitis pigmentosa. Proc. Nat. Acad. Sci. 98: 7718-7723, 2001. [PubMed: 11427722] [Full Text: https://doi.org/10.1073/pnas.141124198]
Keen, T. J., Inglehearn, C. F. Mutations and polymorphisms in the human peripherin-RDS gene and their involvement in inherited retinal degeneration. Hum. Mutat. 8: 297-303, 1996. [PubMed: 8956033] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)8:4<297::AID-HUMU1>3.0.CO;2-5]
Kikawa, E., Nakazawa, M., Chida, Y., Shiono, T., Tamai, M. A novel mutation (asn244-to-lys) in the peripherin/RDS gene causing autosomal dominant retinitis pigmentosa associated with bull's-eye maculopathy detected by nonradioisotopic SSCP. Genomics 20: 137-139, 1994. [PubMed: 8020945] [Full Text: https://doi.org/10.1006/geno.1994.1142]
Kim, R. Y., Dollfus, H., Keen, T. J., Fitzke, F. W., Arden, G. B., Bhattacharya, S. S., Bird, A. C. Autosomal dominant pattern dystrophy of the retina associated with a 4-base pair insertion at codon 140 in the peripherin/RDS gene. Arch. Ophthal. 113: 451-455, 1995. [PubMed: 7710395] [Full Text: https://doi.org/10.1001/archopht.1995.01100040067029]
Kohl, S., Christ-Adler, M., Apfelstedt-Sylla, E., Kellner, U., Eckstein, A., Zrenner, E., Wissinger, B. RDS/peripherin gene mutations are frequent causes of central retinal dystrophies. J. Med. Genet. 34: 620-626, 1997. [PubMed: 9279751] [Full Text: https://doi.org/10.1136/jmg.34.8.620]
Lee, E. S., Burnside, B., Flannery, J. G. Characterization of peripherin/rds and rom-1 transport in rod photoreceptors of transgenic and knockout animals. Invest. Ophthal. Vis. Sci. 47: 2150-2160, 2006. [PubMed: 16639027] [Full Text: https://doi.org/10.1167/iovs.05-0919]
Li, C., Ding, X.-Q., O'Brien, J., Al-Ubaidi, M. R., Naash, M. I. Molecular characterization of the skate peripherin/rds gene: relationship to its orthologues and paralogues. Invest. Ophthal. Vis. Sci. 44: 2433-2441, 2003. [PubMed: 12766040] [Full Text: https://doi.org/10.1167/iovs.02-1152]
Loewen, C. J. R., Moritz, O. L., Molday, R. S. Molecular characterization of peripherin-2 and rom-1 mutants responsible for digenic retinitis pigmentosa. J. Biol. Chem. 276: 22388-22396, 2001. [PubMed: 11297544] [Full Text: https://doi.org/10.1074/jbc.M011710200]
Ma, J., Norton, J. C., Allen, A. C., Burns, J. B., Hasel, K. W., Burns, J. L., Sutcliffe, J. G., Travis, G. H. Retinal degeneration slow (rds) in mouse results from simple insertion of a t haplotype-specific element into protein-coding exon II. Genomics 28: 212-219, 1995. [PubMed: 8530028] [Full Text: https://doi.org/10.1006/geno.1995.1133]
Manes, G., Guillaumie, T., Vos, W. L., Devos, A., Audo, I., Zeitz, C., Marquette, V., Zanlonghi, X., Defoort-Dhellemmes, S., Puech, B., Said, S. M., Sahel, J. A., and 18 others. High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in France and characterization of biochemical and clinical features. Am. J. Ophthal. 159: 302-314, 2015. [PubMed: 25447119] [Full Text: https://doi.org/10.1016/j.ajo.2014.10.033]
McNally, N., Kenna, P. F., Rancourt, D., Ahmed, T., Stitt, A., Colledge, W. H., Lloyd, D. G., Palfi, A., O'Neill, B., Humphries, M. M., Humphries, P., Farrar, G. J. Murine model of autosomal dominant retinitis pigmentosa generated by targeted deletion at codon 307 of the rds-peripherin gene. Hum. Molec. Genet. 11: 1005-1016, 2002. [PubMed: 11978760] [Full Text: https://doi.org/10.1093/hmg/11.9.1005]
Meins, M., Gruning, G., Blankenagel, A., Krastel, H., Reck, B., Fuchs, S., Schwinger, E., Gal, A. Heterozygous 'null allele' mutation in the human peripherin/RDS gene. Hum. Molec. Genet. 2: 2181-2182, 1993. [PubMed: 8111389] [Full Text: https://doi.org/10.1093/hmg/2.12.2181]
Nadeau, J. H. Modifier genes in mice and humans. Nature Rev. Genet. 2: 165-174, 2001. [PubMed: 11256068] [Full Text: https://doi.org/10.1038/35056009]
Nichols, B. E., Drack, A. V., Vandenburgh, K., Kimura, A. E., Sheffield, V. C., Stone, E. M. A 2 base pair deletion in the RDS gene associated with butterfly-shaped pigment dystrophy of the fovea. Hum. Molec. Genet. 2: 601-603, 1993. Note: Erratum: Hum. Molec. Genet. 2: 1347 only, 1993. [PubMed: 8251014] [Full Text: https://doi.org/10.1093/hmg/2.5.601]
Nichols, B. E., Sheffield, V. C., Vandenburgh, K., Drack, A. V., Kimura, A. E., Stone, E. M. Butterfly-shaped pigment dystrophy of the fovea caused by a point mutation in codon 167 of the RDS gene. Nature Genet. 3: 202-207, 1993. [PubMed: 8485574] [Full Text: https://doi.org/10.1038/ng0393-202]
Payne, A. M., Downes, S. M., Bessant, D. A. R., Bird, A. C., Bhattacharya, S. S. Founder effect, seen in the British population, of the 172 peripherin/RDS mutation--and further refinement of genetic positioning of the peripherin/RDS gene. (Letter) Am. J. Hum. Genet. 62: 192-195, 1998. [PubMed: 9443872] [Full Text: https://doi.org/10.1086/301679]
Pendleton, J. W., Violette, S. M., Hunihan, L. W., Greene, L. A., Ruddle, F. H. The peripherin gene maps to mouse chromosome 15. Genomics 9: 369-372, 1991. [PubMed: 2004788] [Full Text: https://doi.org/10.1016/0888-7543(91)90267-i]
Piguet, B., Heon, E., Munier, F. L., Grounauer, P. A., Niemeyer, G., Butler, N., Schorderet, D. F., Sheffield, V. C., Stone, E. M. Full characterization of the maculopathy associated with an arg-172-trp mutation in the RDS/peripherin gene. Ophthalmic Genet. 17: 175-186, 1996. [PubMed: 9010868] [Full Text: https://doi.org/10.3109/13816819609057891]
Reig, C., Serra, A., Gean, E., Vidal, M., Arumi, J., De la Calzada, M. D., Antich, J., Carballo, M. A point mutation in the RDS-peripherin gene in a Spanish family with central areolar choroidal dystrophy. Ophthal. Genet. 16: 39-44, 1995. Note: Erratum: Ophthal. Genet. 16: 179 only, 1995. [PubMed: 7493155] [Full Text: https://doi.org/10.3109/13816819509056911]
Sarra, G.-M., Stephens, C., de Alwis, M., Bainbridge, J. W. B., Smith, A. J., Thrasher, A. J., Ali, R. R. Gene replacement therapy in the retinal degeneration slow (rds) mouse: the effect on retinal degeneration following partial transduction of the retina. Hum. Molec. Genet. 10: 2353-2361, 2001. [PubMed: 11689482] [Full Text: https://doi.org/10.1093/hmg/10.21.2353]
Stuck, M. W., Conley, S. M., Naash, M. I. The Y141C knockin mutation in RDS leads to complex phenotypes in the mouse. Hum. Molec. Genet. 23: 6260-6274, 2014. [PubMed: 25001182] [Full Text: https://doi.org/10.1093/hmg/ddu345]
Travis, G. H., Brennan, M. B., Danielson, P. E., Kozak, C. A., Sutcliffe, J. G. Identification of a photoreceptor-specific mRNA encoded by the gene responsible for retinal degeneration slow (rds). Nature 338: 70-73, 1989. [PubMed: 2918924] [Full Text: https://doi.org/10.1038/338070a0]
Travis, G. H., Christerson, L., Danielson, P. E., Klisak, I., Sparkes, R. S., Hahn, L. B., Dryja, T. P., Sutcliffe, J. G. The human retinal degeneration slow (RDS) gene: chromosome assignment and structure of the mRNA. Genomics 10: 733-739, 1991. [PubMed: 1679750] [Full Text: https://doi.org/10.1016/0888-7543(91)90457-p]
Travis, G. H., Hepler, J. E. A medley of retinal dystrophies. Nature Genet. 3: 191-192, 1993. [PubMed: 8485572] [Full Text: https://doi.org/10.1038/ng0393-191]
Travis, G. H., Sutcliffe, J. G., Bok, D. The retinal degeneration slow (rds) gene product is a photoreceptor disc membrane-associated glycoprotein. Neuron 6: 61-70, 1991. [PubMed: 1986774] [Full Text: https://doi.org/10.1016/0896-6273(91)90122-g]
Vaclavik, V., Tran, H. V., Gaillard, M.-C., Schorderet, D. F., Munier, F. L. Pattern dystrophy with high intrafamilial variability associated with Y141C mutation in the peripherin/RDS gene and successful treatment of subfoveal CNV related to multifocal pattern type with anti-VEGF (ranibizumab) intravitreal injections. Retina 32: 1942-1949, 2012. [PubMed: 22466463] [Full Text: https://doi.org/10.1097/IAE.0b013e31824b32e4]
van Nie, R., Ivanyi, D., Demant, P. A new H-2-linked mutation, rds, causing retinal degeneration in the mouse. Tissue Antigens 12: 106-108, 1978. [PubMed: 705766] [Full Text: https://doi.org/10.1111/j.1399-0039.1978.tb01305.x]
Wang, X., Wang, H., Sun, V., Tuan, H.-F., Keser, V., Wang, K., Ren, H., Lopez, I., Zaneveld, J. E., Siddiqui, S., Bowles, S., Khan, A., and 12 others. Comprehensive molecular diagnosis of 179 Leber congenital amaurosis and juvenile retinitis pigmentosa patients by targeted next generation sequencing. J. Med. Genet. 50: 674-688, 2013. [PubMed: 23847139] [Full Text: https://doi.org/10.1136/jmedgenet-2013-101558]
Weleber, R. G., Carr, R. E., Murphey, W. H., Sheffield, V. C., Stone, E. M. Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch. Ophthal. 111: 1531-1542, 1993. [PubMed: 8240110] [Full Text: https://doi.org/10.1001/archopht.1993.01090110097033]
Wells, J., Wroblewski, J., Keen, J., Inglehearn, C., Jubb, C., Eckstein, A., Jay, M., Arden, G., Bhattacharya, S., Fitzke, F., Bird, A. Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy. Nature Genet. 3: 213-218, 1993. [PubMed: 8485576] [Full Text: https://doi.org/10.1038/ng0393-213]
Wroblewski, J. J., Wells, J. A., III, Eckstein, A., Fitzke, F., Jubb, C., Keen, J., Inglehearn, C., Bhattacharya, S., Arden, G. B., Jay, M., Bird, A. C. Macular dystrophy associated with mutations at codon 172 in the human retinal degeneration slow gene. Ophthalmology 101: 12-22, 1994. [PubMed: 8302543] [Full Text: https://doi.org/10.1016/s0161-6420(94)31377-7]
Yanagihashi, S., Nakazawa, M., Kurotaki, J., Sato, M., Miyagawa, Y., Ohguro, H. Autosomal dominant central areolar choroidal dystrophy and a novel arg195-to-leu mutation in the peripherin/RDS gene. Arch. Ophthal. 121: 1458-1461, 2003. [PubMed: 14557183] [Full Text: https://doi.org/10.1001/archopht.121.10.1458]
Yang, Z., Li, Y., Jiang, L., Karan, G., Moshfeghi, D. M., O'Connor, S. T., Li, X., Yu, Z., Lewis, H., Zack, D. J., Jacobson, S. G., Zhang, K. A novel RDS/peripherin gene mutation associated with diverse macular phenotypes. Ophthalmic Genet. 25: 133-145, 2004. [PubMed: 15370544] [Full Text: https://doi.org/10.1080/13816810490514388]
Yang, Z., Lin, W., Moshfeghi, D. M., Thirumalaichary, S., Li, X., Jiang, L., Zhang, H., Zhang, S., Kaiser, P. K., Traboulsi, E. I., Zhang, K. A novel mutation in the RDS/peripherin gene causes adult-onset foveomacular dystrophy. Am. J. Ophthal. 135: 213-218, 2003. [PubMed: 12566026] [Full Text: https://doi.org/10.1016/s0002-9394(02)01815-9]