title: Autosomal dominant lateral temporal epilepsy: absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins.
abstract: Mutations in the LGI1 gene are linked to autosomal dominant lateral temporal epilepsy (ADTLE) in about half of the families tested, suggesting that ADLTE is genetically heterogeneous. Recently, the Lgi1 protein has been found associated with different protein complexes and two distinct molecular mechanisms possibly underlying ADLTE have been hypothesized: the one recognizes Lgi1 as a novel subunit of the presynaptic Kv1 potassium channel implicated in the regulation of channel inactivation, the other suggests that Lgi1 acts as a ligand that selectively binds to the postsynaptic receptor ADAM22, thereby regulating the glutamate-AMPA neurotransmission. Both mechanisms imply that LGI1 mutations result in alteration of synaptic currents, though of different types. Since their protein products have been found associated with Lgi1, the Kv1 channel subunit genes KCNA1, KCNA4, and KCNAB1 and ADAM22 can be considered strong candidates for ADLTE. We sequenced their coding exons and flanking splice sites in the probands of 9 carefully ascertained ADLTE families negative for LGI1 mutations. We failed to detect any mutation segregating with the disease, but identified several previously unreported polymorphisms. An association study of four non-synonymous variants (three found in ADAM22, one in KCNA4) in a population of 104 non-familial lateral temporal epilepsy cases did not show any modification of susceptibility to this disorder. Altogether, our results suggest that neither ADAM22 nor any of the three Kv1 channel genes are major causative genes for ADLTE.
authors.affiliation: CNR-Institute of Neurosciences, Section of Padua, Padova, Italy.
authors.forename: Erica
authors.initials: E
authors.lastname: Diani
authors.forename: Carlo
authors.initials: C
authors.lastname: Di Bonaventura
authors.forename: Oriano
authors.initials: O
authors.lastname: Mecarelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Gambardella
authors.forename: Maurizio
authors.initials: M
authors.lastname: Elia
authors.forename: Giorgia
authors.initials: G
authors.lastname: Bovo
authors.forename: Francesca
authors.initials: F
authors.lastname: Bisulli
authors.forename: Federica
authors.initials: F
authors.lastname: Pinardi
authors.forename: Simona
authors.initials: S
authors.lastname: Binelli
authors.forename: Gabriella
authors.initials: G
authors.lastname: Egeo
authors.forename: Barbara
authors.initials: B
authors.lastname: Castellotti
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.forename: Salvatore
authors.initials: S
authors.lastname: Striano
authors.forename: Amedeo
authors.initials: A
authors.lastname: Bianchi
authors.forename: Edoardo
authors.initials: E
authors.lastname: Ferlazzo
authors.forename: Valeria
authors.initials: V
authors.lastname: Vianello
authors.forename: Giangennaro
authors.initials: G
authors.lastname: Coppola
authors.forename: Umberto
authors.initials: U
authors.lastname: Aguglia
authors.forename: Paolo
authors.initials: P
authors.lastname: Tinuper
authors.forename: Anna T
authors.initials: AT
authors.lastname: Giallonardo
authors.forename: Roberto
authors.initials: R
authors.lastname: Michelucci
authors.forename: Carlo
authors.initials: C
authors.lastname: Nobile
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D004833:Epilepsy, Temporal Lobe / Q000235:genetics*; D005192:Family Health; D005260:Female; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D012150:Polymorphism, Restriction Fragment Length; D011506:Proteins / Q000235:genetics; D051637:Shaker Superfamily of Potassium Channels / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D009419:Nerve Tissue Proteins; D011506:Proteins; D051637:Shaker Superfamily of Potassium Channels; D051722:ADAM Proteins; C498474:ADAM22 protein, human