A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice.

Abstract	Dynamin-1 (Dnm1) encodes a large multimeric GTPase necessary for activity-dependent membrane recycling in neurons, including synaptic vesicle endocytosis. Mice heterozygous for a novel spontaneous Dnm1 mutation--fitful--experience recurrent seizures, and homozygotes have more debilitating, often lethal seizures in addition to severe ataxia and neurosensory deficits. Fitful is a missense mutation in an exon that defines the DNM1a isoform, leaving intact the alternatively spliced exon that encodes DNM1b. The expression of the corresponding alternate transcripts is developmentally regulated, with DNM1b expression highest during early neuronal development and DNM1a expression increasing postnatally with synaptic maturation. Mutant DNM1a does not efficiently self-assemble into higher order complexes known to be necessary for proper dynamin function, and it also interferes with endocytic recycling in cell culture. In mice, the mutation results in defective synaptic transmission characterized by a slower recovery from depression after trains of stimulation. The DNM1a and DNM1b isoform pair is highly conserved in vertebrate evolution, whereas invertebrates have only one isoform. We speculate that the emergence of more specialized forms of DNM1 may be important in organisms with complex neuronal function.
Authors	Rebecca M Boumil, Verity A Letts, Monica C Roberts, Christine Lenz, Connie L Mahaffey, Zhong-Wei Zhang, Tobias Moser, Wayne N Frankel
Journal	PLoS genetics (PLoS Genet) Vol. 6 Issue 8 (Aug 05 2010) ISSN: 1553-7404 [Electronic] United States
PMID	20700442 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References	Protein Isoforms Dynamin I
Topics	Alternative Splicing Amino Acid Sequence Animals Cell Line Conserved Sequence Disease Models, Animal Dynamin I (genetics, metabolism) Epilepsy (genetics, metabolism, physiopathology) Exons Female Humans Male Mice Mice, Inbred C57BL Molecular Sequence Data Mutation, Missense Protein Isoforms (genetics, metabolism) Sequence Alignment Synaptic Transmission

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