| Human Molecular Genetics | Pages |
©1999 Oxford University Press |
A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus
Introduction
Results
Isolation of mouse mG145 cDNA
Isolation of the human homolog of mouse mG145 cDNA and of the RP1 gene
Localization of the RP1 gene
Screening of an RP1 family for mutations in the RP1 gene
Discussion
Materials And Methods
Mapping of the gene corresponding to mG145 cDNA in the mouse
cDNA and genomic library screening
RT-PCR amplification
Sequence analysis
Northern blot analysis
Mapping of the human RP1 gene
Patients
Mutation analysis
Acknowledgements
References
A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus
Received April 30 1999; Revised and Accepted May 25, 1999
Retinitis pigmentosa (RP) represents a group of inherited human retinal diseases which involve degeneration of photoreceptor cells resulting in visual loss and often leading to blindness. In order to identify candidate genes for the causes of these diseases, we have been studying a pool of photoreceptor-specific cDNAs isolated by subtractive hybridization of mRNAs from normal and photoreceptorless rd mouse retinas. One of these cDNAs was of interest because it mapped to proximal mouse chromosome 1 in a region homologous to human 8q11-q13, the locus of autosomal dominant RP1. Therefore, using the mouse cDNA as probe, we cloned the human cDNA (hG28) and its corresponding gene and mapped it near to D8S509, which lies in the RP1 locus. This gene consists of four exons with an open reading frame of 6468 nt encoding a protein of 2156 amino acids with a predicted mass of 240 kDa. Given its chromosomal localization, we screened this gene for mutations in a large family affected with autosomal dominant RP previously linked to the RP1 locus. We found an R677X mutation that co-segregated with disease in the family and is absent from unaffected members and 100 unrelated controls. This mutation is predicted to lead to rapid degradation of hG28 mRNA or to the synthesis of a truncated protein lacking ~70% of its original length. Our results suggest that R677X is responsible for disease in this family and that the gene corresponding to hG28 is the RP1 gene.
INTRODUCTION
Retinitis pigmentosa (RP) is a genetically and clinically heterogeneous group of inherited retinopathies characterized by night blindness and progressive loss of day vision due to degeneration of photoreceptor cells. RP is the most widely recognized retinal dystrophy with an estimated prevalence of ~1 in 4000. RP presents multiple modes of inheritance: ~15-20% of all cases are autosomal dominant (adRP), 20-25% autosomal recessive (arRP), 10-15% X-linked (XLRP) and the remaining 40-55% cannot be classified genetically. Molecular genetic studies to date have identified mutations associated with adRP in three genes, with arRP in nine genes and with XLRP in two genes. Additionally, there are 14 other RP loci for which the defective genes have not yet been identified (for reviews see 1-3); seven of these are adRP loci.
As an approach to searching for genes involved in retinal degenerations, several years ago we generated a pool of mouse photoreceptor-specific cDNAs isolated by subtractive hybridization of mRNAs from normal and photoreceptorless rd mouse retinas (4). This pool contains 122 cDNAs, 88 of which have been identified: 70 cDNAs encode proteins that are involved in visual phototransduction, including the [beta]-subunit of cGMP-phosphodiesterase, the cause of the rd mouse (5,6), the rcd1 dog (7,8) and human arRP (9-11) retinal degenerations; 17 cDNAs correspond to housekeeping genes; and one cDNA is the mouse ortholog of the gene responsible for human X-linked juvenile retinoschisis (12). We have now characterized three additional cDNAs encoding a novel retina-specific gene which maps to a region of proximal mouse chromosome 1 that is homologous to human 8q11-q13. The adRP known as RP1 has been linked to this region (13,14). Therefore, we cloned the human homolog of the mouse gene in order to screen it for mutations in a family that had previously been linked to the RP1 locus (15). Here we report the detection of a nonsense mutation in this gene.
RESULTS
Isolation of mouse mG145 cDNA
The gene corresponding to one of the clones isolated from our pool of cDNAs enriched in photoreceptor-specific messages was mapped in the mouse by Southern blot analysis. HindIII fragments of 4.9 kb in Mus mus musculus and Mus spretus DNAs and 4.2 kb in NFS/N and C58/J DNAs were scored in the progeny of two sets of genetic crosses typed for >1200 markers on all 19 autosomes and the X chromosome. Results indicated that the gene corresponding to mG145 maps to proximal chromosome 1 with the following gene order and distances: (centromere)-Oprk1-3/139 (1.4 ± 0.8)-mG145 gene-6/193 (3.1 ± 1.2)-D1Mit1. This region is homologous to human 8q11-q13, where the RP1 locus of adRP had been mapped previously (13). Sequence analysis of the mG145 cDNA revealed a 0.9 kb fragment containing the complete 3[prime]-UTR and part of the coding region. In order to isolate the full-length cDNA, the initial fragment was used to screen a mouse retinal cDNA library. Ten cDNA clones were obtained with inserts ranging from 2.7 to 5.3 kb. The sequence upstream of the putative AUG translational initiation codon (5[prime]-UTR) in the 5.3 kb cDNA (GenBank accession no. AF146593) contained multiple stop codons in all three frames. Alignment of the predicted open reading frame (ORF) with GenBank sequences revealed no significant homology with previously described proteins.
By northern blot analysis, we determined that the mG145 mRNA is specifically and abundantly expressed in retinal photoreceptor cells (Fig. 1A) and is not present in any other tissue examined in this study (cerebellum, cortex, heart, kidney, liver, lung and spleen) (Fig. 1B). The size of the mG145 mRNA is ~5.3 kb and matches the size of the cloned cDNA fragment, suggesting that the 5301 nt cDNA sequence represents the full-length message.
Figure 1. Expression of mouse mG145 and human hG28 mRNAs. (A) Northern blot of adult mouse retina RNAs hybridized with the mG145 probe. Lane 1, wild-type; lane 2, (photoreceptorless) rd/rd. For loading control, the same blot was hybridized with [beta]-tubulin cDNA (bottom). (B) Northern blot of various tissue RNAs hybridized with the mG145 probe. Lanes 1-7, cerebellum, cortex, heart, kidney, liver, lung and spleen, respectively; lane 8, retina. The lower panel shows ethidium bromide staining of 28S and 18S rRNAs. (C) Northern blot of human retinal RNA hybridized with hG28. The positions of 18S and 28S rRNAs and of the 7.5 and 4.4 kb RNA markers (Gibco BRL) are indicated in (A) and (C).
Isolation of the human homolog of mouse mG145 cDNA and of the RP1 gene
PCR probes generated from the mouse mG145 cDNA were used to screen a human genomic library and a retinal cDNA library. We isolated two overlapping clones with inserts of ~14-16 kb each from the genomic library and one clone containing the entire 3[prime]-UTR with the poly(A) tail from the cDNA library. The latter clone had a part of the coding region which overlaps the ORF of the clones isolated from the genomic library. A BLAST search for nucleic acid homology revealed 100% identity between the sequences obtained from the genomic clones and a recently released human chromosome 8q11 sequence (GenBank accession no. AF128525). Analysis of the genomic sequence upstream of our ORF revealed the presence of two potential short ORFs separated by intronic sequences, raising the possibility of additional 5[prime] exons. Using sense primers specific for the upstream sequence and antisense primers from our previously sequenced exon, we were able to characterize two additional exons by RT-PCR. BLAST search with these exons revealed homology with a retinal EST sequence (GenBank accession no. AA018811) and the presence of an extra exon. All putative intron/exon boundaries of the human RP1 gene were confirmed by sequencing the cDNA products of RT-PCR using human retinal mRNA as template, and by comparison with genomic sequences (Table 1). Taken together, these sequences allowed us to fully characterize the RP1 gene (GenBank accession nos AF152239, AF152240, AF152241 and AF152242) as well as its cDNA (GenBank accession no. AF146592). The total length of the cDNA is 6991 bp, with an ORF of 6468 nt which encodes a 2156 amino acid protein (Fig. 2) with a predicted mass of 240 kDa. The RP1 gene consists of four exons. The first exon does not contain an ORF. Exons 2 and 3 represent only a small portion of the ORF (627 and 172 bp, respectively), whereas the last exon (6108 bp) encodes most of the protein and contains the entire 3[prime]-UTR.
Figure 2. Predicted amino acid sequence encoded by the RP1 gene. The mutated amino acid in the adRP family is boxed.
Table 1. Exon/intron boundaries of the RP1 gene
| Exon no. | Exon size (bp) | Start position in cDNA | 5[prime] Splice donor | 3[prime] Splice acceptor | Intron size (bp) |
| 1 | 84 | 1 | AAGTTGTG/gtaagtacaaaactat | 4753 | |
| 2 | 627 | 85 | tttctttcttctctag/GTCTCAGC | GAAGGAGG/gtgagcgttctggggg | 534 |
| 3 | 172 | 712 | ctctggtctcttttag/GTTCCCAG | CAGAAAGA/gtaagtcacttattaa | 2381 |
| 4 | 6108 | 884 | cttaaaatctttaaag/TAAGCACA |
Northern blot analysis using a cDNA probe from the coding region (Fig. 1C) shows that the RP1 gene is expressed in human retina. One transcript of ~7 kb was detected in this tissue.
Localization of the RP1 gene
Primers were designed to specifically amplify a 640 bp fragment from exon 4 of the human RP1 gene. Each of the radiation hybrids of the Stanford G3 panel (Research Genetics, Huntsville, AL) was scored for the presence or absence of this fragment. Analysis of the results showed that RP1 localizes between the sequence-tagged sites SHGC-1930 (distance from RP1 ~6 cR, lod score 11.5) and SHGC-18046 (distance from RP1 ~11 cR, lod score 11.1) in a region of 17 cR10 000 (~540 kb) that includes the D8S509 marker. D8S509 lies in the RP1 locus (13,14).
Screening of an RP1 family for mutations in the RP1 gene
Figure 3a shows the pedigree of a family with autosomal dominant RP. Affected members had the ophthalmoscopic hallmarks of retinal degeneration, including attenuated retinal vessels and bone spicule-like pigmentation (Fig. 3b). Standard electroretinograms (ERGs) showed either reduced or non-detectable rod b-waves and reduced cone flicker ERGs with abnormally delayed timing, consistent with the diagnosis of RP. Disease in this family was linked to chromosome 8q11-q13 (15).
Figure 3. (a) Pedigree of the autosomal dominant retinitis pigmentosa family in this study. (b) Fundus photograph of the right eye of a 28-year-old affected member of the family showing pigmentary changes in the nasal retina (arrow).
The entire coding region of the RP1 gene was sequenced in six affected and three unaffected family members and also in three unrelated individuals. All six affecteds exhibited a heterozygous C->T mutation resulting in R677X (Fig. 4a) that was absent from the unaffected and control subjects. This mutation is predicted to lead to rapid degradation of the hG28 mRNA (16) or to the synthesis of a truncated protein lacking ~70% of its original length (Fig. 2). In order to confirm that this mutation is responsible for disease in this family we designed primers to amplify the region of the RP1 gene containing codon 677. We screened the DNAs of 26 members of the RP1 family and a group of 100 unrelated controls for this mutation by single-strand conformational polymorphism electrophoresis (SSCP). We found an additional band which migrated differently from the normal band in each of the 16 affected individuals and in none of the 10 unaffected family members or 100 controls (Fig. 4b).
Figure 4. Mutation in the RP1 gene in members of the adRP family. (a) Representative sequence of DNA fragments containing the site of the R677X mutation in unaffected and affected members. The arrow points to the heterozygous C->T transition in the affected individual. (b) SSCP gels of representative DNA fragments amplified from the region containing R677X from the control, the unaffected and the affected individuals. In the Affected panel, the lower arrow indicates the normal band, which is also shown in both the Control and the Unaffected panels, and the upper arrow the mutant band.
DISCUSSION
RP1 is the fourth identified gene associated with adRP. The other three genes encode rhodopsin (17), RDS-peripherin (18) and NRL (19). RDS-peripherin and rhodopsin are membrane proteins associated with the photoreceptor disk structure, whereas NRL is a transcription factor involved in the regulation of photoreceptor genes (20,21). Six additional adRP loci remain for which the mutated gene has not yet been discovered.
Our study is another example of how the identification and mapping of a mouse gene can lead to the discovery of a human gene that when mutated causes disease. Besides the gene encoding [beta] cGMP-phosphodiesterase, the site of mutation responsible for the rd mouse, rcd1 dog and some human arRP diseases (5-11), there are several other instances where this has occurred. These include: (i) the discovery of RDS-peripherin as the site of mutation in the Rd2 mouse (22) and in many and varied cases of human retinal degeneration (adRP, macular dystrophies, cone dystrophy, cone-rod dystrophy and central areolar choroidal dystrophy; for a review see 1,18); (ii) the finding that MYO7A is the site of mutation for the shaker-1 mouse and human Usher 1b, a syndrome that includes hearing loss and retinal degeneration (23,24); (iii) the identification of the gene mutated in the tubby mouse which led to the discovery of TULP1 gene mutations in some forms of human arRP (25-28).
Another advantage of the discovery of mouse genes homologous to human genes associated with retinal degeneration is that they provide the possibility of studying the function of the protein they encode. A common way to do this is with the generation of mice in which the particular gene has been ablated by homologous recombination. This has been the case for arrestin (29), RPE65 (30) rhodopsin kinase (31) and others. Discovery of the RP1 gene will now allow the development of transgenic mice lacking this gene for functional studies.
MATERIALS AND METHODS
Mapping of the gene corresponding to mG145 cDNA in the mouse
The gene was mapped by analysis of the progeny of two sets of genetic crosses: (NFS/N or C58/J × M.m.musculus) × M.m.musculus (32), and (NFS/N × M.spretus) × M.spretus or C58/J (33). Loci were ordered by minimizing the number of recombinations, and recombination distances were determined according to Green (34).
cDNA and genomic library screening
We have screened one mouse [lambda]ZAP II cDNA library (4), one human macula [lambda]ZAP II cDNA library (kindly provided by Dr Cathy Bowes-Rickman, University of Iowa) and one human [lambda]EMBL3 genomic library (kindly provided by Dr Jeremy Nathans, Johns Hopkins University). The mouse library was screened with the original clone obtained from the pool of photoreceptor-enriched cDNAs. The human libraries were probed with mouse cDNA or PCR fragments obtained during the process of elucidating the RP1 gene sequence. cDNAs or PCR-generated probes were labeled with [[alpha]-32P]dCTP (Amersham, Arlington Heights, IL) and used to screen ~4 × 105 plaques from each cDNA library or 1 × 106 plaques from the genomic library. PCR products were obtained from mouse cDNA using the following primers: M1 (5[prime]-GTTGCCATCACAGAGGAA-3[prime]) and M2 (5[prime]-GGAGCGCTACTCACAGTGC-3[prime]); M3 (5[prime]-ATGCTAATGGCATGGGAGA-3[prime]) and M4 (5[prime]-CTGAGTTTTAATAGTGCCAC-3[prime]). Prehybridization (1 h) and hybridization (12-16 h) were performed in a solution containing 6× SSC, 4× Denhardt's solution, denatured salmon sperm DNA (300 mg/ml), 40 mM Tris-HCl (pH 7.5) and 0.2% SDS at 68°C. Following hybridization, membranes were washed at a final stringency of 0.2× SSC, 0.1% SDS at 58°C and exposed to X-ray film for 12-36 h. Positive plaques from cDNA libraries were purified and plasmids released using in vivo excision according to the manufacturer's protocol (Stratagene, La Jolla, CA). Positive plaques from the genomic library were purified and analyzed by restriction enzyme digestion and Southern blot hybridization. Various fragments of interest were subcloned into the pBluescript II SK vector (Stratagene). Nucleotide sequences were determined using the Taq Dye Deoxy Termination Cycle Sequencing kit (ABI, Foster City, CA).
RT-PCR amplification
Fifty micrograms of total RNA were DNase treated using 10 U RNase-free DNase I (Boehringer Mannheim, Mannheim, Germany) in the presence of 10 U of placental ribonuclease inhibitor (Promega, Madison, WI). RT-PCR was performed on 1 µg DNase-treated total RNA. First-strand cDNA was synthesized using an oligo(dT) primer and MuLV reverse transcriptase (Perkin Elmer, Foster City, CA), and PCR was performed with AmpliTaq DNA polymerase (Perkin Elmer) using primers: H1 (5[prime]-CCTAGTGGTCTTCAGGAATG-3[prime]) and H2 (5[prime]-TTTCAGCCACTTGATCTGTC-3[prime]); H3 (5[prime]-CCAGTGACATTTATTACTA-3[prime]) and H4 (5[prime]-GGTCTACAGGCTGCACCTTC-3[prime]). Gel-purified DNA fragments (Qiagen, Valencia, CA) were subjected to direct sequencing.
Sequence analysis
For homology searches BLAST analyses were performed with the use of the National Center for Biotechnology database (www.ncbi.nlm.nih.gov/BLAST/ ). Sequence alignment, ORF determinations and restriction mapping of DNA fragments were performed using Sequencher software (Gene Codes, Ann Arbor, MI). Protean software (DNA Star, Madison, WI) was used for calculation of the molecular weight of the predicted protein.
Northern blot analysis
Total RNA was extracted with TRIzol (Gibco BRL, Gaithersburg, MD), separated by electrophoresis in 0.9% agarose gels containing 2.2 M formaldehyde and transferred to Hybond-N+ membranes (Amersham). For hybridization, mouse cDNA probes were used with mouse total RNA and human genomic fragments with human total RNA. The probes were labeled with [[alpha]-32P]dCTP with the Multiprime DNA labeling kit (Amersham). Following hybridization the northern blots were washed at a final stringency of 0.3× SSC and 0.3% SDS at 60°C. Blots were exposed to X-ray film (Amersham) for 6 h at room temperature.
Mapping of the human RP1 gene
The H5 (5[prime]-TTGGTAATTTGGCCCCAGGC-3[prime]) and H6 (5[prime]-CATCAAGTCAAATGTGTTAC-3[prime]) primers were used to amplify a 640 bp genomic fragment of the RP1 gene in the 83 hybrids of the Stanford G3 radiation hybrid panel and electrophoresed in 2% agarose gels. The PCR conditions were 28 cycles of 94°C for 45 s, 55°C for 45 s and 72°C for 90 s. Chromosomal localization was determined by submission of data to the Stanford RH server (www-shgc.stanford.edu/RH/rhserverformnew.html ).
Patients
Forty-nine members of a multigeneration family with adRP participated in this study. Records of ocular examinations were obtained from nearly all affected and many presumed unaffected family members. In a subset of nine affected members, clinical examinations and standard ERGs (35) were performed. Informed consent was obtained from all participants. Disease in this family was previously linked to chromosome 8q11-q13 (15). Since variable expression has been reported in an adRP family linked to the RP1 locus (14), only family members with clinical hallmarks of RP were considered affected. Family members without symptoms of RP but also unlinked to chromosome 8q11-q13 were considered unaffected.
Mutation analysis
Two methods were used to screen for mutations in the RP1 gene: direct sequencing of several amplified products encompassing the entire coding region of the gene, and SSCP.
The R677X mutation was found by direct sequencing in a PCR fragment that was obtained using primers H7 (5[prime]-TCCTTTTGGTTGCAAGCTGTC-3[prime]) and H8 (5[prime]-CAAGTGCAATAAGTGCTGGT-3[prime]). Thirty-two cycles of 94°C for 45 s, 57°C for 45 s and 72°C for 75 s were used to amplify the genomic DNA fragment from patients and controls under PCR buffer conditions.
For SSCP, 30 cycles of 94°C for 45 s, 57°C for 45 s and 72°C for 75 s were used to amplify genomic DNA from patients and controls under PCR buffer conditions in the presence of [[alpha]-32P]dCTP using the following primers: H7 and H9 (5[prime]-GGATGGTTTCTGATTTGTGTC-3[prime]). PCR products were electrophoretically separated on 6% non-denaturing polyacrylamide gels at room temperature. Dried gels were exposed to X-ray film overnight.
The presence of the R677X mutation was confirmed by subcloning the PCR product into the pCR2.1 vector (Invitrogen, Carlsbad, CA) and sequencing the resulting clones.
ACKNOWLEDGEMENTS
We thank Ms Jennifer Shih and Ms Christina Ghattas for technical assistance and Mr Manuel Benegas, Mr David Hanna and Mrs Barbara Koernig for study coordination. This research was supported by grants from the Association pour la Recherche sur le Cancer (X.G.), the Foundation Fighting Blindness, the National Institutes of Health [EY08285, EY02651 (D.B.F.) and EY05627 (S.G.J.)] and The Chatlos Foundation Inc. D.B.F. is a recipient of a Senior Scientific Investigators Award from Research to Prevent Blindness.
REFERENCES
*To whom correspondence should be addressed. Tel: +1 310 206 7375; Fax: +1 310 794 7904; Email: farber{at}jsei.ucla.edu
This page is run by Oxford University Press, Great Clarendon Street, Oxford OX2 6DP, as part of the OUP Journals
Comments and feedback: jnl.info{at}oup.co.uk
Last modification:
Copyright© Oxford University Press, 1999.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  Q. Liu, A. Saveliev, and E. A. Pierce The Severity of Retinal Degeneration in Rp1h Gene-Targeted Mice Is Dependent on Genetic Background Invest. Ophthalmol. Vis. Sci., April 1, 2009; 50(4): 1566 - 1574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Azimov, N. Abuladze, P. Sassani, D. Newman, L. Kao, W. Liu, N. Orozco, P. Ruchala, A. Pushkin, and I. Kurtz G418-mediated ribosomal read-through of a nonsense mutation causing autosomal recessive proximal renal tubular acidosis Am J Physiol Renal Physiol, September 1, 2008; 295(3): F633 - F641. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. Stone Genetic Testing for Inherited Eye Disease Arch Ophthalmol, February 1, 2007; 125(2): 205 - 212. [Full Text] [PDF]
|
|
|
|
 |
|
 J. Liu, Q. Huang, J. Higdon, W. Liu, T. Xie, T. Yamashita, K. Cheon, C. Cheng, and J. Zuo Distinct gene expression profiles and reduced JNK signaling in retinitis pigmentosa caused by RP1 mutations Hum. Mol. Genet., October 1, 2005; 14(19): 2945 - 2958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Riazuddin, F. Zulfiqar, Q. Zhang, Y. V. Sergeev, Z. A. Qazi, T. Husnain, R. Caruso, S. Riazuddin, P. A. Sieving, and J. F. Hejtmancik Autosomal Recessive Retinitis Pigmentosa Is Associated with Mutations in RP1 in Three Consanguineous Pakistani Families Invest. Ophthalmol. Vis. Sci., July 1, 2005; 46(7): 2264 - 2270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Lord-Grignon, N. Tetreault, A. J. Mears, A. Swaroop, and G. Bernier Characterization of New Transcripts Enriched in the Mouse Retina and Identification of Candidate Retinal Disease Genes Invest. Ophthalmol. Vis. Sci., September 1, 2004; 45(9): 3313 - 3319. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Cavusoglu, D. Thierse, S. Mohand-Said, F. Chalmel, O. Poch, A. Van-Dorsselaer, J.-A. Sahel, and T. Leveillard Differential Proteomic Analysis of the Mouse Retina: The Induction of Crystallin Proteins by Retinal Degeneration in the rd1 Mouse Mol. Cell. Proteomics, August 1, 2003; 2(8): 494 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K Dietrich, F K Jacobi, S Tippmann, R Schmid, E Zrenner, B Wissinger, and E Apfelstedt-Sylla A novel mutation of the RP1 gene (Lys778ter) associated with autosomal dominant retinitis pigmentosa Br J Ophthalmol, March 1, 2002; 86(3): 328 - 332. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Liu, J. Zhou, S. P. Daiger, D. B. Farber, J. R. Heckenlively, J. E. Smith, L. S. Sullivan, J. Zuo, A. H. Milam, and E. A. Pierce Identification and Subcellular Localization of the RP1 Protein in Human and Mouse Photoreceptors Invest. Ophthalmol. Vis. Sci., January 1, 2002; 43(1): 22 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Kuehn, E. M. Stone, and G. S. Hageman Organization of the Human IMPG2 Gene and Its Evaluation as a Candidate Gene in Age-Related Macular Degeneration and Other Retinal Degenerative Disorders Invest. Ophthalmol. Vis. Sci., December 1, 2001; 42(13): 3123 - 3129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Danciger, J. Hendrickson, J. Lyon, C. Toomes, J. C. McHale, G. A. Fishman, C. F. Inglehearn, S. G. Jacobson, and D. B. Farber CORD9 a New Locus for arCRD: Mapping to 8p11, Estimation of Frequency, Evaluation of a Candidate Gene Invest. Ophthalmol. Vis. Sci., October 1, 2001; 42(11): 2458 - 2465. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. L. Berson, J. L. Grimsby, S. M. Adams, T. L. McGee, E. Sweklo, E. A. Pierce, M. A. Sandberg, and T. P. Dryja Clinical Features and Mutations in Patients with Dominant Retinitis Pigmentosa-1 (RP1) Invest. Ophthalmol. Vis. Sci., September 1, 2001; 42(10): 2217 - 2224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Jacobson, A. V. Cideciyan, A. Iannaccone, R. G. Weleber, G. A. Fishman, A. M. Maguire, L. M. Affatigato, J. Bennett, E. A. Pierce, M. Danciger, et al. Disease Expression of RP1 Mutations Causing Autosomal Dominant Retinitis Pigmentosa Invest. Ophthalmol. Vis. Sci., June 1, 2000; 41(7): 1898 - 1908. [Abstract] [Full Text]
|
|
|
|
|
|
J. G. Hollyfield Hyaluronan and the Functional Organization of the Interphotoreceptor Matrix Invest. Ophthalmol. Vis. Sci., November 1, 1999; 40(12): 2767 - 2769. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||