Human asparaginyl-tRNA synthetase DNA

Details Human asparaginyl-tRNA synthetase DNA Human asparaginyl-tRNA synthetase DNA

1998-10-06

2001-06-12

Achutamurthy, Ponnathapu (Department: 1652)

Chemistry: molecular biology and microbiology

Enzyme , proenzyme; compositions thereof; process for...

C435S320100, C435S282000, C435S252330, C435S419000, C435S254110, C435S325000, C536S023200

Reexamination Certificate

active

06245539

ABSTRACT:

CROSS-REFERENCE TO RELATED APPLICATION
None
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to isolated and sequenced DNA encoding asparaginyl-tRNA synthetase. Further, the present invention relates to test kits and methods for detecting autoimmune diseases which are related to asparaginyl-tRNA synthetase (AsnRS).
(2) Description of Related Art
Aminoacyl-tRNA synthetases (aaRS) are enzymes involved in protein biosynthesis catalyzing the specific attachment of amino acids to their cognate tRNAs. Two classes of synthetases have been defined, each of 10 members, based on their primary and tertiary structures (Eriani, G., et al., Nature 347:203-206 (1990); and Cusack, S., et al., Nature 347:249-255 (1990)). Class II enzymes have three consensus sequence motifs; motif 1 contributes to the dimer interface, whereas motifs 2 and 3 are constituents of the catalytic site. Sub-classification can be made of the class II enzymes based on more extensive sequence and structural similarities (Cusack, S., et al., Nucleic Acids Res. 19:3489-3498 (1991)). In higher eukaryotes, nine aaRS of different specificities (not including AsnRS) are associated within a multi-enzyme complex (Mirande, M., et al., Eur. J. Biochem. 147:281-289 (1985)).
Asparaginyl-tRNA synthetase (AsnRS) is classified as a sub-class IIb enzyme together with the aspartyl- and lysyl-enzymes on the basis of similarities in their N-terminal extensions and the catalytic domains (Cusack, S., et al., Nucleic Acids Res. 19:3489-3498 (1991); Anselme, J., et al., Gene 84:481-485 (1989); Gatti, D. L., et al., J. Mol. Biol. 218:557-568 (1991); and Eriani, G., et al., Nucleic Acids Res., 18:7109-7118 (1990)). The three-dimensional structure of an AsnRS of
Thermus thermophilus
(Seignovett, I., et al., Eur. J. Biochem. 239:501-508 (1996)) further illustrates the strong structural homology between the three class IIb synthetases.
Illustrative of the patent art relating to amino acid synthetases are the following patents: U.S. Patent No. 5,561,054 to Kron et al; U.S. Pat. No. 5,629,188 to Shiba et al; U.S. Pat. No. 5,663,066 to Raben et al; U.S. Pat. No. 5,695,962 to Kron et al; U.S. Pat. No. 5,721,116 to Kron et al; U.S. Pat. No. 5,726,195 to Hill et al; U.S. Pat. No. 5,747,315 to Lawlor; U.S. Pat. No. 5,756,327 to Sassanfar et al; and U.S. Pat. No. 5,759,833 to Shiba et al.
Autoantibodies are found in many patients with polymyositis or dermatomyositis. Some of these patients have antibodies raised against aaRS, of which anti-Jo-1, directed at histidyl-tRNA synthetase (HisRS) is by far the most common (Targoff, I. N., J. Invest. Dermatol., 100:116S-123S (1993)).
Autoantibodies directed against aminoacyl-tRNA synthetases can be found in approximately 25-35% of patients with the chronic, inflammatory muscle disorders, polymyositis (PM) and dermatomyositis (DM) (Targoff, I. N., Rheum. Dis. Clin. North. Am. 20:857-880 (1994)). Each member of this family of enzymes catalyzes the formation of an aminoacyl-tRNA from a specific amino acid and its cognate tRNAs. Autoantibodies to five of these synthetases (histidyl-, threonyl-, alanyl-, isoleucyl-, and glycyl-tRNA synthetases) have been identified in patients with PM and DM (Targoff, I. N., Rheum. Dis. Clin. North. Am 20:857-880 (1994); Mathews, M. B., et al., Nature 304:177-179 (1983); Mathews, M. B., et al., J. Exp. Med. 160:420-434 (1984); Bunn, C. C., et al., J. Exp. Med. 163:1281-1291 (1986); Targoff, I. N., J. Immunol. 144:1737-1743 (1990)). Among these “anti-synthetase antibodies”, anti-histidyl tRNA synthetase (anti-Jo-1) is the most common, found in 20-30% of such patients (Targoff, I. N., et al., J. Immunol. 138:2874-2882 (1987); Oddis, C. V., et al., Arthritis Rheum. 33:1640-1645 (1990); Love, L. A., et al., Medicine (Baltimore) 70:360-374 (1991); Hirakata, M., et al., Arthritis Rheum. 35:449-456 (1992); and Marguerie, D., et al., Q. J. Med. 77:1019-1038 (1990)). Anti-threonyl tRNA synthetase (anti-PL-7) and anti-alanyl tRNA synthetase (anti-PL-12) antibodies are less common, found in 3 to 4% of all patients with PM/DM (Mathews, M. B., et al., J. Exp. Med. 160:420-434 (1984); Bunn, C. C., et al., J. Exp. Med. 163:1281-1291 (1986); Marguerie, C., et al., Q. J. Med. 77:1019-1038 (1990); Targoff, I. N., et al., Arthritis Rheum. 31:515-524 (1988); Targoff, I. N., et al., Am. J. Med. 88:241-251 (1990)), while autoantibodies to isoleucyl-tRNA synthetase (anti-OJ) and glycyl-tRNA synthetase (anti-EJ) are the least common, occurring in <2% (Targoff, I. N., J. Immunol. 144:1737-1743 (1990); Targoff, I. N., et al., J. Clin. Invest. 91:2556-2564 (1993); and Targoff, I. N., et al., Arthritis Rheum. 35:821-830 (1992)). Isoleucyl-tRNA synthetase is the only one of these synthetase autoantigens that is a component of the multi-enzyme synthetase complex, and some anti-OJ sera also react with other components of the synthetase complex, but such additional reactivity does not change the immunoprecipitation picture of anti-OJ. Thus, excluding the 9 synthetase activities that are part of the complex, and the 4 other described anti-synthetases, 7 aminoacyl-tRNA syntheses exist for which autoantibodies have not been described, as determined by immunoprecipitation of tRNA. The reason for this selectivity for certain synthetases is not known. With the exception mentioned for anti-OJ, it is extremely rare for a patient to have more than one anti-synthetase (Gelpi, C., et al., Arthritis Rheum. 39:692-697 (1996)).
Anti-Jo-1 and other anti-synthetases have each been associated with a similar syndrome marked by myositis with a high frequency of interstitial lung disease (ILD) (50-80%) and arthritis (50-90%) (Oddis, C. V., et al., Arthritis Rheum. 33:1640-1645 (1990); Love, L A., et al., Medicine (Baltimore) 70:360-374 (1991); Hirakata, M., et al., Arthritis Rheum. 35:449-456 (1992); Marguerie, C., et al., Q. J. Med. 77:1019-1038 (1990); Yoshida, S., et al., Arthritis Rheum. 26:604-611 (1983); and Bernstein, R. M., et al., Br. Med. J. 289:151-152 (1984)), as well as an increase when compared to the overall myositis population in Raynaud's phenomenon (60%), fever with exacerbations (80%), and the skin lesion of the fingers referred to as mechanic's hands (70%) (Love, L. A., et al., Medicine (Baltimore) 70:360-374 (1991)). Other associations, such as an increase in sicca and sclerodactyly have been observed by some investigators (Marguerie, C., et al., Q. J. Med. 77:1019-1038 (1990)). Although the similarities between patients with different anti-synthetases are most striking, certain differences have been observed, which must be considered preliminary due to the small number of patients with non-Jo-1 anti-synthetases reported. One important difference is that patients with anti-PL-12 are more likely than anti-Jo-1 patients to have ILD and/or arthritis either without myositis or with subclinical signs of muscle disease. Absence of significant myositis over the full course of patients with anti-Jo-1 is rare (<5%), although it may occur. Clinically significant myositis was seen in 60% of U.S. patients with anti-PL-12 (Targoff, I. N., et al., Am. J. Med. 88:241-251 (1990); and Friedman, A. W., et al., Semin. Arthritis Rheum. 26:459-467 (1996)), whereas none of 6 Japanese patients with anti-PL-12 antibodies fulfilled criteria for myositis (Hirakata, M., et al., Arthritis Rheum. 38:S321 (Abstract) (1995)). In the limited number of patients thus far observed, 2/10 anti-OJ patients had ILD without detectable myositis, and one had ILD with subclinical myositis.
Most sera with any of the five reported anti-synthetases specifically inhibit the aminoacylation of the respective tRNAs, indicating inhibition of the enzymatic function of the synthetase (Mathews, M. B., et al., Nature 304:177-179 (1983); Bunn, C. C., et al., J. Exp. Med. 163:1281-1291 (1986); Targoff, I. N., J. Immunol. 144:1737-1743 (1990); Targoff, I. N., et al., J. Immunol. 138:2874-2882 (1987); and Targoff, I. N., et al., Arthritis Rheum. 31:515-524 (1988)). For example, anti-Jo-l serum, IgG fraction, and affini

Affiliated with

Also associated with

Rating

Human asparaginyl-tRNA synthetase DNA does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Human asparaginyl-tRNA synthetase DNA, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Human asparaginyl-tRNA synthetase DNA will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-2507017