title: Similarity of molecular phenotype between known epilepsy gene LGI1 and disease candidate gene LGI2.
abstract: BACKGROUND
  The LGI2 (leucine-rich, glioma inactivated 2) gene, a prime candidate for partial epilepsy with pericentral spikes, belongs to a family encoding secreted, beta-propeller domain proteins with EPTP/EAR epilepsy-associated repeats. In another family member, LGI1 (leucine-rich, glioma inactivated 1) mutations are responsible for autosomal dominant lateral temporal epilepsy (ADLTE). Because a few LGI1 disease mutations described in the literature cause secretion failure, we experimentally analyzed the secretion efficiency and subcellular localization of several LGI1 and LGI2 mutant proteins corresponding to observed non-synonymous single nucleotide polymorphisms (nsSNPs) affecting the signal peptide, the leucine-rich repeats and the EAR propeller.
  
  
  RESULTS
  Mapping of disease-causing mutations in the EAR domain region onto a 3D-structure model shows that many of these mutations co-localize at an evolutionary conserved surface region of the propeller. We find that wild-type LGI2 is secreted to the extracellular medium in glycosylated form similarly to LGI1, whereas several mutant proteins tested in this study are secretion-deficient and accumulate in the endoplasmic reticulum. Interestingly, mutations at structurally homologous positions in the EAR domain have the same effect on secretion in LGI1 and LGI2.
  
  
  CONCLUSIONS
  This similarity of experimental mislocalization phenotypes for mutations at homologous positions of LGI2 and the established epilepsy gene LGI1 suggests that both genes share a potentially common molecular pathogenesis mechanism that might be the reason for genotypically distinct but phenotypically related forms of epilepsy.
authors.affiliation: Bioinformatics Institute, Agency for Science, Technology and Research, 30 Biopolis Street, #07-01 Matrix, 138671 Singapore. sharmilaa@bii.a-star.edu.sg
authors.forename: Vachiranee
authors.initials: V
authors.lastname: Limviphuvadh
authors.forename: Ling Ling
authors.initials: LL
authors.lastname: Chua
authors.forename: Rabi Atul Adawiyah Bte
authors.initials: RA
authors.lastname: Rahim
authors.forename: Frank
authors.initials: F
authors.lastname: Eisenhaber
authors.forename: Sebastian
authors.initials: S
authors.lastname: Maurer-Stroh
authors.forename: Sharmila
authors.initials: S
authors.lastname: Adhikari
mesh_terms: D004828:Epilepsies, Partial / Q000235:genetics*; D004833:Epilepsy, Temporal Lobe / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020125:Mutation, Missense; D010641:Phenotype; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000145:classification / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; C456923:LGI2 protein, human; D011506:Proteins