Using presence of myofibrillogenesis regulator 1 (MR-1) gene as diagnostic tool in detection of paroxysmal dystonic choreoathetosis
Inventors
Fink, John K. • Rainier, Shirley
Assignees
US Department of Veterans Affairs
Publication Number
US-7727719-B2
Publication Date
2010-06-01
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. In particular, it identifies mutations in the myofibrillogenesis regulator 1 (MR-1) gene associated with such conditions. The invention includes isolated and purified nucleic acids encoding variant MR-1 proteins, antibodies for detecting these variants, methods for detecting variant MR-1 polypeptides in biological samples, and kits for diagnostic use.
PDC is an episodic movement disorder characterized by attacks of dystonia, chorea, and athetosis that begin in childhood or early adulthood and can last from several minutes to more than an hour. These attacks occur spontaneously at rest and can be precipitated by factors including alcohol and caffeine consumption. Presently, there is no cure for PDC, and medications available only mask symptoms. Although genetic linkage to chromosome 2q33-2q35 has been identified, the underlying molecular cause and better diagnostic and treatment options were needed.
The invention solves this problem by identifying specific mutations (C66T and C72T) in exon 1 of the MR-1 gene that segregate with PDC in affected kindreds, leading to alanine to valine substitutions at residues 7 and 9 in an amino-terminal alpha helix of the protein. This exon containing the mutations is expressed only in the brain, corresponding to the neurological specificity of PDC symptoms. This discovery enables improved genetic diagnosis, insight into pathophysiology, and potential therapeutic strategies targeting MR-1.
Claims Coverage
The patent includes three claims covering a method for assessing risk of paroxysmal dystonic choreoathetosis based on detecting MR-1 gene sequence variations and their encoded polymorphic proteins.
Method for assessing risk of paroxysmal dystonic choreoathetosis using MR-1 gene sequence variations
Providing a biological sample from a human subject and detecting the presence of MR-1 gene sequence variations encoded by SEQ ID NO:1 that correspond to polymorphic MR-1 proteins SEQ ID NO:6, SEQ ID NO:7, or SEQ ID NO:8, wherein such presence indicates increased risk for paroxysmal dystonic choreoathetosis.
Detection of polymorphic MR-1 protein in a sample
Detecting a polymorphic MR-1 protein directly in the biological sample as part of the risk assessment method.
Use of antibody for detecting polymorphic MR-1 protein
Detecting the presence of polymorphic MR-1 protein in a sample using an antibody specific to the polymorphic protein.
The claims cover methods to detect MR-1 gene mutations and corresponding variant proteins linked to increased risk of PDC, including direct protein detection and use of specific antibodies, providing a diagnostic approach based on MR-1 polymorphisms.
Stated Advantages
Provides laboratory-based and clinical diagnostic testing for paroxysmal dystonic choreoathetosis.
Enables identification and characterization of treatments for PDC and related episodic movement disorders.
Offers insights into causes and treatments of other episodic and drug-induced movement disorders.
Facilitates genetic testing to determine vulnerability to neurotoxic effects of alcohol, caffeine, and drugs causing involuntary movements.
Provides therapeutic pathways including MR-1 protein or gene replacement strategies for episodic movement disorders.
Documented Applications
Use of MR-1 gene sequence analysis for diagnosing paroxysmal dystonic choreoathetosis and distinguishing it from other movement disorders.
Genetic counseling based on MR-1 mutations associated with PDC.
Screening individuals for susceptibility to drug-induced movement disorders such as neuroleptic-induced tardive dyskinesia.
Genetic screening for vulnerability to neurotoxic effects of alcohol, caffeine, and other drugs causing involuntary movements.
Development of therapeutic interventions, including gene or protein replacement, based on MR-1 pathway variations for treating PDC and related episodic movement disorders.
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