Sodium-channel alpha1-subunit and their polypeptides and their treatment of generalised epilepsy with febrile seizures plus
AssigneeBionomics Limited
InventorsRobyn Heather Wallace, John Charles Mulley, Samuel Frank Berkovic
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Abstract
The mutations D188V, V1353L, I1656M in the neuronal gene sodium-channel alpha1-subunit, SCN1A, are disclosed. The methods of using their associated polypeptides for treating sodium channel dysfunction disorders including generalised epilepsy are also disclosed.
Claims75
An isolated nucleic acid molecule encoding a mutant alpha subunit of a mammalian voltage-gated sodium channel, 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 sodium channel so as to produce an epilepsy phenotype, with the proviso that the mutation event is not a C2624T transition or a G4943A transition in an alpha-1 subunit.
An isolated nucleic acid molecule encoding a mutant alpha subunit of a mammalian voltage-gated sodium channel, wherein a mutation event selected from the group consisting of point mutations, deletions, insertions and rearrangements has occurred in an intracellular loop, in the S4 segment of domain IV at nucleotide position 4968 of the alpha-1 subunit coding sequence or homologous nucleotide position in the coding sequence of other alpha subunits, or in an S5 segment of a transmembrane domain so as to produce an epilepsy phenotype.
An isolated nucleic acid molecule consisting of the nucleotide sequence set forth in SEQ ID NO:1.
An isolated nucleic acid molecule consisting of the nucleotide sequence set forth in SEQ ID NO:3.
An isolated nucleic acid molecule consisting of the nucleotide sequence set forth in SEQ ID NO:5.
An isolated nucleic acid molecule selected from the group consisting of DNA molecules comprising the nucleotide sequence set forth in any one of SEQ ID NO:7, 8, 9, 11 and 89.
An isolated polypeptide, said polypeptide being a mutant alpha subunit of a mammalian voltage-gated sodium channel, wherein a mutation event selected from the group consisting of substitutions, deletions, insertions and rearrangements has occurred and said mutation event disrupts the functioning of an assembled sodium channel so as to produce an epilepsy phenotype, with the proviso that the mutation event is not a T875M transition or a R1648H transition in an alpha-1 subunit.
An isolated polypeptide, said polypeptide being a mutant α-subunit of a mammalian voltage-gated sodium channel, wherein a mutation event selected from the group of substitutions, deletions, insertions and rearrangements has occurred in an intracellular loop, in the S4 segment of domain IV at amino acid position 1656 of the alpha-1 subunit or homologous amino acid position of other alpha subunits, or in an S5 segment of a transmembrane domain.
An isolated polypeptide having the amino acid sequence set forth in SEQ ID NO:2.
An isolated polypeptide having the amino acid sequence set forth in SEQ ID NO:4.
An isolated polypeptide having the amino acid sequence set forth in SEQ ID NO:6.
An isolated polypeptide selected from the group consisting of polypeptides with the amino acid sequence set forth in SEQ ID NO:10 or SEQ ID NO:12.
Dependencies are inferred from the claim text.