title: 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.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA. rebecca.boumil@jax.org
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Boumil
authors.forename: Verity A
authors.initials: VA
authors.lastname: Letts
authors.forename: Monica C
authors.initials: MC
authors.lastname: Roberts
authors.forename: Christine
authors.initials: C
authors.lastname: Lenz
authors.forename: Connie L
authors.initials: CL
authors.lastname: Mahaffey
authors.forename: Zhong-Wei
authors.initials: ZW
authors.lastname: Zhang
authors.forename: Tobias
authors.initials: T
authors.lastname: Moser
authors.forename: Wayne N
authors.initials: WN
authors.lastname: Frankel
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D017124:Conserved Sequence; D004195:Disease Models, Animal; D034284:Dynamin I / Q000235:genetics* / Q000378:metabolism; D004827:Epilepsy / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D005091:Exons; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D009435:Synaptic Transmission
chemical_list: D020033:Protein Isoforms; D034284:Dynamin I