TY - JOUR
T1 - Autosomal dominant lateral temporal epilepsy
T2 - Absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins
AU - Diani, Erica
AU - Di Bonaventura, Carlo
AU - Mecarelli, Oriano
AU - Gambardella, Antonio
AU - Elia, Maurizio
AU - Bovo, Giorgia
AU - Bisulli, Francesca
AU - Pinardi, Federica
AU - Binelli, Simona
AU - Egeo, Gabriella
AU - Castellotti, Barbara
AU - Striano, Pasquale
AU - Striano, Salvatore
AU - Bianchi, Amedeo
AU - Ferlazzo, Edoardo
AU - Vianello, Valeria
AU - Coppola, Giangennaro
AU - Aguglia, Umberto
AU - Tinuper, Paolo
AU - Giallonardo, Anna T.
AU - Michelucci, Roberto
AU - Nobile, Carlo
PY - 2008/7
Y1 - 2008/7
N2 - 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.
AB - 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.
KW - ADAM22 receptor
KW - Association studies
KW - Autosomal dominant lateral temporal epilepsy
KW - Genetics
KW - Kv1 channel
KW - LGI1
UR - http://www.scopus.com/inward/record.url?scp=44749086359&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=44749086359&partnerID=8YFLogxK
U2 - 10.1016/j.eplepsyres.2008.03.001
DO - 10.1016/j.eplepsyres.2008.03.001
M3 - Article
C2 - 18440780
AN - SCOPUS:44749086359
VL - 80
SP - 1
EP - 8
JO - Epilepsy Research
JF - Epilepsy Research
SN - 0920-1211
IS - 1
ER -