A common protein interaction domain links two recently identified epilepsy genes

Hum Mol Genet. 2002 Jul 15;11(15):1757-62. doi: 10.1093/hmg/11.15.1757.


Until recently, all genes found to be mutated in hereditary idiopathic epilepsies encoded subunits of ion channels, leading to the view of this class of diseases as channelopathies. Two apparent exceptions to this rule are the MASS1 gene, which is mutated in the Frings mouse model of audiogenic epilepsy, and the LGI1 gene, which is mutated in autosomal dominant partial epilepsy with auditory features (ADPEAF). Careful sequence analysis of the two protein products encoded by those genes shows a common feature: both sequences harbour a novel homology domain consisting of a 7-fold repeated 44-residue motif. The architecture and structural features of this new domain make it a likely member of the growing class of protein interaction domains with a seven-bladed beta-propeller fold. In the MASS1 gene product, which has recently been shown to be a fragment of the very large G-protein-coupled receptor VLGR1, this EAR domain (for epilepsy-associated repeat) is part of the ligand-binding ectodomain. LGI1, as well as a number of newly identified LGI1 relatives, is predicted to be a secreted protein, and consists of an N-terminal leucine-rich repeat region and a C-terminal EAR region. The known portion of the human genome encodes six EAR proteins, some of which map to chromosome regions associated with seizure disorders. The EAR domain is likely to play an important role in the pathogenesis of epilepsy, either by binding to an unknown anti-epileptic ligand, or more likely by interfering with axon guidance or synaptogenesis.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Epilepsy / genetics*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice
  • Molecular Sequence Data
  • Nerve Tissue Proteins / genetics*
  • Nerve Tissue Proteins / metabolism
  • Protein Structure, Tertiary
  • Proteins / genetics*
  • Proteins / metabolism
  • Receptors, G-Protein-Coupled*
  • Sequence Alignment
  • Sequence Homology*


  • ADGRV1 protein, human
  • Intracellular Signaling Peptides and Proteins
  • LGI1 protein, human
  • Lgi1 protein, mouse
  • Mass1 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Proteins
  • Receptors, G-Protein-Coupled