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 let...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-08-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC2916854?pdf=render |
| _version_ | 1819094828854542336 |
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| author | Rebecca M Boumil Verity A Letts Monica C Roberts Christine Lenz Connie L Mahaffey Zhong-Wei Zhang Tobias Moser Wayne N Frankel |
| author_facet | Rebecca M Boumil Verity A Letts Monica C Roberts Christine Lenz Connie L Mahaffey Zhong-Wei Zhang Tobias Moser Wayne N Frankel |
| author_sort | Rebecca M Boumil |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T23:33:37Z |
| format | Article |
| id | doaj.art-f8148b7982534ebeb974caae44237bc6 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-12-21T23:33:37Z |
| publishDate | 2010-08-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj.art-f8148b7982534ebeb974caae44237bc62022-12-21T18:46:25ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042010-08-016810.1371/journal.pgen.1001046A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice.Rebecca M BoumilVerity A LettsMonica C RobertsChristine LenzConnie L MahaffeyZhong-Wei ZhangTobias MoserWayne N FrankelDynamin-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.http://europepmc.org/articles/PMC2916854?pdf=render |
| spellingShingle | Rebecca M Boumil Verity A Letts Monica C Roberts Christine Lenz Connie L Mahaffey Zhong-Wei Zhang Tobias Moser Wayne N Frankel A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. PLoS Genetics |
| title | A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. |
| title_full | A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. |
| title_fullStr | A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. |
| title_full_unstemmed | A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. |
| title_short | A missense mutation in a highly conserved alternate exon of dynamin-1 causes epilepsy in fitful mice. |
| title_sort | missense mutation in a highly conserved alternate exon of dynamin 1 causes epilepsy in fitful mice |
| url | http://europepmc.org/articles/PMC2916854?pdf=render |
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