A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice.
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.
Boumil
Rebecca M
RM
The Jackson Laboratory, Bar Harbor, Maine, USA. rebecca.boumil@jax.org
Letts
Verity A
VA
Roberts
Monica C
MC
Lenz
Christine
C
Mahaffey
Connie L
CL
Zhang
Zhong-Wei
ZW
Moser
Tobias
T
Frankel
Wayne N
WN
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
D020033:Protein Isoforms; D034284:Dynamin I