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(Investigative Ophthalmology and Visual Science. 2001;42:2217-2224.)
© 2001 by The Association for Research in Vision and Ophthalmology, Inc.

Clinical Features and Mutations in Patients with Dominant Retinitis Pigmentosa-1 (RP1)

Eliot L. Berson1, Jonna L. Grimsby1, Scott M. Adams1, Terri L. McGee1, Elizabeth Sweklo1, Eric A. Pierce2, Michael A. Sandberg1 and Thaddeus P. Dryja1

1 From the Berman-Gund Laboratory for the Study of Retinal Degenerations and the Ocular Molecular Genetics Institute, Harvard Medical School and the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; and the 2 F. M. Kirby Center for Molecular Ophthalmology, University of Pennsylvania, Scheie Eye Institute, Philadelphia, Pennsylvania.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PURPOSE. To survey patients with dominant retinitis pigmentosa (RP) for mutations in the RP1 gene to determine the spectrum of dominant mutations in this gene, to estimate the proportion of dominant RP caused by this gene, and to determine whether the clinical features of patients with RP1 mutations differ from features of those with rhodopsin mutations.

METHODS. A set of 241 patients who did not have mutations in the rhodopsin gene (based on previous work) formed the basis for the study. Of these patients, 117 had also been previously evaluated and were found not to carry mutations in the RDS gene. The single-strand conformation polymorphism (SSCP) method was used to search for sequence variants, which were then directly sequenced. The relatives of selected patients were recruited for segregation analyses. Clinical evaluations of patients included a measurement of Snellen visual acuity, final dark adaptation thresholds, visual fields, and ERGs. Clinical data were compared with those obtained earlier from a study of 128 patients with dominant rhodopsin mutations.

RESULTS. Of the 241 patients, all were screened for the most common RP1 mutation (Arg677Ter), and 10 patients were found to have this mutation. In addition, an evaluation of a subset of 189 patients in whom the entire coding sequence was evaluated revealed the following mutations: Gln679Ter (1 case), Gly723Ter (2 cases), Glu729(1-bp del) (1 case), Leu762(5-bp del) (2 cases), and Asn763(4-bp del) (1 case). All of these mutations cosegregated with RP in the families of the index patients. Nine missense mutations that were each found in six or fewer patients were encountered. The segregation of eight of these was evaluated in the respective patients’ families, and only one segregated with dominant RP. This cosegregating missense change was in cis with the nonsense mutation Gln679Ter. Although patients with RP1 mutations had, on average, slightly better visual acuity than patients with rhodopsin mutations, there was no statistically significant difference in final dark-adaptation thresholds, visual field diameters, or cone electroretinogram (ERG) amplitudes. Comparably aged patients with RP1 mutations had visual function that varied by approximately two orders of magnitude, based on visual fields and ERG amplitudes.

CONCLUSIONS. Dominant RP1 alleles typically have premature nonsense codons occurring in the last exon of the gene and would be expected to encode mutant proteins that are only approximately one third the size of the wild-type protein, suggesting that a dominant negative effect rather than haploinsufficiency is the mechanism leading to RP caused by RP1 mutations. On average, patients with RP1 mutations have slightly better visual acuity than patients with dominant rhodopsin mutations; otherwise, they have similarly severe disease. The wide range in severity among patients with RP1 mutations indicates that other genetic or environmental factors modulate the effect of the primary mutation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Although there are at least nine different loci where dominant mutations cause retinitis pigmentosa (RP), only four of these genes have been identified. The four genes encode rhodopsin (RHO; mapped to chromosome 3q21-24), retinal degeneration slow (RDS; 6p21.1-cen), a protein containing a leucine zipper motif (NRL; 14q11.1-11.2), and an oxygen-regulated photoreceptor protein (RP1; 8q11-13). In North America, mutations in the rhodopsin gene account for approximately 20% to 25% of cases of dominant RP,1 and mutations in the RDS gene account for approximately 2% of cases.2 A European study identified a single NRL mutation in 3 of 200 families with dominant RP.3 We conducted this study to estimate the proportion of dominant RP in North America that is caused by mutations in RP1 and to increase our knowledge of the spectrum of dominant mutations in this gene. In addition, we evaluated the clinical findings in the patients with RP1 mutations, with specific attention devoted to measuring the range of severity of disease among these patients and their severity in comparison with 128 patients of comparable age previously found to have dominant mutations in the rhodopsin gene.1 4


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
This research conformed to the guidelines for the studies of human subjects required by the Declaration of Helsinki. Index patients were enrolled in this study at the time of their ocular evaluations for RP, after giving informed consent. We included only patients with a family history indicating a dominant inheritance pattern. All patients were evaluated for mutations in the rhodopsin gene.1 Those with rhodopsin mutations were excluded from the survey, leaving 241 unrelated patients. Of these, 117 had been evaluated for mutations in the RDS gene and were found to have none.2

Leukocyte DNA was purified and screened for mutations in the RP1 gene by single-strand conformation analysis (SSCP), as described previously.5 Patients with variantly migrating fragments were evaluated further by directly sequencing the corresponding amplicon. To search specifically for the mutation Arg677Ter, we amplified patient DNA samples with the following primer pair (sense/antisense): 5'-AGGTTCAGTCCTATTTCAGCAGATG-3'/5'-ATTCTACCTTTTGTGTTTATTCTCTCA-3'. The amplified fragment was digested with the enzyme TaqI (the Arg677Ter mutation destroys a TaqI recognition sequence), and the resultant DNA fragments were separated by electrophoresis through agarose gels. When sequence abnormalities were detected by SSCP or the TaqI analysis, the patient’s relatives were invited to participate by donating a blood sample and, in some cases, by coming to the project laboratory for an ocular examination including an electroretinogram (ERG). Selected regions of the RP1 gene were evaluated in DNA from up to 187 unrelated, unaffected control individuals without a family history of RP.

Ocular examinations were performed with techniques previously described.6 Specifically, dark-adaptation thresholds after 45 minutes of dark adaptation were measured in the Goldmann-Weekers dark adaptometer to an 11° white test light projected either centrally or, if the patient’s field was sufficiently large, 7° below fixation. Kinetic perimetry was performed with a V4e white test light in all patients and with a I4e or II4e test light in approximately one third of patients. Each test light was brought from the nonseeing to the seeing areas. We used the V4e test light for these analyses because this is the only test light for which we have a full data set on our patients. Visual field areas were determined with a desk-top planimeter or with images of the visual fields scanned into a computer. Equivalent visual field diameters were calculated as twice the square root of the visual field area divided by {pi}: 2(area/{pi})1/2.

Full-field ERGs were elicited to single flashes (1/2 Hz) of white light (0.22 candelas [cd]/sec · m2) and to 30-Hz white flashes of the same luminance in a Ganzfeld dome. Responses were recorded with or without computer averaging. All responses with amplitudes of less than 10 µV were obtained with computer averaging. Amplitudes were measured from the trough of the a-wave (or from the baseline, if the a-wave was absent) to the peak of the b-wave for responses to 0.5-Hz light flashes, and from trough to peak for the responses to 30-Hz flashes. Nondetectable responses, defined as amplitudes less than 1 µV for responses to 0.5-Hz light flashes or less than 0.05 µV for responses to 30-Hz light flashes, were coded as 1 or 0.05 µV, respectively, because these are the limits of detectability. The reproducibility of submicrovolt signals in response to 30-Hz light flashes has been documented in the past.7 8

When patients had more than one clinical evaluation, data from the initial visit were used for analysis. Test results from both eyes were averaged. With the exception of visual acuities, the data were transformed to the log scale to approximate a normal distribution. Mean values were corrected for age and refractive error and compared with data obtained from 128 patients of similar age who had previously been found to have RP due to dominant mutations in the rhodopsin gene.1 4


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of the 241 unrelated patients with dominant RP included in this study, 189 were evaluated for mutations in the entire coding region of the RP1 gene and in the splice acceptor and donor sites of all introns, except for the splice donor site of intron 1. Sequence anomalies that we discovered were grouped into four categories listed in Tables 1 and 2 . There were 6 distinct nonsense changes (3 of which were the result of frameshifts), 16 missense changes, 5 isocoding changes, and 1 intron change, as discussed in the following sections.


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  		Table 1. Mutations and Rare Missense Changes

 

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  		Table 2. Polymorphisms and Other Rare Variants

 
Nonsense Mutations
The relatively high frequency of one nonsense mutation, Arg677Ter, led us to survey an additional 52 unrelated patients (for a total of 241 patients) for that mutation only. In all, 10 of the 241 unrelated patients carried this mutation. Two other nonsense changes (Gly723Ter and Leu762[5-bp del]) were present in two separate patients each (of the fully screened set of 189 patients), and the remaining three nonsense changes (Gln679Ter, Glu729[1-bp del], and Asn763[4-bp del]) were found in only one patient each (of 189). The mutations Gly723Ter and Glu729(1-bp del) are novel. The sequences of the relevant regions in the index patients carrying these mutations are illustrated in Figure 1 . The nonsense mutations Arg677Ter, Gln679Ter, Gly723Ter, and Leu762(5-bp del) have been reported previously.5 9 10 11 12 13 At least one family with each of the six nonsense mutations was recruited for a segregation study. The results obtained for the families with the novel mutations Gly723Ter and Glu729(1-bp del) are shown in Figure 1 . Examples of families with the other mutations have been previously reported.5 In every case, the nonsense mutation cosegregated with dominant RP, as expected for a pathogenic mutation. Normal control individuals were surveyed for five of the nonsense changes, and none of these mutations was found (Table 1) .



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  		Figure 1. Sequences of the novel mutations Gly723Ter and Glu729(1-bp del) in the index patients in whom they were first detected. The sequences of the relevant regions are compared with the sequences of control individuals with the normal sequence. Below each sequence is a schematic pedigree illustrating the cosegregation of dominant RP with the mutation in the family of the index case.

 
Missense Changes
Nine missense changes were found heterozygously in only one to six unrelated patients each (Table 1) ; seven are novel. We categorized eight of these nine missense changes as likely to be nonpathogenic sequence variants based on the following data. Three of the missense changes (Thr373Ile, Leu1417Pro, and Asp2066Asn) were also found among a set of 95 normal control individuals who were evaluated (Table 1) . We were able to recruit families of index patients with eight of the nine missense changes. In seven of the families, the missense change segregated independently of dominant RP (Fig. 2) , indicating that these seven missense changes (Arg168Gly, Thr373Ile, Asp1072Gly, Leu1356Ser, Leu1417Pro, Phe1935Leu, and Asp2066Asn) were not the cause of RP in the respective families. The eighth missense change in which segregation was evaluated (Pro1793Ser) was found in an index patient who also carried the nonsense mutation Gln679Ter. Evaluation of this family indicated that Gln679Ter and Pro1793Ser were in cis (Fig. 2) , and we conclude that the nonsense mutation rather than the downstream missense change is the reason for the pathogenicity of this allele.



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  		Figure 2. Families of index patients with rare nonpathogenic missense changes in RP1. In every case, the missense change did not segregate with dominant RP, except for Pro1793Ser in family 0286; however, in this family, the missense change was on the same allele as the pathogenic mutation Gln679Ter. No family was available to compare the segregation of Ala218Thr and dominant RP. In families 6983, 6674, 0286, and 6809, obligate carriers were unaffected by history but were not examined. The unaffected obligate carrier in family 2474 was clinically evaluated and the unaffected status was confirmed.

 
We were unable to recruit the family of the index patient with the missense change Ala218Thr for a segregation analysis. Although the Ala218Thr change was not found among normal control subjects, the association between Ala218Thr and dominant RP is not statistically significant (1/189 patients vs 0/95 control subjects; P = 0.67, calculated with Fisher’s exact test). Whether Ala218Thr is a dominant mutation causing RP or a rare, nonpathogenic variant remains uncertain.

Nonpathogenic Missense Polymorphisms and Rare Variants
Four additional missense changes (Asn985Tyr, Ala1670Thr, Ser1691Pro, and Cys2033Tyr) were each found at an allele frequency greater than 0.25 among the 189 unrelated patients with dominant RP (Table 2) . All four have been reported previously.9 12 The missense polymorphism Arg872His, previously reported to have an allele frequency of 0.25,9 was not detected by our SSCP method but was identified among several patients by directly sequencing codon 872. The allele frequencies of these changes are listed in Table 2 , except for Arg872His because of our difficulties in detecting it by SSCP. We concluded that these five missense changes were nonpathogenic polymorphisms for the following reasons: The frequency of these alleles was high; each of them was found in at least one patient who also had a definitely pathogenic nonsense mutation in RP1 (data not shown); in at least one family each, we showed that they did not segregate with disease (data not shown); and the frequencies of heterozygotes and homozygotes indicated that the alleles were in apparent Hardy-Weinberg equilibrium (data not shown).

The missense changes Ala1670Thr and Ser1691Pro and the isocoding change at Gln1725 (described later) were usually found together, indicating that they reflect an allele with the less common sequence at all three codons. However, we found a few patients with an allele with the Ser1691Pro change but not with the less common sequence at codons 1670 and 1725. Two other novel missense changes, Arg376Leu and Leu1425Pro, were found only among normal control subjects at low frequencies and not in any patients (Table 2) , and we considered them to be rare, nonpathogenic variants.

Isocoding and Intron Changes
Isocoding changes affecting codons Leu76, Thr93, Ser1233, and Gln1725 were found among patients, and an isocoding change affecting Pro138 was found in a control individual. All these isocoding changes were at a low frequency and were presumed not to be pathogenic (Table 2) . A change in intron 2 (IVS2-6T->C) was also found at a low frequency in patients and control subjects and was presumed not to be pathogenic. Of these isocoding and intron changes, the changes affecting codons 138 and 1233 are novel.

Clinical Evaluation of Patients with Nonsense RP1 Alleles
Based on the cosegregation of the mutations with dominant RP and their absence among control subjects, we concluded that all six nonsense mutations were pathogenic. We clinically evaluated the 17 index patients with these mutations and 7 of their affected relatives. The ages of the 24 patients ranged from 16 to 66 years (Table 3) . Some of the patients had no symptomatic night blindness or symptomatic visual field loss at the time of their initial examination (Table 3) . Most patients had intraretinal bone-spicule pigment deposits in all four quadrants of both eyes, and 9 of the 24 patients had cataracts in one or both eyes (Table 3) .


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  		Table 3. Ocular Findings in Patients with RP1 Mutations

 
Average Snellen acuity was 20/25 (range, 20/20–20/42; Table 4 ). Despite good central acuities, widespread loss of retinal function was observed by visual field and ERG testing. There was a profound reduction of full-field rod-plus-cone and cone ERG amplitudes, with the average mixed rod-plus-cone amplitude being 8.3 µV (geometric mean) and the range from 1 to 145.3 µV (normal, >=350 µV). The geometric mean cone amplitude was 2.0 µV (normal, >=50 µV). Visual fields were also reduced, with the geometric mean visual field equivalent diameter reduced to 85° (normal is >=120°). None of our patients exhibited a preferential loss of the superior temporal visual field when evaluated with the V4e test light at their initial evaluation except patient 001-240 who had bone-spicule pigment deposits exclusively inferonasally; he had superotemporal loss of visual field in both eyes, as measured with the V4e and I4e lights.


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  		Table 4. Visual Function in Patients with RP1 Mutations

 
Marked variation was seen among patients of comparable age with the same mutation. For example, patients 226-664, 226-665, and 226-666 with the Asn763(4-bp del) mutation, who were aged 16 to 21, had rod-plus-cone ERG amplitudes ranging from 1.0 to 145 µV and cone ERG amplitudes ranging from 2.5 to 38 µV.

Figure 3 shows a comparison of visual acuity, visual field equivalent diameter, final dark-adaptation threshold, and cone ERG amplitude between the 24 patients with RP1 mutations and 128 patients with dominant rhodopsin mutations. Each measurement is plotted as a function of age. When we used multiple regression, controlling for age and refractive error, patients with an RP1 mutation had better visual acuity than patients with a rhodopsin mutation (P = 0.017). Other measures of visual function were not significantly different between the two groups of patients (P = 0.33, 0.40, and 0.21 for dark-adaptation thresholds, visual field equivalent diameters, and 30-Hz cone ERG amplitudes, respectively).



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  		Figure 3. Scatterplots and linear regression of best-corrected Snellen decimal visual acuity, dark-adapted threshold above normal, visual field equivalent circular diameter, and 30-Hz ERG amplitude versus age in 24 patients with dominant RP1 mutations (x, solid fitted lines) and 128 patients with dominant rhodopsin mutations ({blacksquare}, dashed fitted lines).4 A significant difference between patients with RP1 mutations and patients with rhodopsin mutations was seen only in visual acuity.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Except for a few missense changes of uncertain pathogenicity, the dominant mutations in the RP1 gene that we report, as well as those reported by other groups,9 10 11 12 13 cluster within a region extending from codons 658-1053 in exon 4 (Fig. 4) . All these mutants lead to premature stops between codons 660 and 1055, and all would be expected to encode truncated proteins without approximately half to two thirds of the carboxyl-terminal end. It is a general rule that nonsense mutations in mammalian genes lead to unstable mRNA molecules and very little or no translated protein. However, investigations of nonsense-mediated degradation of mRNA suggest that the pathway mediating this process is activated when an intron follows a nonsense mutation.14 This mechanism would not affect nonsense mutations in the terminal exon of a gene. Because all the pathogenic nonsense and frameshift RP1 mutations are in the terminal exon, it is likely that they would result in stable mRNAs that would be translated. The retinal degeneration caused by these mutations is probably not due to haploinsufficiency but rather to some deleterious property of the truncated proteins.



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  		Figure 4. Schematic diagram of the RP1 gene showing the locations of pathogenic mutations (below the schematic gene) and polymorphisms or rare variants (above the schematic gene) found by our group and others.5 9 10 11 12 13 Of the missense changes shown above the gene, nine are of uncertain pathogenicity (Ala218Thr, Ser504Ala, Lys663Asn, Lys792Gln, Arg798Thr, Lys900Thr, Gly1402Phe, Leu1808Pro, and Thr2113Asn). The remainder are considered not to be causes of dominant RP. The in-frame mutation Gly724(15-bp del) reported by Payne et al.13 is not included in this figure, because this mutation was reported in error; it is actually Gly724(14-bp del) (Bhattacharya S, personal communications, January 23 and February 23, 2001).

 
In contrast to the apparent clustering of definitely pathogenic mutations, the polymorphisms, rare nonpathogenic variants, and changes of uncertain pathogenicity were scattered throughout the gene (Fig. 4) . Most of the missense changes that we and others have identified do not cause dominant RP. Some missense changes remain of uncertain pathogenicity because they have been found rarely among patients, and no segregation analyses have been performed. A few of the rare variants initially placed in this "uncertain" category by other groups have been recategorized as nonpathogenic by more recent studies. For example, Arg1595Gln was found only among affected patients by Jacobson et al.12 and Payne et al.,13 but was subsequently found in normal control subjects by Bowne et al.11 Additionally, our data allow the recategorization of Thr373Ile, previously considered to be pathogenic because of cosegregation with dominant RP in a large pedigree,13 as nonpathogenic because it did not cosegregate with disease in one of our families, and we found it in normal control subjects. Of the missense changes that are still considered of uncertain pathogenicity (Fig. 4) , some may truly cause dominant RP, perhaps because they encode proteins with toxicity to the retina similar to that presumed for the truncation mutants. It is possible that true null mutations in RP1 may be recessive alleles also leading to RP or perhaps to some other retinal disease.

Based on our results, we can estimate the proportion of dominant RP due to RP1 gene mutations. Based on our survey of 241 unrelated patients for the Arg677Ter mutation and a subset of 189 patients for mutations in the entire coding region, we found RP1 defects in 7.7% of unrelated cases. Because patients with rhodopsin mutations had been excluded and because they account for approximately 25% of dominant RP in our patient population,1 the true proportion of RP1 mutations in dominant RP would be reduced by approximately 25%, for an estimated proportion of 5.8%. Cases due to RDS mutations that were previously identified in our laboratory have also been excluded. Because not all the patients in this study had been evaluated for RDS mutations and because the reported proportion of dominant RP due to RDS mutations is low (approximately 4%),2 the adjustment to the calculated proportion of dominant RP due to RP1 is small. We estimate that the adjustment would decrease the proportion by only 0.1 to 0.2 percentage points, so that the best estimate of the proportion of dominant RP families due to RP1 mutations is approximately 5.6%.

This is based on data only from our laboratory, whose patients come mainly from the United States and Canada. This proportion can be compared with that obtained by a recent study of 266 British patients with dominant RP that found 21 (8%), with RP1 mutations.13 However, that study did not specify whether it excluded patients known to have mutations in other dominant RP genes. If patients with rhodopsin mutations had been excluded, then the proportion of dominant RP caused by RP1 mutations would be about 6%, close to our value. Another study from the United States surveyed 250 unrelated patients with dominant RP and found 17 with mutations (7%), but the entire coding region of the gene was evaluated in only 56 of the patients.11

Our clinical evaluation of patients with RP1 mutations indicates that there is a wide range in the severity of the disease even in patients with the same mutation. Measures of retinal function, such as visual field diameters or cone ERG amplitudes, can vary approximately 100-fold between the most severely affected patients and the least severely affected, even at comparable ages. Others have also reported a wide range of severity of disease caused by RP1 mutations, including asymptomatic carriers.12 15 A similar range of severity has been seen in patients with rhodopsin mutations.4 This variation must be due to factors other than the primary gene defect.

It has been reported that patients with RP1 mutations can exhibit a regional variation in disease, with more loss of superior and temporal visual field and more intraretinal pigment deposits in the corresponding regions of the inferior fundus.12 In our cohort, only once did we observe this pattern (patient 001-240). Even in this patient, the full-field cone ERG implicit times were delayed, suggesting generalized retinal degeneration.

Our comparison of the clinical findings in patients with RP1 mutations with those in patients with dominant rhodopsin mutations did not reveal any features that were sufficiently distinctive, alone or in combination, to allow us to predict the causative gene from the phenotype. All our measures of visual function in patients with RP1 mutations were similar to those seen in patients with rhodopsin mutations, with the exception of visual acuity. Patients with RP1 mutations retained, on average, slightly better central acuity, but the difference was modest, and there was substantial overlap in the two groups of patients. At age 30, for example, patients with RP1 mutations had an average acuity of 20/23, whereas patients with rhodopsin mutations had an average acuity of 20/27. At age 60 the average acuities were 20/30 and 20/40, respectively. There may be asymptomatic affected individuals in families with mutations in RP1 as well as the rhodopsin gene. Nonetheless, abnormal ERGs were present in asymptomatic carriers (e.g., patient 226-665 at age 18 years and 001-281 at age 28), consistent with the RP1 mutations’ having complete penetrance. Clinicians should be reminded that absence of visual symptoms, particularly among young patients, does not exclude the disease.


   Footnotes
 
Supported by National Institutes of Health Grants EY00169 and EY08683, the Foundation Fighting Blindness, and Research to Prevent Blindness.

Submitted for publication January 22, 2001; revised May 9, 2001; accepted May 31, 2001.

Commercial relationships policy: N.

The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

Corresponding author: Eliot L. Berson, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA 02114.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Dryja, TP, McEvoy, JA, McGee, TL, Berson, EL (2000) Novel rhodopsin mutations Gly114Val and Gln184Pro in dominant retinitis pigmentosa Invest Ophthalmol Vis Sci 41,3124-3127[Abstract/Free Full Text]
  2. Dryja, TP, Hahn, LB, Kajiwara, K, Berson, EL (1997) Dominant and digenic mutations in the peripherin/RDS and ROM1 genes in retinitis pigmentosa Invest Ophthalmol Vis Sci 38,1972-1982[Abstract/Free Full Text]
  3. Bessant, DA, Payne, AM, Plant, C, Bird, AC, Swaroop, A, Bhattacharya, SS (2000) NRL S50T mutation and the importance of "founder effects" in inherited retinal dystrophies Eur J Hum Genet 8,783-787[Medline][Order article via Infotrieve]
  4. Sandberg, MA, Weigel-DiFranco, C, Dryja, TP, Berson, EL (1995) Clinical expression correlates with location of rhodopsin mutation in dominant retinitis pigmentosa Invest Ophthalmol Vis Sci 36,1934-1942[Abstract/Free Full Text]
  5. Pierce, EA, Quinn, T, Meehan, T, McGee, TL, Berson, EL, Dryja, TP (1999) Mutations in a gene encoding a new oxygen-regulated photoreceptor protein cause dominant retinitis pigmentosa Nat Genet 22,248-254[Medline][Order article via Infotrieve]
  6. Berson, EL, Rosner, B, Sandberg, MA, Dryja, TP (1991) Ocular findings in patients with autosomal dominant retinitis pigmentosa and a rhodopsin gene defect (Pro23His) Arch Ophthalmol 109,92-101[Abstract]
  7. Andréasson, SOL, Sandberg, MA, Berson, EL (1988) Narrow-band filtering for monitoring low-amplitude cone electroretinograms in retinitis pigmentosa Am J Ophthalmol 105,500-503[Medline][Order article via Infotrieve]
  8. Birch, DG, Sandberg, MA (1997) Submicrovolt full-field cone electroretinograms: artifacts and reproducibility Doc Ophthalmol 92,269-280
  9. Sullivan, LS, Heckenlively, JR, Bowne, SJ, et al (1999) Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa Nat Genet 22,255-259[Medline][Order article via Infotrieve]
  10. Guillonneau, X, Piriev, NI, Dancinger, M, et al (1999) A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus Hum Mol Genet 8,1541-1546[Abstract/Free Full Text]
  11. Bowne, SJ, Daiger, SP, Hims, MM, et al (1999) Mutations in the RP1 gene causing autosomal dominant retinitis pigmentosa Hum Mol Genet 8,2121-2128[Abstract/Free Full Text]
  12. Jacobson, SG, Cideciyan, AV, Iannaccone, A, et al (2000) Disease expression of RP1 mutations causing autosomal dominant retinitis pigmentosa Invest Ophthalmol Vis Sci 41,1898-1908[Abstract/Free Full Text]
  13. Payne, A, Vithana, E, Khaliq, S, et al (2000) RP1 protein truncating mutations predominate at the RP1 ADRP locus Invest Ophthalmol Vis Sci 41,4069-4073[Abstract/Free Full Text]
  14. Hentze, MW, Kulozik, AE (1999) A perfect message: RNA surveillance and nonsense-mediated decay Cell 96,307-310[Medline][Order article via Infotrieve]
  15. Xu, SY, Denton, M, Sullivan, L, Daiger, SP, Gal, A. (1996) Genetic mapping of RP1 on 8q11–q21 in an Australian family with autosomal dominant retinitis pigmentosa reduces the critical region to 4 cM between D8S601 and D8S285 Hum Genet 98,741-743[Medline][Order article via Infotrieve]



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Q. Liu, J. Zuo, and E. A. Pierce
The Retinitis Pigmentosa 1 Protein Is a Photoreceptor Microtubule-Associated Protein
J. Neurosci., July 21, 2004; 24(29): 6427 - 6436.
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Q. Liu, A. Lyubarsky, J. H. Skalet, E. N. Pugh Jr, and E. A. Pierce
RP1 Is Required for the Correct Stacking of Outer Segment Discs
Invest. Ophthalmol. Vis. Sci., October 1, 2003; 44(10): 4171 - 4183.
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S. B. Schwartz, T. S. Aleman, A. V. Cideciyan, A. Swaroop, S. G. Jacobson, and E. M. Stone
De Novo Mutation in the RP1 Gene (Arg677ter) Associated with Retinitis Pigmentosa
Invest. Ophthalmol. Vis. Sci., August 1, 2003; 44(8): 3593 - 3597.
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 Proc. Natl. Acad. Sci. USAHome page
J. Gao, K. Cheon, S. Nusinowitz, Q. Liu, D. Bei, K. Atkins, A. Azimi, S. P. Daiger, D. B. Farber, J. R. Heckenlively, et al.
Progressive photoreceptor degeneration, outer segment dysplasia, and rhodopsin mislocalization in mice with targeted disruption of the retinitis pigmentosa-1 (Rp1) gene
PNAS, April 16, 2002; 99(8): 5698 - 5703.
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