TBC1D24, an ARF6-Interacting Protein, Is Mutated in Familial Infantile Myoclonic Epilepsy
| Autor: | Veronica La Padula, Franca Dagna Bricarelli, Fabia Filipello, Federico Zara, Fabio Benfenati, Fabrizio A. de Falco, Carlo Minetti, Antonio Falace, Davide De Pietri Tonelli, Pasquale Striano, Francesca Madia, Nicola Vanni, Anna Fassio |
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| Rok vydání: | 2010 |
| Předmět: |
Male
DNA Mutational Analysis Molecular Sequence Data ADP-Ribosylation Factors Animals Base Sequence Carrier Proteins DNA Mutational Analysis Epilepsies Myoclonic Family Female Gene Expression Profiling Gene Expression Regulation GTPase-Activating Proteins Humans Male Mice Molecular Sequence Data Mutant Proteins Mutation Pedigree Protein Binding Epilepsies Myoclonic Nerve Tissue Proteins Locus (genetics) Epilepsies Biology Compound heterozygosity Mice Epilepsy Genetic linkage Report Genetics medicine Animals Humans Missense mutation Family Genetics(clinical) Allele Gene Genetics (clinical) Base Sequence ADP-Ribosylation Factors Gene Expression Profiling GTPase-Activating Proteins Membrane Proteins medicine.disease Penetrance Pedigree Gene Expression Regulation ADP-Ribosylation Factor 6 Mutation Female Mutant Proteins Carrier Proteins Myoclonic Protein Binding |
| Zdroj: | The American Journal of Human Genetics. 87:365-370 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2010.07.020 |
| Popis: | Idiopathic epilepsies (IEs) are a group of disorders characterized by recurrent seizures in the absence of detectable brain lesions or metabolic abnormalities. IEs include common disorders with a complex mode of inheritance and rare Mendelian traits suggesting the occurrence of several alleles with variable penetrance. We previously described a large family with a recessive form of idiopathic epilepsy, named familial infantile myoclonic epilepsy (FIME), and mapped the disease locus on chromosome 16p13.3 by linkage analysis. In the present study, we found that two compound heterozygous missense mutations (D147H and A509V) in TBC1D24, a gene of unknown function, are responsible for FIME. In situ hybridization analysis revealed that Tbc1d24 is mainly expressed at the level of the cerebral cortex and the hippocampus. By coimmunoprecipitation assay we found that TBC1D24 binds ARF6, a Ras-related family of small GTPases regulating exo-endocytosis dynamics. The main recognized function of ARF6 in the nervous system is the regulation of dendritic branching, spine formation, and axonal extension. TBC1D24 overexpression resulted in a significant increase in neurite length and arborization and the FIME mutations significantly reverted this phenotype. In this study we identified a gene mutation involved in autosomal-recessive idiopathic epilepsy, unveiled the involvement of ARF6-dependent molecular pathway in brain hyperexcitability and seizures, and confirmed the emerging role of subtle cytoarchitectural alterations in the etiology of this group of common epileptic disorders. |
| Databáze: | OpenAIRE |
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