Compositions for diagnosing episodic movement disorders and related conditions
Inventors
Fink, John K. • Rainier, Shirley
Assignees
US Department of Veterans Affairs • University of Michigan Ann Arbor
Publication Number
US-9758832-B2
Publication Date
2017-09-12
Expiration Date
2025-06-27
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Abstract
The present invention provides compositions and methods for research, diagnostic, drug screening, and therapeutic applications related to paroxysmal dystonic choreoathetosis and related conditions. In particular, the present invention provides mutations in the myofibrillogenesis regulator 1 (MR-1) gene associated with such conditions.
Core Innovation
The invention provides compositions and methods for research, diagnostic, drug screening, and therapeutic applications related to paroxysmal dystonic choreoathetosis (PDC) and related conditions. It particularly focuses on mutations in the myofibrillogenesis regulator 1 (MR-1) gene associated with these episodic movement disorders. The invention describes isolated and purified nucleic acids encoding MR-1 proteins and variants thereof, kits for detecting variant MR-1 polypeptides in biological samples, and methods for detecting such variants in various subjects including embryos, fetuses, newborn, and young animals.
The problem addressed is the lack of cure and limited treatment options for PDC, an episodic movement disorder characterized by attacks of involuntary dystonia, chorea, and athetosis. Current medications only mask symptoms and do not address the underlying pathophysiology. There is a pressing need for better understanding of the genetics and biochemistry of episodic movement disorders like PDC, improved diagnostic methods, and more effective treatments.
The invention locates the PDC locus interval on chromosome 2q33-2q35 and identifies two specific missense mutations in exon 1 of the brain-expressed MR-1 transcript NM_015488. These mutations result in alanine to valine substitutions at amino acid positions 7 and 9, which disrupt an amino-terminal alpha helix of MR-1. The brain-specific expression of this exon explains the neurological phenotype of PDC. The discovery provides diagnostic genetic testing capabilities, insights into the pathogenesis of PDC and related disorders, and avenues for therapeutic intervention including gene or protein replacement strategies.
Claims Coverage
The independent claims focus on nucleic acids specifically hybridizing to MR-1 genes with mutations at amino acid positions 7 and/or 9, and kits for detecting these variants.
Nucleic acid specific hybridization to MR-1 mutations
A nucleic acid that specifically hybridizes to a nucleic acid sequence encoding an MR-1 gene with mutations at amino acid positions 7 and/or 9, comprising either a C to T transition at position 66 or 72 of SEQ ID NO: 1, with 10 to 500 nucleotides, and being detectably labeled.
Detectable labeling of nucleic acids
The nucleic acid is detectably labeled with an enzymatic, fluorescent, radioactive, and/or luminescent moiety for detection purposes.
Attachment of nucleic acids to solid supports
The nucleic acid can be attached to a solid support to facilitate its use in detection assays.
Kits for detection of variant MR-1 sequences
A kit containing the above nucleic acids for detecting variant MR-1 nucleic acid sequences with mutations at amino acid positions 7 and/or 9.
Inclusion of instructions in kits
The kit further comprises instructions for the detection of variant MR-1 nucleic acid sequences corresponding to mutations at amino acid positions 7 and/or 9.
The independent claims cover nucleic acids detecting specific MR-1 mutations at amino acids 7 and 9, their labeling and attachment for diagnostic use, and kits including these nucleic acids and instructions for variant detection.
Stated Advantages
Provides laboratory-based and clinical diagnostic testing for PDC.
Enables identification and characterization of treatments for PDC.
Offers insights into causes and treatments of other episodic movement disorders and drug-induced movement disorders.
Facilitates genetic testing for susceptibility to neurotoxic effects of substances like alcohol and caffeine.
Provides therapeutic pathways including protein or gene replacement strategies for disorders caused by MR-1 mutations.
Documented Applications
Research, diagnostic, drug screening, and therapeutic applications related to PDC and related episodic movement disorders.
Diagnostic genetic screening for MR-1 mutations to detect susceptibility to PDC.
Development of kits for detection of variant MR-1 polypeptides in biological samples.
Gene therapy approaches to treat MR-1-related neurological disorders.
Screening of candidate drugs that modulate MR-1 activity and signaling for treatment of episodic movement disorders.
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