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Mutation associated with epilepsy

a technology of mutation and epilepsy, applied in the field of mutation associated with epilepsy, can solve the problems of varying degrees of involuntary muscle contraction, loss of consciousness, persistent increase in neuronal excitability, etc., to reduce the density of functional gabaa receptors, increase neuronal excitability and seizures, and reduce inhibitory responses to gaba

Inactive Publication Date: 2006-04-27
WALLACE ROBYN +4
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0021] Without wishing to be bound by theory, this dominant-negative effect is most likely due to a reduction in the density of functional GABAA receptors leading to decreased inhibitory responses to GABA, thereby increasing neuronal excitability and seizures.
[0129] Also optionally, activity of the subject's functional receptors can be increased. In this embodiment, a wild-type GABAA receptor or a GABAA receptor subunit is introduced by gene therapy.

Problems solved by technology

This results in varying degrees of involuntary muscle contraction and often a loss of consciousness.
However the single feature that is common to all syndromes is the persistent increase in neuronal excitability that is both occasionally and unpredictably expressed as a seizure.
GEFS+ was initially difficult to recognise as a distinct syndrome due to clinical heterogeneity within each affected family.
This genetic heterogeneity, coupled with the phenotypic heterogeneity and incomplete penetrance, has impeded attempts to identify the genes involved.

Method used

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Examples

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example 2

Genotyping and Linkage Analysis

[0153] Automated genotyping of DNA samples obtained from Family 1 was carried out by the Australian Genome Research Facility. A genome-wide scan of 400 markers spread at an average genetic distance of 10 cM was performed. For the linkage analysis, all individuals with febrile seizures (FS), febrile seizures plus (FS+) or childhood absence epilepsy (CAE) were considered affected. Those individuals with unclassified epilepsy or abnormal electroencephalograms were assigned an unknown affection status. Lod scores were determined using FASTLINK v4.0P (Lathrop and Lalouel, 1984). Two point lod scores were calculated assuming autosomal dominant inheritance, 75% penetrance, a disease allele frequency of 0.0001 and equal marker allele frequencies.

[0154] Additional microsatellite markers from chromosome 5 were manually genotyped as previously described by Phillips et al (1995). Briefly, PCR amplification was carried out on 100 ng of genomic DNA using [α-32P]dC...

example 3

Mutation Analysis of GABRG2 in Family 1

[0157] SSCP analysis of GABRG2 exons followed by sequencing of SSCP bandshifts was performed on individuals from Family 1 to identify disease causing mutations. The primers used to analyse Family 1 are shown in Table 2. The sequences of these primers are represented by SEQ ID Numbers:7-24.

[0158] PCR reactions using exon specific primers contained 67 mM Tris-HCl (pH 8.8); 16.5 mM (NH4)2SO4; 6.5 μM EDTA; 1.5 mM MgCl2; 200 μM each DNTP; 10% DMSO; 0.17 mg / ml BSA; 10 mM β-mercaptoethanol; 15 μg / ml each primer; 200 μCi / ml [α-32P]dCTP; 100 U / ml Taq DNA polymerase, and 10 μg / ml genomic DNA. PCR reactions were performed using 10 cycles of 94° C. for 60 seconds, 60° C. for 90 seconds, and 72° C. for 90 seconds followed by 25 cycles of 94° C. for 60 seconds, 55° C. for 90 seconds, and 72° C. for 90 seconds. A final extension reaction for 10 minutes at 72° C. followed. Completed PCR reactions were subsequently mixed with an equal volume of formamide load...

example 4

Mutation Analysis of GABRG2 in Family 2

[0161] SSCP analysis of GABRG2 exons followed by sequencing of SSCP bandshifts was performed on individuals from Family 2 to identify disease causing mutations. The primers used to analyse Family 2 are shown in Table 3. The sequences of these primers are represented by SEQ ID Numbers:7-17, 19-24 and 25-29.

[0162] For the analysis of this family primers used for SSCP were labelled at their 5′ end with HEX. Typical PCR reactions were performed in a total volume of 10 μl using 30 ng of patient DNA. All PCR reactions contained 67 mM Tris-HCl (pH 8.8); 16.5 mM (NH4)2SO4; 6.5 μM EDTA; 1.5 mM MgCl2; 200 μM each dNTP; 10% DMSO; 0.17 mg / ml BSA; 10 mM β-mercaptoethanol; 5 μg / ml each primer and 100 U / ml Taq DNA polymerase. PCR reactions were performed using 10 cycles of 94° C. for 30 seconds, 60° C. for 30 seconds, and 72° C. for 30 seconds followed by 25 cycles of 94° C. for 30 seconds, 55° C. for 30 seconds, and 72° C. for 30 seconds. A final extension...

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Abstract

An isolated mammalian DNA molecule encoding a mutant γ-aminobutyric acid type A (GABAA) receptor subunit, wherein a mutation event selected from the group consisting of point mutations, deletions, insertions and rearrangements has occurred and said mutation event disrupts the functioning of an assembled GABAA receptor, or an otherwise functional fragment or homologue thereof.

Description

RELATED APPLICATIONS [0001] This application is a divisional patent application which claims the benefit of the filing date of U.S. patent application Ser. No. 10 / 312,184, filed Dec. 20, 2002, which claims benefit to PCT International Patent Application Serial No. PCT / AU01 / 00729, filed Jun. 20, 2001, the disclosures of which are incorporated herein by reference in their entirety.TECHNICAL FIELD [0002] The present invention is concerned with a mutation associated with epilepsy. BACKGROUND ART [0003] Epilepsies constitute a diverse collection of brain disorders that affect about 3% of the population at some time in their lives (Annegers, 1996). An epileptic seizure can be defined as an episodic change in behaviour caused by the disordered firing of populations of neurons in the central nervous system. This results in varying degrees of involuntary muscle contraction and often a loss of consciousness. Epilepsy syndromes have been classified into more than 40 distinct types based upon c...

Claims

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Application Information

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IPC IPC(8): C07K14/705C07H21/04C12P21/06A01K67/027A61K31/5513A61K38/00A61K39/395A61K45/00A61K48/00A61P3/04A61P25/06A61P25/08A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P43/00C07K16/28C12N1/15C12N1/19C12N1/21C12N5/10C12N15/09C12N15/12C12P21/02C12P21/08C12Q1/02C12Q1/44C12Q1/68G01N33/15G01N33/48G01N33/50G01N37/00
CPCA01K2217/00A01K2217/05C07K14/70571C07K16/286C12Q1/6883G01N33/6896G01N2800/2857C12Q2600/156A61P25/06A61P25/08A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P3/04A61P43/00
Inventor WALLACE, ROBYNMULLEY, JOHNBERKOVIC, SAMUELHARKIN, LOUISEDIBBENS, LEANNE
Owner WALLACE ROBYN
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