Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1997-10-22
2001-07-31
Myers, Carla J. (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C435S091200, C536S024310, C536S024330, C536S023500
Reexamination Certificate
active
06268130
ABSTRACT:
BACKGROUND OF THE INVENTION
Retinitis pigmentosa (alternatively referred to herein using its full name or the abbreviation “RP”) is a group of human hereditary retinal degenerations which are named for the characteristic intraretinal pigment which appears around the mid-peripheral retina of individuals with RP (Berson, E. L. (1996)
PNAS
93:4526-4528). Individuals with RP suffer from degeneration of photoreceptor cells which in turn leads to various clinical features which are common among these individuals. For example, RP results in night blindness, gradual loss of peripheral visual field, and eventual loss of central vision. In typical cases, rod photoreceptors are more severely affected early in the disease, hence the early symptom of night blindness. Later in the disease, cone photoreceptors degenerate. Most cases of RP have no extraocular abnormalities. In a minority of families, however, RP is associated with other disease manifestations such as hearing loss in Usher syndrome, polydactyly, obesity, hypogonadism, mental retardation in Bardet-Biedl syndrome, and cardiac conduction defects in Keams-Sayre syndrome. Dryja, T. P. and Li, T. (1995)
Human Mol. Genet
. 4:1739-1743.
RP can be inherited by an autosomal dominant, autosomal recessive, X-linked, or digenic mode (Kajiwara, K. et al. (1994)
Science
264:1604-1608). Substantial genetic heterogeneity has been observed in this condition, with over 20 loci mapped (Dryja, T. P. and Li, T. (1995)
Human Mol. Genet
. 4:1739-1743; Daiger, S. P. et al. (1995)
Behav. Brain Sci
. 18:452-467). Mutations have been identified in seven genes which map to seven different chromosomes (Kajiwara, K. et al. (1994)
Science
264:1604-1608; Dryja, T. B. et al. (1990)
Nature
343:364-366; Farrar, G. J. et al. (1991)
Nature
354::478-480; Kajiwara, K. et al. (1991)
Nature
354:480-483; McLaughlin, M. E. et al. (1993)
Nature Genet
. 4:130-133; Dryja, T. P. et al. (1995)
PNAS
92:10177-10181; Huang, S. H. et al. (1995)
Nature Genet
. 11:468-471; Bascom, R. A. et al. (1995)
Human Mol. Genet
. 4:1895-1902; Weil, D. et al. (1995)
Nature
374-60-61). Four of these genes encode proteins in the rod phototransduction cascade-namely rhodopsin (mapped to chromosomes 3q21-q24 (autosomal dominant, autosomal recessive)), the &agr; and &bgr; subunits of rod cGMP phosphodiesterase (mapped to chromosomes 5q31.2-q34 (autosomal recessive), and 4p16.3 (autosomal recessive), respectively)), and the rod cGMP cation-gated channel protein &agr; subunit (mapped to chromosome 4p14-q13 (autosomal recessive)) (Berson, E. L. (1996)
PNAS
93:4526-4528; Dryja, T. P. and Li, T. (1995)
Human Mol. Genet
. 4:1739-1743). Two of these genes, peripherin/RDS (mapped to chromosome 6p11.2-p21.1 (autosomal dominant, autosomal recessive)) and rod outer segment membrane protein 1 (mapped to chromosome 11q13 (digenic)), encode proteins involved in maintaining photoreceptor outer segment disc structure (Berson, E. L. (1996)
PNAS
93:4526-4528; Dryja, T. P. and Li, T. (1995)
Human Mol. Genet
. 4:1739-1743). Mutations in the gene encoding myosin VIIa (mapped to chromosome 11q13.5 (autosomal recessive)) have been found in a form of RP with associated profound congenital deafness (Usher syndrome) (Berson, E. L. (1996)
PNAS
93:4526-4528; Dryja, T. P. and Li, T. (1995)
Human Mol. Genet
. 4:1739-1743).
An additional locus for autosomal recessive RP 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 peripherin/RDS gene, and thus represents a novel disease locus.
SUMMARY OF THE INVENTION
This invention is based on the discovery of a novel gene which, as described herein, was mapped very close (2.8 cR which is about 1 Mb) to the marker D6S291 on chromosome 6. The D6S291 marker is the most tightly-linked marker to the retinitis pigmentosa locus 14 (RP14) on chromosome 6 (Knowles et al. (1994)
Hum. Mol. Genet
. 3:1401-1403). Thus, this gene was designated the retinitis pigmentosa (“rp”) gene. The rp gene encodes a polypeptide, referred to herein as an rp polypeptide. The rp polypeptide is involved in signal transduction pathways which regulate sensory functions, e.g., vision and/or hearing functions. In a preferred embodiment, the rp polypeptides are involved in signal transduction pathways which regulate the function of cells of the eye, e.g., cells of the retina, e.g., neural cells of the retina, e.g., the rod and cone photoreceptor cells of the retina.
The rp gene and polypeptide were also found to share sequence similarity with the human TUB gene and the TUB gene product, respectively. Mutations in the mouse homologue of the human TUB gene are characterized by progressive sensory deterioration such as progressive retinal and cochlear degeneration (Heckenlively, J. R. et al. (1995)
PNAS
92:11100-11104; Ohlemiller, K. K. et al. (1995)
NeuroReport
6:845-849), maturity-onset obesity with insulin resistance, and impaired glucose tolerance (Coleman, D. L. and Eicher, E. M. (1990)
J. Hered
. 81:424-427). It has also been found that rp polypeptides of the invention interact with (e.g., bind to) at least one protein which is a member of the human TUB interactor (“hTI”) family of proteins. Specifically, the rp polypeptides have been found to interact with hTI-2, a TUB interactor described in U.S. Ser. No. 08/715,032, filed Sep. 17, 1996, the contents of which are incorporated herein by reference. Thus, by their similarity to the TUB gene product and their ability to interact with at least one TUB interactor protein, the rp polypeptides of the invention are also involved in signal transduction pathways which regulate body weight and pathways involved in metabolism, e.g., glucose metabolism.
Accordingly, one aspect of the invention pertains to an isolated rp nucleic acid molecule (e.g., genomic DNAs, cDNAs, RNAs) comprising a nucleotide sequence encoding an rp polypeptide or a bioactive fragment thereof, as well as nucleic acid fragments suitable as primers or hybridization probes for the detection of rp-encoding nucleic acid (e.g., mRNA). In one embodiment, the rp polypeptide or bioactive fragment encoded by the nucleic acid molecule is a vertebrate, e.g., mammalian, polypeptide or bioactive fragment thereof. In particularly preferred embodiments, the isolated nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO:1, the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98144, the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98147, or the coding region or a complement of one of these nucleotide sequences. In other particularly preferred embodiments, the isolated nucleic acid molecule of the invention comprises a nucleotide sequence which hybridizes to or is at least about 60-65%, preferably at least about 70-75%, more preferably at least about 80-85%, and even more preferably at least about 90-95% or more homologous to the nucleotide sequence shown in SEQ ID NO:1, the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98144, or the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98147 or a portion of one of these nucleotide sequences. In other preferred embodiments, the isolated nucleic acid molecule encodes an amino acid sequence which is at least about 50-60%, preferably at least about 65-70%, more preferably at least about 75-80%, and even more preferably at least about 85, 90, 95% or more homologous to the amino acid sequence encoded by the nucleotide sequence shown in SEQ ID NO:1, the amino acid sequence encoded by the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98144, or the amino acid sequence encoded by the nucleotide sequence of the DNA insert of the plasmid deposited with ATCC as Accession Number 98147 or a portion of an amino acid sequence encoded by a portion of one of these nucleoti
Kleyn Patrick W.
Moore Karen J.
Lahive & Cockfield LLP
Mandragouras Amy E.
Millennium Pharmaceuticals Inc.
Myers Carla J.
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