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Matched Legal Cases: ['Application No. 18465', 'Application No. 04718885', 'art 1', 'Application No. 04718885', 'Application No. 07075566', 'Application No. 07075566', 'Application No. 2004200978', 'Application No. 01271383']

Patent US7989182 - Nucleic acid encoding SCN1A variant - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Advanced Patent Search | Sign inAdvanced Patent SearchPatentsA method of identifying a subject predisposed to a disorder associated with ion channel dysfunction, comprising ascertaining whether at least one of the genes encoding ion channel subunits in said subject has undergone a mutation event such that a cDNA derived from said subject has the sequence set forth...http://www.google.com/patents/US7989182?utm_source=gb-gplus-sharePatent US7989182 - Nucleic acid encoding SCN1A variantPublication numberUS7989182 B2Publication typeGrantApplication numberUS 12/696,769Publication dateAug 2, 2011Filing dateJan 29, 2010Priority dateJul 18, 2001Also published asCA2454073A1, CA2454073C, DE60222422D1, EP1407013A1, EP1407013A4, EP1407013B1, EP1852505A1, EP1852505B1, US20050074764, US20100136623, WO2003008574A1Publication number12696769, 696769, US 7989182 B2, US 7989182B2, US-B2-7989182, US7989182 B2, US7989182B2InventorsJohn Charles Mulley, Louise Anne Harkin, Leanne Michelle Dibbens, Robyn Heather Wallace, Hilary Anne Phillips, Sarah Elizabeth Heron, Samuel Frank Berkovic, Ingrid Eileen SchefferOriginal AssigneeBionomics LimitedPatent Citations (34), Non-Patent Citations (196), Classifications (51), Legal Events (1) External Links: USPTO, USPTO Assignment, EspacenetNucleic acid encoding SCN1A variantUS 7989182 B2Abstract A method of identifying a subject predisposed to a disorder associated with ion channel dysfunction, comprising ascertaining whether at least one of the genes encoding ion channel subunits in said subject has undergone a mutation event such that a cDNA derived from said subject has the sequence set forth in one of SEQ ID NOS: 1-134.
CROSS REFERENCE TO RELATED APPLICATIONS This application is a divisional application of U.S. patent application Ser. No. 10/482,834, filed Oct. 12, 2004 now abandoned, which claims the benefit of PCT International Patent Application Serial No. PCT/AU02/00910, filed Jul. 8, 2002, which claims the benefit of Australian Provisional Patent Application Serial No. PS 2292, filed May 13, 2002, Australian Provisional Patent Application Serial No. PS 0910, filed Mar. 5, 2002, and Australian Provisional Patent Application Serial No. PR 6452, filed Jul. 18, 2001, the disclosure of each of which is incorporated herein by reference in their entirety.
A genetic contribution to the aetiology of epilepsy has been estimated to be present in approximately 40% of affected individuals (Gardiner, 2000). As epileptic seizures may be the end-point of a number of molecular aberrations that ultimately disturb neuronal synchrony, the genetic basis for epilepsy is likely to be heterogeneous. There are over 200 Mendelian diseases which include epilepsy as part of the phenotype. In these diseases, seizures are symptomatic of underlying neurological involvement such as disturbances in brain structure or function. In contrast, there are also a number of �pure� epilepsy syndromes in which epilepsy is the sole manifestation in the affected individuals. These are termed idiopathic and account for over 60% of all epilepsy cases.
In addition, a host cell strain may be chosen for its ability to modulate is expression of the inserted sequences or to process the expressed protein in the desired fashion. Such modifications of the polypeptide include, but are not limited to, acetylation, glycosylation, phosphorylation, and acylation. Post-translational cleavage of a �prepro� form of the protein may also be used to specify protein targeting, folding, and/or activity. Different host cells having specific cellular machinery and characteristic mechanisms for post-translational activities (e.g., CHO or HeLa cells), are available from the American Type Culture Collection (ATCC) and may be chosen to ensure the correct modification and processing of the foreign protein.
The polypeptides of the present invention may also be used for screening compounds developed as a result of combinatorial library technology. This provides a way to test a large number of different substances for their ability to modulate activity of a polypeptide. A substance identified as a modulator of polypeptide function may be peptide or non-peptide in nature. Non-peptide �small molecules� are often preferred for many in vivo pharmaceutical applications. In addition, a mimic or mimetic of the substance may be designed for pharmaceutical use. The design of mimetics based on a known pharmaceutically active compound (�lead� compound) is a common approach to the development of novel pharmaceuticals. This is often desirable where the original active compound is difficult or expensive to synthesise or where it provides an unsuitable method of administration. In the design of a mimetic, particular parts of the original active compound that are important in determining the target property are identified. These parts or residues constituting the active region of the compound are known as its pharmacophore. Once found, the pharmacophore structure is modelled according to its physical properties using data from a range of sources including x-ray diffraction data and NMR. A template molecule is then selected onto which chemical groups which mimic the pharmacophore can be added. The selection can be made such that the mimetic is easy to synthesise, is likely to be pharmacologically acceptable, does not degrade in vivo and retains the biological activity of the lead compound. Further optimisation or modification can be carried out to select one or more final mimetics useful for in vivo or clinical testing.
MODES FOR PERFORMING THE INVENTION Potassium channels are the most diverse class of ion channel. The C. elegans genome encodes about 80 different potassium channel genes and there are probably more in mammals. About ten potassium channel genes are known to be mutated in human disease and include four members of the KCNQ gene sub-family of potassium channels. KCNQ proteins have six transmembrane domains, a single P-loop that forms the selectivity filter of the pore, a positively charged fourth transmembrane domain that probably acts as a voltage sensor and intracellular amino and carboxy termini. The C terminus is long and contains a conserved �A domain� followed by a short stretch thought to be involved in subunit assembly.
Example 1 Identification of Mutations in Ion Channels Previous studies by reference (Wallace et al., 1998; PCT/AU01/00581; Wallace et al., 2001b; Australian patent AU-B-56247/96; Steinlein et al., 1995; PCT/AU01/00541; Phillips et al., 2001; PCT/AU01/00729; PCT/AU01/01648; Wallace et al., 2001a, the disclosures of which are incorporated herein by reference) have identified mutations in a number of ion channel subunits associated with epilepsy. These include ion channel subunits of voltage-gated (eg SCN1A, SCN1B, KCNQ2, KCNQ3) or ligand-gated (eg CHRNA4, CHRNB2, GABRG2, GABRD) types. To identify further mutations in ion channel genes, subunits which comprise the ion channels were screened for molecular defects in epilepsy patients.
Example 4 Nicotinic Acetylcholine Receptor Mutations Outside M2 Domain Initially, a rare variant (I225S) of the CHRNA4 subunit (also referred to as I257S) originally identified by Phillips et al., 1998) was examined functionally. Sequence analysis of the I225S CHRNA4 protein reveals that this amino acid change lies within the putative M1 segment of the protein and therefore raises the question of its possible effects on the receptor physiological properties. To examine possible receptor modifications, expression experiments in Xenopus oocytes were designed. However, because it is known that all patients that carry this mutation are heterozygous all experiments were carried out by co-expression of equal amounts of the patient control and mutated cDNA. Amplitude of the ACh-evoked currents evoked by saturating agonist concentrations showed no significant difference between the control and heterozygous expression. A marked difference was, however, observed when examining the receptor sensitivity to acetylcholine (ACh). Mutant containing receptors display a greater response at low ACh concentrations than their control counterpart. As previous functional studies of the first CHRNA4 mutation (S248F, Phillips et al., 1995) showed an increased receptor desensitization, the time course of the response for the I225S mutation was thoroughly monitored. Results showed that the average time course of the ACh-evoked current was not significantly different from the control and thereby suggests a minimal effect of this M1 mutation on the receptor desensitization properties.
Example 5 Digenic Model Examples In some instances a single mutation in an ion channel alone is insufficient to give rise to an epilepsy phenotype. However combinations of mutations each conferring a subtle change of function to an ion channel, as proposed by the digenic model (PCT/AU01/00872), may be sufficient to produce an epilepsy phenotype.
The hypothesis that similar phenotypes can be caused by the combination of mutations in two (or more) different subunits (outbred communities), or by the same mutation in two (or more) alleles of the same subunit (inbred communities), may seem implausible. However, applying the digenic hypothesis to the theoretical pentameric channel shown in FIG. 1, in outbred communities IGE will be due to subunit combinations such as α*αβ*βΔ, α*α*ββΔ* or ααβ*βΔ* (mutated subunits indicated by *). In inbred communities α*α*ββΔ or ααβ*β*Δ combinations might cause IGE phenotypes. We assume that the mutations will not cause reduced expression of the alleles and that the altered ion channel excitability, and consequent IGE phenotype, caused by mutations in two different alleles is similar to that caused by the same mutation in both alleles of one subunit. Finally, subunit mutations with more severe functional consequences (eg breaking a disulphide bridge in SCN1B or amino acid substitution in the pore forming regions of SCN1A for GEFS+) cause autosomal dominant generalized epilepsies with a penetrance of 60-90%. Such �severe� mutations are rare (allele frequency <0.01%) and are infrequent causes of GEFS+. They very rarely, or perhaps never, cause classical IGE.
The relative separate segregation of classical IGE and GEFS+ phenotypes is an anecdotal clinical observation of ours (Singh et al., 1999), although the separation is not absolute. The separation is supported by previous family and EEG studies of Doose and colleagues who described �type A� and �type B� liabilities which we may approximate the GEFS+ and classical IGE groupings respectively (Doose and Baler, 1987).
Example 6 Analysis of Receptors and Receptor Subunits The following methods are used to determine the structure and function of the ion channels and ion channel subunits.
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Genet., vol. 66, pp. 1552-1557 (2000).* Cited by examinerClassifications U.S. Classification435/69.1, 435/252.3, 536/23.5, 536/24.3, 435/320.1, 435/71.1, 530/350International ClassificationG01N33/68, A01K67/02, C12N15/09, A61P25/18, A61P9/06, A61P21/02, C12Q1/02, C12P21/08, A61P29/02, C12Q1/68, C12P21/02, A61K45/00, G01N33/50, A61P25/24, A01K67/027, C07K16/28, C07K14/47, A61P25/06, C07H21/02, A61P25/22, A61K39/395, A61P25/28, C12N5/10, A61P3/12, A61K38/00, A61P43/00, C12N1/21, C07H21/04, A61P3/10, A61K31/711, C12N15/12, C12N15/00, C07K14/705, A61P25/14, C12N1/15, G01N33/15, A61P21/04, A61P25/02, A61P25/16, A61P25/08, C12N1/19, A61K48/00Cooperative ClassificationC12Q1/6883European ClassificationC12Q1/68M6Legal EventsDateCodeEventDescriptionFeb 2, 2010ASAssignmentFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MULLEY, JOHN CHARLES;HARKIN, LOUISE ANNE;DIBBENS, LEANNEMICHELLE AND OTHERS;SIGNED BETWEEN 20031009 AND 20040128;REEL/FRAME:23888/561Owner name: BIONOMICS LIMITED,AUSTRALIAFree format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:MULLEY, JOHN CHARLES;HARKIN, LOUISE ANNE;DIBBENS, LEANNEMICHELLE;AND OTHERS;SIGNING DATES FROM 20031009 TO 20040128;REEL/FRAME:023888/0561Owner name: BIONOMICS LIMITED, AUSTRALIARotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google