Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1996-08-29
2002-06-04
Low, Christopher S. F. (Department: 1653)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S023100, C536S022100, C435S069100, C435S252300, C435S325000, C435S320100, C435S440000
Reexamination Certificate
active
06399760
ABSTRACT:
BACKGROUND OF THE INVENTION
Retinitis pigmentosa (RP) is a group of human hereditary retinal degenerations characterized by night blindness and loss of peripheral vision. RP sometimes progresses to total blindness. Cardinal clinical features of RP include retinal pigmentary disturbances, attenuation of the retinal vasculature, a waxy pale appearance of the optic nerve head, and abnormalities of retinal function. RP is the most common mendelian degenerative retinal disorder, affecting 1.5 million individuals worldwide (Kumar Singh, R., Farrar, G. J., Mansergh, F., Kenna, P., Bhattacharya, S., Gal, A. and Humphries, P. (1993)
Hum. Mol. Genet
. 2, 875-878). Among Caucasians in the United States, when not associated with other abnormalities, RP is inherited most frequently as an autosomal recessive (84% of cases), next as an autosomal dominant (10%), and least frequently as an X-linked recessive disorder (6%) (Boughman, J. A., Conneally, P. M. and Nance, W. E. (1980)
Am. J Hum. Genet
. 32, 223-235).
Significant nonallelic heterogeneity has been found in autosomal dominant RP (adRP) and in X-linked RP. For adRP, mutations in the rhodopsin gene on 3q (Sung, c. H., Davenport, C. M., Hennessey, J. C., Maumenee, I. H., Jacobson, S. G., Heckenlively, J. R., Nowakowski, R., Fishmanm, G., Gouras, P. and Nathan, J. (1991)
Proc. Natl. Acad. Sci. USA
88, 6481-6485; Ingleheam, C. F., Keen, T. J., Bashir, R., Jay, M., Fitzke, F., Bird, A. C., Crombie, A. and Bhattacharya, S. (1992)
Hum. Mol. Genet
. 1, 41-45; Humphries, P., Kenna, P. and Farrar, G. J. (1992)
Science
256, 804-808), and the peripherin gene on 6p have been found (Farrar, G. J., Kenna, P., Jordan, S. A., Kumar Singh, R., Humphries, M. M., Sharp, E. M., Sheils, d. M. and Humphries, P. (1991)
Nature
354, 478-480; Kajiwara, K., Hah, L. B., Mukai, S., Travis, G. H., Berson, E. L. and Dryja, T. P. (1991)
Nature
354, 480-483; Farrar, G. J., Kenna, P., Jordan, S. A., Kumar Singh, R., Humphries, M. M., Sharp, E. M., Sheils, D. and Humphries, P. (1993)
Genomics
15, 466). In addition, genetic linkage of adRP is observed to loci on chromosomes 8 (Blanton, S. H., Heckenlively, J. R., Cottingham, A. W., Friedman, J., Sadler, L. A., Wagner, M., Friedman, L. H. and Daiger, S. P. (1991)
Genomics
11, 857-869), 7p (Inglehearn, C. F., Carter, S. A., Keen, T. J., Lindsey, J., Stephenson, A. M., Bashir, R., al Maghtheh, M., Moore, A. T., Jay, M., Bird, A. C. and Bhattacharya, S. S. (1993)
Nature Genet
. 4, 51-53), 7q (Jordan, S. A., Farrar, G. J., Kenna, P., Humphries, M. M., Sheils, D. M., Kumar Singh, R., Sharp, E. M., Soriano, N., Ayuso, C., Benitez, J. and et al, (1993)
Nature Genet
. 4, 130-134), and 19 (Al-Maghtheh, M., Inglehearn, C. F., Keen, T. J., Evans, K., Moore, A. T., Jay, M., Bird, A. C. and Bhattacharya, S. S. (1994)
Hum. Mol. Genet
. 3, 351-354). For the X-linked form of the disorder, two loci have been implicated (Ott, J., Bhattacharya, S., Chen, J. D., Denton, M. J., Donald, J., Dubay, C., Farrar, G. J., Fishman, G. A., Frey, D., Gal, A., Humphries, P., Jay, B., Jay, M., Litt, M., Machler, M., Musarella, M., Neugebauer, M., Nussbaum, R. L., Terwilliger, J. D., Weleber, R. G., Wirth, B., Wong, F., Worton, R. G. and Wright, A. F. (1990)
Proc. Natl. Acad. Sci. USA
87, 701-704). Genetic linkage has not been reported for autosomal recessive RP (arRP), but mutations that cosegregate with arRP have been found in the &bgr;-subunit of rod phosphodiesterase on chromosome 4p (McLaughlin, M. E., Sandberg, M. A., Berson, E. L. and Dryja, T. P. (1993)
Nature Genet
. 4, 130-134), rhodopsin (Rosenfeld, P. J., Cowley, G. S., McGee, T. L., Sandberg, M. A., Berson, E. L. and Dryja, T. P. (1992)
Nature Genet
. 1, 209-213), and possibly the rod cGMP-gated channel gene (McGee, T. L., Lin, D., Berson, E. L. and Dryja, T. P. (1994)
Invest. Ophthalmol. Vis. Sci
. (Suppl.) 35, 1716 (Abstract)). The regions around rhodopsin and peripherin have been excluded as a cause of arRP in a large Dutch pedigree (Bleeker Wagemakers, L. M., Gal, A., Kumar Singh, R., Ingeborgh van den Born, L., Li, Y., Schwinger, E., Sandkuijl, L. A., Bergen, A. A., Kenna, P., Humphries, P. and Farrar, G. J. (1992)
Genomics
14, 811-812), suggesting that the recessive form of the disorder is also genetically heterogeneous.
A locus for autosomal recessive retinitis pigmentosa has been mapped on chromosome 6p by linkage analysis (Knowles, J. A., et. al., (1994)
Hum. Mol. Genet
. 3:1401-1403). This locus is approximately 20 centimorgans telomeric from the previously described adRP disease gene, peripherin, and thus represents a novel disease locus. The approximate 95% confidence interval for arRP spanning the D6S291 locus is 8.5% centimorgans. This interval of chromosome 6p contains the HLA complex. HLA associations have been found in several human uveitic diseases (Nussenblatt, R. B. et al., (1989)
Uveitis: Fundamentals and Clinical Practice: Year Book Medical Publishers
), and the 1-A subregion of the H-2 complex in a mouse model of autoimmune uveoretinitis (Caspi, R. R., et. al., (1992),
Curr. Eye Res
. 11 (Suppl.) 81-86; Caspi, R. R., et, al., (1992)
J. Immunol
., 148:2384-2389).
2. SUMMARY OF THE INVENTION
The present invention is based on the discovery of novel molecules, referred to herein as rp nucleic acid and polypeptide molecules. Exemplary rp molecules, the first containing a Bac clone genomic DNA and the second containing the cDNA shown in
FIGS. 1A-1B
have been deposited with the American Type Culture Collection (ATCC) and have been assigned ATCC designation numbers: 98144 (deposited Aug. 22, 1996) and 98147 (deposited Aug. 23, 1996), respectively.
The human rp gene (FIG.
1
), which is approximately 1050 nucleotides in length, is predominantly expressed in the retina, consistent with the phenotypic abnormalities seen in Retinitis Pigmentosa patients. In addition, the gene was found to map very close (2.8 cR or about 1 Mb) to marker D6S291 on chromosome 6. This marker is the most tightly linked marker to the RP14 retinitis pigmentosa locus. The human rp gene encodes a 349 amino acid protein, that weighs approximately 38880 daltons.
The human rp gene is 56.4% identical to the human tub gene; and the hrp protein is 46% identical to htub. Although the N-terminus of the two gene products are dissimilar, the most conserved region of the two gene products are 66.4% identical. Accordingly and as discussed further herein, the tub and rp genes may perform similar molecular functions in different biochemical pathways or may even function in the same biochemical pathway(s).
In one aspect, the invention features isolated vertebrate rp nucleic acid molecules. The disclosed molecules can be non-coding, (e.g. probe, antisense or ribozyme molecules) or can encode a functional rp polypeptide (e.g. a polypeptide which specifically modulates, e.g., by acting as either an agonist or antagonist, at least one bioactivity of the human rp polypeptide). In one embodiment, the nucleic acid molecules hybridize to the rp gene contained in ATCC Designation Nos. 98144 or 98147 or to the complement of the rp gene contained in ATCC Designation Nos. 98144 or 98147. In another embodiment, the nucleic acids of the present invention can hybridize to a vertebrate rp gene or to the complement of a vertebrate rp gene. In a further embodiment, the claimed nucleic acid hybridizes with the coding sequence designated in at least one of SEQ ID Nos: 1 or 3 or to the complement to the coding sequence designated in at least one of SEQ ID Nos: 1 or 3. In a preferred embodiment, the hybridization is conducted under mildly stringent or stringent conditions.
In further embodiments, the nucleic acid molecule is a rp nucleic acid that is at least 70%, preferably 80%, more preferably 85%, and even more preferably at least 95% homologous in sequence to the nucleic acids shown as SEQ ID Nos: 1 or 3 or to the complement of the nucleic acids shown as SEQ ID Nos: 1 or 3. In another embodiment, the rp nucleic acid molecule encodes a polypeptide that is at least 90% and more preferably at least 94% similar i
Gimeno Carlos J.
Kleyn Patrick W.
Moore Karen J.
Laccotripe Maria C.
Lahive & Cockfield LLP
Low Christopher S. F.
Mandragouras Amy E.
Millennium Pharmaceuticals Inc.
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