Emily's research paper

Emily Peterson
Genetics
Dr. Rachel Robson
Retinitis Pigmentosa
12 March 2009

Two types of cells control human eyesight (Sung, Ching-Hwa, Carol M. Davenport, Jill C. Hennessey, et. al.). Rods are responsible for vision in dim light, and cones are responsible for color vision (Sung, Ching-Hwa, Carol M. Davenport, Jill C. Hennessey, et. al.). A group of heritable retinal dystrophies known as retinitis pigmentosa affect approximately 1.5 million people (Dryja, Thaddeus P., Lauri B. Hahn, Glenn S. Cowley, et. al.). In just the United States 50,000 to 100,000 people suffer from retinitis pigmentosa (Kajiwara, Kazuto, Eliot L. Berson, and Thaddeus P. Dryja). Retinitis pigmentosa is brought on by degeneration of the rod and cone cells (Hartong, Dyanne, Eliot L. Berson and Thaddeus P. Dryja). Night blindness is the first symptom of retinitis pigmentosa, typically followed by progressive loss of peripheral vision and then loss of central vision, subretinal pigmentary patches, and a discolored optic nerve head (Dryja, Thaddeus P., Lauri B. Hahn, Glenn S. Cowley, et. al.). Retinitis pigmentosa patients are usually legally blind by the age of 40 (Hartong, Dyanne, Eliot L. Berson and Thaddeus P. Dryja). There are three ways that retinitis pigmentosa is inherited, autosomal dominant retinitis pigmentosa (adRP), autosomal recessive retinitis pigmentosa (arRP), and X-linked retinitis pigmentosa (xlRP) (Chiang, SWY, DY Wang, WM Chan, et. al.). Each type has a different change to the developmental pathway, and within each type, there are many different genetic causes.
There are three phenotypes of adRP (Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al.). Classical retinitis pigmentosa (CLRP) symptoms include early onset night blindness, then progressive loss of peripheral vision or tunnel vision, and then loss of central vision (Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al.). The second type of adRP is pericentral retinal dystrophy (PRD). Its symptoms include night blindness typically occurring in the patient’s thirties, peripheral vision is only slightly affected, and visual acuity remains fairly normal (Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al.). The final type of adRP is central and pericentral retinal dystrophy (CPRD). Mild night blindness, loss of central vision, and deteriorating visual acuity are some of the most common symptoms (Dryja Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al.). CPRD is the only phenotype that affects color vision, but only in advanced cases (Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al.).
There are at least 13 mutations that are hypothesized to cause adRP, including mutations to the PRPF31 gene, the rhodopsin gene, the IMPDH1 gene, the Peripherin/rds gene, and the Rom-1 gene (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). The most common causes of adRP are mutations to the rhodopsin gene (Dryja, Thaddeus P., Lauri B. Hahn, Glenn S. Cowley, et. al.). The rhodopsin gene produces the protein rhodopsin which serves as the pigment in the rod cells in the eye (Sung, Ching-Hwa, Carol M. Davenport, Jill C. Hennessey, et. al.). In this gene alone, more than 100 distinct mutations have been found (Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al.). One study found a frame shift mutation in the rhodopsin gene causing a longer rhodopsin protein in patients with CLRP (Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al.). A missense mutation in the same gene altered the rhodopsin function affecting the binding of vitamin A in patients with PRD (Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al.). Some patients with PRD also had misssense mutations in this gene that caused a loss of rod function, followed by a loss of cone function (Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al.). Another study found eighteen different mutations to the rhodopsin gene that were directly related to adRP (Dryja, Thaddeus P., Lauri B. Hahn, Glenn S. Cowley, et. al.). That study concluded that many different mutations to the rhodopsin gene can cause adRP; however, seventeen of the eighteen known mutations are single-base substitutions (Dryja, Thaddeus P., Lauri B. Hahn, Glenn S. Cowley, et. al.). These eighteen mutations fall into two different classes. Class 1 genes are not associated with pathogenic mechanisms, while class 2 mutations appear to destabilize proteins by preventing the formation of disulfide bonds (Sung, Ching-Hwa, Barbara G. Schneider, Neeraj Agarwal, et. al.). Mutations in the rhodopsin gene correlate with the presence of adRP (Sung, Ching-Hwa, Carol M. Davenport, Jill C. Hennessey, et. al.).
Over thirty mutations to the peripherin/rds gene have been found in adRP (Goldberg, Andrew F.X., and Robert S. Molday). Peripherin/rds seems to be responsible for forming and maintaining photoreceptors. Pheripherin/rds is located on the periphery of the photoreceptors (Farjo, Rafal and Muna I. Nash). One study found a L185P mutation which can explain digenic RP inheritance patterns. This mutation prevents the peripherin/rds protein from forming its correct structure (Goldberg, Andrew F.X., and Robert S. Molday). When it does not form correctly, it results in unstable photoreceptors and retinal degeneration (Goldberg, Andrew F.X., and Robert S. Molday). Another study suggested a Leu185Pro allele mutation that must be in conjunction with another mutation (Kajiwara, Kazuto, Eliot L. Berson, and Thaddeus P. Dryja). This makes discovering the exact genetic cause of retinitis pigmentosa much more difficult (Kajiwara, Kazuto, Eliot L. Berson, and Thaddeus P. Dryja).
Finally, adRP can be caused by premature stop codons in PRPF32 (Rio Frio, Thomas, Nicholas M. Wade, Adriana Ransjin, et. al.). PRPF31 is a gene that codes for a pre-mRNA splicing factor (Rio Frio, Thomas, Nicholas M. Wade, Adriana Ransjin, et. al.). However, this gene is not unique to the eye. It is actually essential for cell metabolism (Rio Frio, Thomas, Nicholas M. Wade, Adriana Ransjin, et. al.). Strangely, adRP patients that have PRPF31 mutations do not suffer from other syndromes (Rio Frio, Thomas, Nicholas M. Wade, Adriana Ransjin, et. al.). Some of the mutations to PRPF31 cause premature stop codons and are not destroyed because they occur in the last exon (Rio Frio, Thomas, Nicholas M. Wade, Adriana Ransjin, et. al.). Non-sense mediated mRNA should destroy mRNA strands that have premature stop codons, however, it will not destroy the mutant mRNA if the stop codon exists in the last exon of the gene (Rio Frio, Thomas, Nicholas M. Wade, Adriana Ransjin, et. al.).The results of this study show that these mutations likely cause adRP via a haploinsufficiency mechanism. A haploinsufficiency occurs when only one of a pair of genes is functional and does not produce enough gene product for a healthy cell.
At least 20 genes may be responsible for autosomal recessive retinitis pigmentosa (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). Major genes and mutations for arRP include RPE65, ABCA4, CRB1, USH2A, MERTK, SAG, RHO, PED6A and PED6B, CNGA1, TULP1, RGR, NR2E3, and RLBP1 (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). The RPE65 mutation causes disorganized rod photoreceptors, and has been found in all patients with arRP (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). ABCA4 mutations lead to a nonfunctional ABCA4 transporter protein (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). USH2A mutations are found in a few arRP patients without hearing loss, and almost all patients with arRP and mild hearing loss, which is called Usher syndrome (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). MERTK mutations cause photoreceptor death (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). The SAG gene codes for arrestin, which is involved in the recovery phase of phototransduction, and a SAG mutation can cause arRP in some patients (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). RHO mutations generally cause adRP, but a few have been found in patients with arRP (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). PDE6A and PDE6B code for an enzyme that is vital for the retinal rod phototransduction cascade, and mutations have been known to cause arRP (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). Mutations to the CNGAI gene that codes for the alpha subunit of the cGMP-gated cation channel have been found in patients with arRP (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). The TULPI gene has been found in families with arRP, although not much is known about the TULPI gene’s function (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). RGR is found in both adRP and arRP (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). NR2E3 mutations interfere with DNA binding, and are found in patients with arRP (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al). Finally RLBP1 mutations create proteins that are less soluble, and therefore interrupting vitamin A metabolism in the retina and causing arRP (Wang, Qing, Qiuyun Chen, Kanxing Zhao, et.al).
The most severe form of retinitis pigmentosa is xlRP, which causes loss of night vision, progressive visual field loss, and a severe loss of visual acuity (Linari, Marco, Marius Ueffing, Forbes Manson, et. al.). Most xlRP patients are blind by their thirties or forties (Linari, Marco, Marius Ueffing, Forbes Manson, et. al.). The most common type of xlRP is retinitis pigmentosa 3 (RP3) which is caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene (Linari, Marco, Marius Ueffing, Forbes Manson, et. al.). When mutations occur to RPGR gene, they affect its binding with PDEδ, which interacts with a GTP-binding protein (Linari, Marco, Marius Ueffing, Forbes Manson, et. al.). These mutations have been found in RP3 patients, but not in healthy patients, which links mutations in RPGR with xlRP (Linari, Marco, Marius Ueffing, Forbes Manson, et. al.).
Another cause of all types of retinitis pigmentosa is mutations to the retinitis pigmentosa 1 (RP1) gene (Chiang, SWY, DY Wang, WM Chan, et. al.). RP1 codes for a polypeptide chain of 2156 amino acids, and more than twenty mutations that cause retinitis pigmentosa have been found in this gene (Chiang, SWY, DY Wang, WM Chan, et. al.). The RP1 protein is located in the photoreceptor’s connecting cilia and axoneme. The N-terminal 233 residue of this polypeptide is important for normal function of the protein (Chiang, SWY, DY Wang, WM Chan, et. al.). The R677X mutation tells us that part of the polypeptide that occurs after residue 677 is also very important to normal function of the protein (Chiang, SWY, DY Wang, WM Chan, et. al.). Another mutation D984G also causes retinitis pigmentosa (Chiang, SWY, DY Wang, WM Chan, et. al.).
It was suspected that another cause of all types of retinitis pigmentosa was a mutation to the membrane-type frizzled-related protein (MFRP) (Pauer, Gayle J.T. and Quangshen Xi). A frizzled protein is a receptor for the Wnt family of proteins (Pauer, Gayle J.T. and Quangshen Xi). Retinal pigment epithelial cells and ciliary epithelial cells of the eye are the primary sites for MRFP expression (Pauer, Gayle J.T. and Quangshen Xi). In mice, a mutation to MFRP caused a type of retinal degeneration; however, this study showed that although it cannot be ruled out, a MRFP mutation is not a likely cause of any type of retinitis pigmentosa.
Because of the relationship between opsin and all types of retinitis pigmentosa, another study tested the relationship between peropsin and retinitis pigmentosa (Ksantini, Mohamed, Audrey Sénéchal, and Ghyslaine Humbert). Although they found several mutations, they were unable to conclude that those mutations could cause retinitis pigmentosa (Ksantini, Mohamed, Audrey Sénéchal, and Ghyslaine Humbert).
Many studies have been done to try to determine the genetic cause of retinitis pigmentosa. Because of the different phenotypes, and the many different genes that make up the photoreceptors and epithelial cells in the retina, it is not possible to find just one cause for the disease. Mutations to the RP1 gene, the rhodopsin gene, and many other genes are thought to be responsible for these genes, while MRPF mutations and peropsin mutations are not suspected causes. Currently, there are so many genes, inheritance patterns, and mutations per gene, that it has been very difficult to determine exact causes (Koenekoop, Robert K. MD PhD, Irma Lopez PhD, Annette I den Hollander PhD, et. al.). However, because of some recent discoveries, genetic counseling is now possible for patients with retinitis pigmentosa and in the future it may be possible for even more causes of retinitis pigmentosa to be found.

Works Cited
Chiang, SWY, DY Wang, WM Chang, et. al. “A Novel Missense RP1 Mutation in Retinitis Pigmentosa.” Eye. 2006.
Dryja, Thaddeus P., Lauri B. Hahn, Glenn S. Cowly, et. al. “Mutation Spectrum of the Rhodopsin Gene Among Patients with Autosomal Dominant Retinitis Pigmentosa.” Proceedings of the National Academy of Sciences of the United States of America. October 15, 1991.
Farjo, Rafal and Muna I. Naash. “The Role of Rds in Outer Segment Morphogenesis and Human Retinal Disease.” Ophthalmic Genetics. 2006.
Goldberg, Andrew F. X. and Robert S. Molday. “Defective Subunit Assembly Underlies a Digenic Form of Retinitis Pigmentosa Linked to Mutations in Peripherin/rds and Rom-1.” Proceedings of the National Academy of Sciences of the United States of America. November 36, 1996.
Grøndahl, Jan, Ruth Riise, Arvid Heiberg, et. al. “Autosomal dominant retinitis pigmentosa in Norway; a 20-year clinical follow-up study with molecular genetic analysis. Two Novel rhodopsin mutations: 1003delG and I170F.” Acta Ophthalmol Scand. 2007.
Hartong, Dyanne, Eliot L. Berson, and Thaddeus P. Dryja “Retinitis Pigmentosa.” www.thalancet.com. November 18, 2006.
Kajiwara, Kazuto, Eliot L. Berson, and Thaddeus P. Drya. “Digenic Retinitis Pigmentosa Due to Mutations at the Unlinked Peripherin/RDS and ROM1 Loci.” Science. June 10, 1994.
Koenekoop Robert K. MD PhD, Irma Lopez PhD, Anneke I den Hollander PhD, et. al. “Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas, and solutions.” Clinical and Experimental Ophthalmology. 2007.
Ksantini, Mohamed, Audrey Sénéchal, and Ghyslaine Humbert. “RRH Encoding the RPE- Expressed Opsin-Like Peropsin, Is not Mutated in Retinitis Pigmentosa, and Allied Diseases.” Ophthalmic Genetics. 2007.
Linari, Marco, Marius Ueffing, Forbes Manson, et. al. “The Retinitis Pigmentosa GTPase Regulator, RPGR, interacts with the Delta Subunit of Rod Cyclic GMP Phosphodiesterase.” Proceedings of the National Academy of Sciences of the United States of America. 1999.
Pauer, Gayle J.T., and Quanshen Xi. “Mutation Screen of the Membrane-Type Frizzled-Related Protein (MFRP) Gene in Patients with Inherited Retinal Degenerations.” Ophthalmic Genetics. 2005.
Rio Frio, Thomas, Nicholas M. Wade, Adriana Ransijn, et. al. “Premature termination codons in PRPF31 cause retinitis pigmentosa via haploinsufficiency due to nonsense-mediated mRNA decay.” Journal of Clinical Investigation. 2008.
Sung, Ching-Hwa, Barbara G. Schneider, Neerajn Agarwal, et. al. “Functional Heterogeneity of Mutant Rhodopsins Responsible for Autosomal Dominant Retinitis Pigmentosa.” Proceedings of the National Academy of Sciences of the United States of America. 1991.
Sung, Ching-Hwa, Carol M. Davenport, Jill C. Hennesey, et. al. “Rhodopsin Mutations in Autosomal Dominant Retinitis Pigmentosa.” Proceedings of the National Academy of Sciences of the United States of America. 1991.
Wang, Qing, Qiuyen Chen, Kanxing Zhao, et. al. “Update on the molecular genetics of retinitis pigmentosa.” Ophthalmic Genetics. 2001.

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