Nucleic acids, methods and kits for the diagnosis of DYT6 primary torsion dystonia
Inventors
Ozelius, Laurie • Bressman, Susan
Assignees
Icahn School of Medicine at Mount Sinai
Publication Number
US-12188091-B2
Publication Date
2025-01-07
Expiration Date
2030-01-27
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Abstract
The invention relates generally to the THAP1 gene and mutations in this gene, as well as the THAP1 protein and mutations in this protein, that are associated with dystonia. The invention relates to the identification, isolation, cloning and characterization of the DNA sequence corresponding to the wild type and mutant THAP1 genes, as well as isolation and characterization of their transcripts and gene products. The invention further relates to methods and kits useful for detecting mutations in THAP1 that are associated with dystonia, as well as to methods and kits useful for diagnosing dystonia. The present invention also relates to therapies for treating dystonia, including gene therapeutics and protein/antibody based therapeutics.
Core Innovation
The invention is directed to the THAP1 gene and its protein product, including mutations in both, that are associated with dystonia, particularly DYT6 primary torsion dystonia. It involves the identification, isolation, cloning, and characterization of DNA sequences corresponding to wild type and mutant THAP1 genes, as well as their transcripts and gene products. The invention includes methods and kits useful for detecting mutations in THAP1 associated with dystonia and for diagnosing dystonia. It also relates to therapies for treating dystonia, including gene therapeutics and protein/antibody-based therapeutics.
The problem being solved is the lack of understanding of the genetic basis of DYT6 dystonia, a primary form of dystonia characterized by twisting movements and abnormal postures, with autosomal dominant inheritance and incomplete penetrance. While the genetic cause of DYT1 dystonia was previously identified, the genes causing other forms, such as DYT6, remained unknown. DYT6 was mapped to a region on chromosome 8 containing approximately 120 genes, but the specific gene and mutations responsible were not identified. The invention addresses this by discovering mutations in the THAP1 gene that co-segregate with dystonia in multiple families and clarifying the functional consequences of these mutations.
Claims Coverage
The patent contains one independent claim, covering a nucleic acid probe comprising a specific isolated nucleic acid sequence and its labeled forms, as well as kit applications thereof.
Nucleic acid probe comprising SEQ ID NO: 64 labeled with detectable moiety
A nucleic acid probe that includes an isolated nucleic acid or its complementary sequence comprising the exact sequence of SEQ ID NO: 64 and is labeled with a moiety selected from radioisotopes, fluorescent compounds, enzymes, and enzyme co-factors.
Nucleic acid encoding THAP1 peptide of SEQ ID NO: 81
The nucleic acid probe according to the invention specifically encodes a THAP1 peptide comprising the amino acid sequence of SEQ ID NO: 81.
Kit for detecting THAP1 mutation comprising the nucleic acid probe
A kit designed for detecting the presence of a THAP1 mutation in a biological sample, which includes the nucleic acid probe described, enabling identification of mutations in THAP1.
Inclusion of primer pair SEQ ID NO: 20 and SEQ ID NO: 21 in the kit
The kit further contains a primer pair consisting of SEQ ID NO: 20 and SEQ ID NO: 21, facilitating amplification of sequences of interest.
Provision of instructions with the kit
The kit includes instructions for use, guiding the accurate detection of THAP1 mutations with the components provided.
The claims focus on nucleic acid probes of specific THAP1 sequences and labeled detection moieties, kits incorporating these probes and primers for mutation detection, and accompanying instructions, collectively covering diagnostic tools for THAP1 mutation identification associated with dystonia.
Stated Advantages
The methods and kits allow for specific and accurate detection of THAP1 mutations associated with dystonia.
Identification of founder mutations in distinct populations enables targeted genetic diagnosis and carrier detection.
Mutations characterized are shown to disrupt THAP1 protein function such as DNA binding, providing diagnostic and therapeutic insight.
The availability of isolated nucleic acids, peptides, expression constructs, and antibodies facilitates both diagnosis and treatment development for dystonia.
Documented Applications
Genetic diagnosis of DYT6 primary torsion dystonia through detection of THAP1 mutations in biological samples.
Use of nucleic acid probes and PCR to amplify and detect mutant THAP1 sequences in DNA or RNA derived samples.
Restriction enzyme digestion and hybridization assays to identify specific THAP1 mutations.
Use of antibodies specific to wild type or mutant THAP1 proteins for immunoassays to detect THAP1 protein variants.
Delivery of therapeutic nucleic acids or peptides encoding wild-type THAP1 as treatments for dystonia.
Development of kits comprising probes, primers, and antibodies for clinical and research identification of THAP1 mutations.
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