Methods for diagnosing episodic movement disorders and related conditions
Inventors
Fink, John K. • Rainier, Shirley
Assignees
US Department of Veterans Affairs
Publication Number
US-8481260-B2
Publication Date
2013-07-09
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 present invention provides compositions and methods for research, diagnostic, drug screening, and therapeutic applications related to paroxysmal dystonic choreoathetosis (PDC) and related conditions. It discloses mutations in the myofibrillogenesis regulator 1 (MR-1) gene associated with such conditions, particularly missense mutations C66T and C72T in exon 1 of MR-1 that predict alanine to valine substitutions at residues 7 (A7V) and 9 (A9V). These mutations segregate with individuals suffering from PDC and are absent in unaffected individuals and controls.
The problem being solved arises from the lack of a cure and the insufficient understanding of the pathophysiology, genetics, and biochemistry underlying episodic movement disorders, such as PDC. Existing treatments only mask symptoms, and better diagnostic tools, treatments, and genetic understanding are needed. PDC is an episodic movement disorder characterized by attacks of involuntary movements beginning in childhood or early adulthood and precipitated by factors such as alcohol and caffeine consumption. The inventors identified mutations in MR-1 that provide a genetic basis for PDC and address the need for improved diagnosis and treatment.
The invention includes isolated and purified nucleic acids encoding MR-1 polypeptides and variants thereof, detection methods for variant MR-1 sequences in biological samples from subjects, and diagnostic kits comprising reagents (e.g., antibodies) specific for variant MR-1 polypeptides. It encompasses methods for detecting variant MR-1 polypeptides containing alanine to valine substitutions at positions 7 and/or 9 using differential antibody binding, Western blot, or nucleic acid sequence detection. It also covers vectors containing MR-1 variant sequences, host cells comprising such vectors, and polypeptides encoded by nucleic acids with the C66T or C72T mutations.
Claims Coverage
The claims include one independent claim focusing on a diagnostic method, with dependent claims specifying assay types and sample sources. The main inventive features relate to the detection of specific MR-1 gene sequence variations associated with increased risk of PDC.
Detection of specific MR-1 gene sequence variations associated with PDC risk
A method for determining a human subject's risk for paroxysmal dystonic choreoathetosis by providing a sample and detecting the presence of one or more sequence variations in exon 1 of the MR-1 gene. These variations are a C to T change at position 66 or 72 of the wild type MR-1 gene sequence (SEQ ID NO: 1), detected by nucleic acid sequencing assays, wherein their presence indicates increased risk for PDC.
Use of nucleic acid sequencing assays for detection
The detection is performed using nucleic acid sequencing assays selected from direct sequencing, fragment polymorphism assays, or hybridization assays to identify the presence of the MR-1 gene variations.
Use of various biological samples for detection
The method includes using samples selected from blood, tissue, urine, or amniotic fluid for detecting the MR-1 gene sequence variations.
The claim collectively covers a diagnostic method for assessing the risk of PDC in a human subject by detecting specific MR-1 mutations in exon 1 using nucleic acid sequencing assays on various biological sample types.
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 for other episodic movement disorders including dystonias, Parkinson's disease, tics, Tourette's syndrome, choreas, drug-induced movement disorders, and other paroxysmal neurologic diseases.
Improves understanding of neurophysiologic effects of alcohol and caffeine on the nervous system.
Allows genetic testing to determine individual susceptibility to drug-induced movement disorders and neurotoxic effects of substances like alcohol and caffeine.
Facilitates development of therapeutic pathways including MR-1 protein or gene replacement for episodic movement disorders.
Documented Applications
Research, diagnostic, drug screening, and therapeutic applications related to paroxysmal dystonic choreoathetosis and related episodic movement disorders.
Genetic testing to diagnose PDC and related movement disorders.
Screening for individual sensitivity to drug-induced movement disorders.
Genetic counseling for families with history of PDC or related disorders.
Identifying compounds for treatment of PDC through drug screening assays.
Use of transgenic animals expressing mutant MR-1 genes for research and drug screening.
Gene therapy approaches for treatment of PDC and related disorders using MR-1 gene or protein delivery.
Use of RNA interference (RNAi) targeting MR-1 for research or therapeutic applications.
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