Using polymorphic variation in nuclear interacting partner of anaplastic lymphoma kinase (NIPA) gene as diagnostic indicator of hereditary nervous system disorders; paralysis
Inventors
Fink, John K. • Rainier, Shirley • Nicholls, Robert D. • Chai, Jinghua
Assignees
University of Pennsylvania Penn • US Department of Veterans Affairs
Publication Number
US-8518638-B2
Publication Date
2013-08-27
Expiration Date
2024-08-19
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Abstract
The present invention relates to the NIPA-1 proteins and nucleic acids encoding the NIPA-1 proteins. The present invention further provides assays for the detection of NIPA-1 polymorphisms and mutations associated with disease states, as well as methods of screening for ligands and modulators of NIPA-1 proteins.
Core Innovation
The invention relates to the NIPA-1 proteins and nucleic acids encoding these proteins. It provides assays for detecting polymorphisms and mutations in the NIPA-1 gene associated with disease states, particularly hereditary nervous system disorders such as hereditary spastic paraplegia (HSP). The invention also covers methods for screening for therapeutic agents, ligands, and modulators of NIPA-1 proteins.
The background highlights that hereditary spastic paraplegia is a group of clinically and genetically diverse disorders characterized by progressive lower extremity spasticity and weakness, often leading to gait disturbances and urinary bladder issues. There is variability in symptom onset and progression, and currently, no specific treatment exists to prevent or reverse HSP progression. The molecular pathogenesis of HSP is poorly understood, and there is a need for treatments that can reduce and prevent symptoms as well as a better understanding of the molecular mechanisms involved.
The invention addresses the unmet need to detect and characterize polymorphisms and mutations in the NIPA-1 gene that are linked to hereditary spastic paraplegia. It provides isolated nucleic acid sequences encoding wild-type and variant NIPA-1 proteins, compositions comprising these nucleic acids and polypeptides, and methods to reduce NIPA-1 activity, including RNA interference approaches. It also includes diagnostic methods for detecting NIPA-1 polymorphisms linked to disease states, as well as methods for screening compounds modifying NIPA-1 activity, and gene therapy approaches for treating or preventing symptoms of hereditary spastic paraplegia.
Claims Coverage
The patent includes eight main inventive features extracted from independent claims that cover compositions and methods related to NIPA-1 nucleic acids, proteins, and diagnostic assays for hereditary spastic paraplegia.
Isolated nucleic acid molecule highly identical to SEQ ID NO: 6
The invention provides a composition comprising an isolated nucleic acid molecule that has at least 90% (preferably 95%) sequence identity to SEQ ID NO: 6, including the exact SEQ ID NO: 6 sequence.
Nucleic acid sequences encoding specific NIPA-1 proteins
Compositions comprising isolated and purified nucleic acid sequences encoding NIPA-1 proteins having the amino acid sequences of SEQ ID NO: 3 or SEQ ID NO: 4.
Compositions comprising NIPA-1 nucleic acid molecules
Compositions comprising nucleic acid molecules of SEQ ID NOs: 1, 2, or 5.
Method for detecting polymorphisms in NIPA-1 nucleic acids
A method to detect the presence or absence of polymorphisms in a NIPA-1 nucleic acid from a test sample by sequencing the nucleic acid, comparing to a control nucleic acid sequence (e.g., SEQ ID NO: 5), determining differences, and identifying the polymorphism. This includes detection in DNA or RNA, and specifically detecting a C to G substitution at position 159 in SEQ ID NO: 5.
Method for identifying individuals having or at risk for hereditary spastic paraplegia
A method comprising obtaining a biological sample from the individual, assaying for the presence of a G at position 159 of SEQ ID NO: 5 in NIPA-1 nucleic acid, and identifying the individual as having or being at risk of HSP if the substitution is detected.
Detection of mutations resulting in amino acid substitution T to R in NIPA-1 protein
A method for diagnosing HSP wherein a mutation in NIPA-1 nucleic acid that results in threonine to arginine substitution at position 45 of SEQ ID NO: 3 or position 53 of SEQ ID NO: 7 is detected. This mutation can be a C to G substitution at position 134 of SEQ ID NO: 1 or at position 159 of SEQ ID NO: 5, determined by direct sequencing or other applicable methods.
The claims primarily cover compositions of isolated nucleic acid molecules and proteins corresponding to NIPA-1 wild-type and variants, along with methods for detecting specific polymorphisms and mutations in the NIPA-1 gene associated with hereditary spastic paraplegia, for diagnosis and risk identification of the disease.
Stated Advantages
Provides the ability to diagnose hereditary spastic paraplegia by detecting mutations in the NIPA-1 gene.
Enables genetic counseling and early intervention based on identification of disease-associated NIPA-1 alleles.
Offers targets for therapeutic intervention including screening for ligands and modulators of NIPA-1 proteins, potentially leading to treatments for spastic paraplegia.
Documented Applications
Detection of NIPA-1 gene polymorphisms and mutations as diagnostic indicators of hereditary nervous system disorders, specifically hereditary spastic paraplegia.
Screening for therapeutic agents, ligands, and modulators of NIPA-1 proteins for treatment of hereditary spastic paraplegia and related neurological disorders.
RNA interference-based methods to reduce NIPA-1 activity to treat or prevent symptoms of hereditary spastic paraplegia.
Use of transgenic animals expressing NIPA-1 variants for research and drug screening related to neurological disorders.
Methods and kits for genetic testing to identify individuals at risk of hereditary spastic paraplegia by detecting specific mutations in NIPA-1.
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