TBC1D24, an ARF6-interacting protein, is mutated in familial infantile myoclonic epilepsy

Am J Hum Genet. 2010 Sep 10;87(3):365-70. doi: 10.1016/j.ajhg.2010.07.020. Epub 2010 Aug 19.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-Ribosylation Factors / metabolism*
  • Animals
  • Base Sequence
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism*
  • DNA Mutational Analysis
  • Epilepsies, Myoclonic / genetics*
  • Family
  • Female
  • GTPase-Activating Proteins / genetics*
  • GTPase-Activating Proteins / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Male
  • Membrane Proteins
  • Mice
  • Molecular Sequence Data
  • Mutant Proteins / genetics
  • Mutant Proteins / metabolism
  • Mutation / genetics*
  • Nerve Tissue Proteins
  • Pedigree
  • Protein Binding

Substances

  • Carrier Proteins
  • GTPase-Activating Proteins
  • Membrane Proteins
  • Mutant Proteins
  • Nerve Tissue Proteins
  • TBC1D24 protein, human
  • Tbc1d24 protein, mouse
  • ADP-Ribosylation Factors
  • ADP-ribosylation factor 6