Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Reexamination Certificate
1998-12-22
2002-05-14
Fredman, Jeffrey (Department: 1655)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
C436S091000, C536S023100, C536S027400
Reexamination Certificate
active
06387616
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates, in general, to torsin genes, preferably, torsina which encodes the torsion dystonia gene, DYT1. In particular, the present invention relates to nucleic acid molecules coding for the torsin protein; purified torsin proteins and polypeptides; recombinant nucleic acid molecules; cells containing the recombinant nucleic acid molecules; antibodies having binding affinity specifically to torsin proteins and polypeptides; hybridomas containing the antibodies; nucleic acid probes for the detection of nucleic acids encoding torsin proteins; a method of detecting nucleic acids encoding torsin proteins or polypeptides in a sample; kits containing nucleic acid probes or antibodies; bioassays using the nucleic acid sequence, protein or antibodies of this invention to diagnose, assess, or prognose a mammal afflicted with torsion dystonia; therapeutic uses; and methods of preventing torsion dystonia in an animal (preferably, a human).
2. Related Art
Movement disorders constitute a group of human neurologic diseases in which aberrant neurotransmission in the basal ganglia is associated with uncontrollable body movements, such as chorea in Huntington disease, tremor and rigidity in Parkinson disease, and twisting contraction in torsion dystonia. Dystonic symptoms can be secondary to a number of neurologic conditions, and to drug or traumatic injury to the brain, but primary or torsion dystonia is distinguished by lack of other neurologic involvement (Fahn, S.,
Adv Neurol
50:1-8 (1988); Chutorian, A. H.,
Acta Neuropediatricia
2:33-45 (1996)) and, in contrast to these other two neurodegenerative diseases, the absence of any distinct neuropathology. The clinical manifestations of dystonia show wide variations in age and site of onset, as well as body regions involved. The prevalence of all forms of primary dystonia is estimated at 3/10,000 in North America (Nutt, J. G., et al.,
Mov Disord
3:188-194 (1988)).
Early onset, generalized dystonia is the most disabling form of primary dystonia. Symptoms usually begin in an arm or leg at around 12 yrs (range 4-44 years) and spread to involve other limbs within about 5 years (Bressman, S. B., et al.,
Annal Neurol
36:771-777 (1994b); Greene, P., et al.,
Mov Disord
10:143-152 (1995)). The clinical spectrum of early onset dystonia is similar in all ethnic populations, with highest prevalence in the Ashkenazi Jewish (termed here AJ) population (Zeman, W., & Dyken, P.,
Psychiatr Neurol Neurochir
10:77-121 (1967); Korczyn, A. D., et al.,
Ann Neurol
8:387-391 (1980); Eldridge, R.,
Neurology
20:1-78 (1970)), due to a founder mutation (Ozelius, L., et al.,
Am. J. Hum. Genet
. 50:619-628 (1992); Risch, N. J., et al.,
Nature Genetics
9:152-159 (1995)). Early onset dystonia follows an autosomal dominant mode of inheritance with 30-40% penetrance (Bressman, S. B., et al.,
Ann Neurol
26:612-620 (1989); Risch, N. J., et al.,
Am J Hum Genet
46:533-538 (1990)). The responsible gene in Jewish and non-Jewish families has been mapped to human chromosome 9q34 (Ozelius, L., et al.,
Neuron
2:1427-1434 (1989); Kramer, P. L., et al.,
Ann Neurol
27:114-120 (1990) and Kramer, P., et al.,
Am J Hum Gen
55:468-475 (1994)). Haplotype analysis of the founder mutation in AJ families placed the DYT1 gene in a 1-2 cM interval centromeric to the ASS locus on chromosome 9 (Ozelius, L., et al.,
Am. J. Hum. Genet
. 50:619-628 (1992)) with highest lod scores obtained with adjacent markers, D9S62a/b and D9S63 (Risch, N., et al.,
Nature Genetics
9:152-159 (1985)).
SUMMARY OF THE INVENTION
The present invention relates to dystonia, dystonia genes and encoded proteins and mutations in dystonia genes that result in a dystonia disorder. In particular, the invention provides isolated nucleic acid molecules coding for torsin, preferably, torsinA which encodes the torsion dystonia gene, DYT1.
The invention further provides purified polypeptides comprising amino acid sequences encoding torsin proteins.
The invention also provides nucleic acid probes for the specific detection of the presence of and mutations in nucleic acids encoding torsin proteins or polypeptides in a sample.
The invention further provides a method of detecting the presence of and mutations in a nucleic acid encoding torsin protein in a sample.
The invention also provides a kit for detecting the presence of and mutations in a nucleic acid encoding torsin protein in a sample.
The invention further provides a recombinant nucleic acid molecule comprising, 5′ to 3′, a promoter effective to initiate transcription in a host cell and the above-described isolated nucleic acid molecule.
The invention also provides a recombinant nucleic acid molecule comprising a vector and the above-described isolated nucleic acid molecule.
The invention further provides a recombinant nucleic acid molecule comprising a sequence complimentary to an RNA sequence encoding an amino acid sequence corresponding to the above-described polypeptide.
The invention also provides a cell that contains the above-described recombinant nucleic acid molecule.
The invention further provides a non-human organism that contains the above-described recombinant nucleic acid molecule.
The invention also provides an antibody having binding affinity specifically to a torsin protein or polypeptide.
The invention further provides a method of detecting torsin protein or polypeptide in an sample.
The invention also provides a method of measuring the amount of torsin protein or polypeptide in a sample.
The invention further provides a method of detecting antibodies having binding affinity specifically to a torsin protein or polypeptide.
The invention further provides a diagnostic kit comprising a first container means containing a conjugate comprising a binding partner of the monoclonal antibody and a label.
The invention also provides a hybridoma which produces the above-described monoclonal antibody.
The invention further provides diagnostic methods for dystonia disorders in humans, in particular, torsion dystonia. Preferably, a method of diagnosing the presence or absence of dystonia; predicting the likelihood of developing or a predisposition to develop dystonia in a human is provided herein. Specifically, methods of the present invention encompass detecting the presence, or absence of, a mutation in a gene wherein the mutation results in a dystonia disorder that affects humans. For example, the method comprises obtaining a sample from a human patient; evaluating the characteristics of torsinA nucleic acid in the sample, wherein the evaluation comprises detecting the GAGGAG region (SEQ ID NO: 5 at nucleotide positions 946-951) in the sample; and diagnosing the presence or predisposition to develop torsion dystonia in a patient wherein the absence of three nucleotides from the GAGGAG region indicates the presence or predisposition to develop torsion dystonia.
The present invention also encompasses methods for diagnosing the presence or absence of a dystonia disorder in a human comprising detecting the presence or absence of at least one mutation in a dystonia gene, wherein the presence of a mutation in the dystonia gene is indicative of a positive diagnosis and the absence of the mutation is indicative of the absence of a dystonia disorder. The dystonia disorder can be, for example, torsion dystonia. A biological sample obtained from a human can be used in the diagnostic methods. The biological sample can be a bodily fluid sample such as blood, saliva, semen, vaginal secretion, cerebrospinal and amniotic bodily fluid sample. Alternatively or additionally, the biological sample is a tissue sample such as a chorionic villus, neuronal, epithelial, muscular and connective tissue sample. In both bodily fluid and tissue samples, nucleic acids are present in the samples. In another embodiment the sample is a nucleic acid preparation obtained from human chromosome 9q34.
The dystonia gene can be the DYT1 gene (SEQ ID NO: 1). In normal humans (humans who are not affected
Breakefield Xandra O.
Ozelius Laurie J.
Einsmann Juliet
Fredman Jeffrey
Hamilton Brook Smith & Reynolds PC
The General Hospital Corporation
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