Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1995 Sep 26;92(20):9176–9180. doi: 10.1073/pnas.92.20.9176

Recoverin, a photoreceptor-specific calcium-binding protein, is expressed by the tumor of a patient with cancer-associated retinopathy.

A S Polans 1, D Witkowska 1, T L Haley 1, D Amundson 1, L Baizer 1, G Adamus 1
PMCID: PMC40947  PMID: 7568096

Abstract

Recoverin is a member of the EF-hand family of calcium-binding proteins involved in the transduction of light by vertebrate photoreceptors. Recoverin also was identified as an autoantigen in the degenerative disease of the retina known as cancer-associated retinopathy (CAR), a paraneoplastic syndrome whereby immunological events lead to the degeneration of photoreceptors in some individuals with cancer. In this study, we demonstrate that recoverin is expressed in the lung tumor of a CAR patient but not in similar tumors obtained from individuals without the associated retinopathy. Recoverin was identified intially by Western blot analysis of the CAR patient's biopsy tissue by using anti-recoverin antibodies generated against different regions of the recoverin molecule. In addition, cultured cells from the biopsy tissue expressed recoverin, as demonstrated by reverse transcription-PCR using RNA extracted from the cells. The immunodominant region of recoverin also was determined in this study by a solid-phase immunoassay employing overlapping heptapeptides encompassing the entire recoverin sequence. Two linear stretches of amino acids (residues 64-70, Lys-Ala-Tyr-Ala-Gln-His-Val; and 48-52, Gln-Phe-Gln-Ser-Ile) made up the major determinants. One of the same regions of the recoverin molecule (residues 64-70) also was uniquely immunopathogenic, causing photoreceptor degeneration upon immunization of Lewis rats with the corresponding peptide. These data demonstrate that the neural antigen recoverin more than likely is responsible for the immunological events associated with vision loss in some patients with cancer. These data also establish CAR as one of the few autoimmune-mediated diseases for which the specific self-antigen is known.

Full text

PDF
9176

Images in this article

9177Fig. 1
on p.9177
9177Fig. 2
on p.9177
9178Fig. 3
on p.9178
9178Fig. 4
on p.9178
9179Fig. 7
on p.9179

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adamus G., Guy J., Schmied J. L., Arendt A., Hargrave P. A. Role of anti-recoverin autoantibodies in cancer-associated retinopathy. Invest Ophthalmol Vis Sci. 1993 Aug;34(9):2626–2633. [PubMed] [Google Scholar]
  2. Adamus G., Ortega H., Witkowska D., Polans A. Recoverin: a potent uveitogen for the induction of photoreceptor degeneration in Lewis rats. Exp Eye Res. 1994 Oct;59(4):447–455. doi: 10.1006/exer.1994.1130. [DOI] [PubMed] [Google Scholar]
  3. Alexander K. R., Fishman G. A., Peachey N. S., Marchese A. L., Tso M. O. 'On' response defect in paraneoplastic night blindness with cutaneous malignant melanoma. Invest Ophthalmol Vis Sci. 1992 Mar;33(3):477–483. [PubMed] [Google Scholar]
  4. Baizer L., Ciment G., Hendrickson S. K., Schafer G. L. Regulated expression of the neurofibromin type I transcript in the developing chicken brain. J Neurochem. 1993 Dec;61(6):2054–2060. doi: 10.1111/j.1471-4159.1993.tb07442.x. [DOI] [PubMed] [Google Scholar]
  5. Buchanan T. A., Gardiner T. A., Archer D. B. An ultrastructural study of retinal photoreceptor degeneration associated with bronchial carcinoma. Am J Ophthalmol. 1984 Mar;97(3):277–287. doi: 10.1016/0002-9394(84)90623-8. [DOI] [PubMed] [Google Scholar]
  6. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  7. Dizhoor A. M., Chen C. K., Olshevskaya E., Sinelnikova V. V., Phillipov P., Hurley J. B. Role of the acylated amino terminus of recoverin in Ca(2+)-dependent membrane interaction. Science. 1993 Feb 5;259(5096):829–832. doi: 10.1126/science.8430337. [DOI] [PubMed] [Google Scholar]
  8. Dizhoor A. M., Ray S., Kumar S., Niemi G., Spencer M., Brolley D., Walsh K. A., Philipov P. P., Hurley J. B., Stryer L. Recoverin: a calcium sensitive activator of retinal rod guanylate cyclase. Science. 1991 Feb 22;251(4996):915–918. doi: 10.1126/science.1672047. [DOI] [PubMed] [Google Scholar]
  9. Flaherty K. M., Zozulya S., Stryer L., McKay D. B. Three-dimensional structure of recoverin, a calcium sensor in vision. Cell. 1993 Nov 19;75(4):709–716. doi: 10.1016/0092-8674(93)90491-8. [DOI] [PubMed] [Google Scholar]
  10. Furneaux H. M., Rosenblum M. K., Dalmau J., Wong E., Woodruff P., Graus F., Posner J. B. Selective expression of Purkinje-cell antigens in tumor tissue from patients with paraneoplastic cerebellar degeneration. N Engl J Med. 1990 Jun 28;322(26):1844–1851. doi: 10.1056/NEJM199006283222604. [DOI] [PubMed] [Google Scholar]
  11. Gery I., Chanaud N. P., 3rd, Anglade E. Recoverin is highly uveitogenic in Lewis rats. Invest Ophthalmol Vis Sci. 1994 Jul;35(8):3342–3345. [PubMed] [Google Scholar]
  12. Gray-Keller M. P., Polans A. S., Palczewski K., Detwiler P. B. The effect of recoverin-like calcium-binding proteins on the photoresponse of retinal rods. Neuron. 1993 Mar;10(3):523–531. doi: 10.1016/0896-6273(93)90339-s. [DOI] [PubMed] [Google Scholar]
  13. Greenlee J. E., Lipton H. L. Anticerebellar antibodies in serum and cerebrospinal fluid of a patient with oat cell carcinoma of the lung and paraneoplastic cerebellar degeneration. Ann Neurol. 1986 Jan;19(1):82–85. doi: 10.1002/ana.410190117. [DOI] [PubMed] [Google Scholar]
  14. Kawamura S. Rhodopsin phosphorylation as a mechanism of cyclic GMP phosphodiesterase regulation by S-modulin. Nature. 1993 Apr 29;362(6423):855–857. doi: 10.1038/362855a0. [DOI] [PubMed] [Google Scholar]
  15. Keltner J. L., Roth A. M., Chang R. S. Photoreceptor degeneration. Possible autoimmune disorder. Arch Ophthalmol. 1983 Apr;101(4):564–569. doi: 10.1001/archopht.1983.01040010564006. [DOI] [PubMed] [Google Scholar]
  16. Kim Y. I., Neher E. IgG from patients with Lambert-Eaton syndrome blocks voltage-dependent calcium channels. Science. 1988 Jan 22;239(4838):405–408. doi: 10.1126/science.2447652. [DOI] [PubMed] [Google Scholar]
  17. Kornguth S. E., Klein R., Appen R., Choate J. Occurrence of anti-retinal ganglion cell antibodies in patients with small cell carcinoma of the lung. Cancer. 1982 Oct 1;50(7):1289–1293. doi: 10.1002/1097-0142(19821001)50:7<1289::aid-cncr2820500711>3.0.co;2-9. [DOI] [PubMed] [Google Scholar]
  18. Milam A. H., Saari J. C., Jacobson S. G., Lubinski W. P., Feun L. G., Alexander K. R. Autoantibodies against retinal bipolar cells in cutaneous melanoma-associated retinopathy. Invest Ophthalmol Vis Sci. 1993 Jan;34(1):91–100. [PubMed] [Google Scholar]
  19. Murakami A., Yajima T., Inana G. Isolation of human retinal genes: recoverin cDNA and gene. Biochem Biophys Res Commun. 1992 Aug 31;187(1):234–244. doi: 10.1016/s0006-291x(05)81483-4. [DOI] [PubMed] [Google Scholar]
  20. Newsom-Davis J. Lambert-Eaton myasthenic syndrome. Springer Semin Immunopathol. 1985;8(1-2):129–140. doi: 10.1007/BF00197251. [DOI] [PubMed] [Google Scholar]
  21. Polans A. S., Buczyłko J., Crabb J., Palczewski K. A photoreceptor calcium binding protein is recognized by autoantibodies obtained from patients with cancer-associated retinopathy. J Cell Biol. 1991 Mar;112(5):981–989. doi: 10.1083/jcb.112.5.981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Polans A. S., Burton M. D., Haley T. L., Crabb J. W., Palczewski K. Recoverin, but not visinin, is an autoantigen in the human retina identified with a cancer-associated retinopathy. Invest Ophthalmol Vis Sci. 1993 Jan;34(1):81–90. [PubMed] [Google Scholar]
  23. Rizzo J. F., 3rd, Gittinger J. W., Jr Selective immunohistochemical staining in the paraneoplastic retinopathy syndrome. Ophthalmology. 1992 Aug;99(8):1286–1295. doi: 10.1016/s0161-6420(92)31806-8. [DOI] [PubMed] [Google Scholar]
  24. Sawyer R. A., Selhorst J. B., Zimmerman L. E., Hoyt W. F. Blindness caused by photoreceptor degeneration as a remote effect of cancer. Am J Ophthalmol. 1976 May;81(5):606–613. doi: 10.1016/0002-9394(76)90125-2. [DOI] [PubMed] [Google Scholar]
  25. Steinman L. Escape from "horror autotoxicus": pathogenesis and treatment of autoimmune disease. Cell. 1995 Jan 13;80(1):7–10. doi: 10.1016/0092-8674(95)90443-3. [DOI] [PubMed] [Google Scholar]
  26. Weinstein J. M., Kelman S. E., Bresnick G. H., Kornguth S. E. Paraneoplastic retinopathy associated with antiretinal bipolar cell antibodies in cutaneous malignant melanoma. Ophthalmology. 1994 Jul;101(7):1236–1243. doi: 10.1016/s0161-6420(94)31183-3. [DOI] [PubMed] [Google Scholar]
  27. Wiechmann A. F., Akots G., Hammarback J. A., Pettenati M. J., Rao P. N., Bowden D. W. Genetic and physical mapping of human recoverin: a gene expressed in retinal photoreceptors. Invest Ophthalmol Vis Sci. 1994 Feb;35(2):325–331. [PubMed] [Google Scholar]
  28. Wiechmann A. F., Hammarback J. A. Molecular cloning and nucleotide sequence of a cDNA encoding recoverin from human retina. Exp Eye Res. 1993 Apr;56(4):463–470. doi: 10.1006/exer.1993.1059. [DOI] [PubMed] [Google Scholar]
  29. Zozulya S., Stryer L. Calcium-myristoyl protein switch. Proc Natl Acad Sci U S A. 1992 Dec 1;89(23):11569–11573. doi: 10.1073/pnas.89.23.11569. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES