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. (C) 2008 Elsevier B.V. All rights reserved.

Autosomal dominant lateral temporal epilepsy: Absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins / Erica, Diani; Carlo Di, Bonaventura; Mecarelli, Oriano; Antonio, Gambardella; Maurizio, Elia; Giorgia, Bovo; Francesca, Bisulli; Federica, Pinardi; Simona, Binelli; Gabriella, Egeo; Barbara, Castellotti; Pasquale, Striano; Salvatore, Striano; Amedeo, Bianchi; Edoardo, Ferlazzo; Valeria, Vianello; Giangennaro, Coppola; Umberto, Aguglia; Paolo, Tinuper; Giallonardo, Anna Teresa; Roberto, Michelucci; Carlo, Nobile. - In: EPILEPSY RESEARCH. - ISSN 0920-1211. - 80:1(2008), pp. 1-8. [10.1016/j.eplepsyres.2008.03.001]

Autosomal dominant lateral temporal epilepsy: Absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins

MECARELLI, Oriano;GIALLONARDO, Anna Teresa;
2008

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. (C) 2008 Elsevier B.V. All rights reserved.
adam22 receptor; association studies; autosomal dominant lateral temporal epilepsy; genetics; kv1 channel; lgi1
01 Pubblicazione su rivista::01a Articolo in rivista
Autosomal dominant lateral temporal epilepsy: Absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins / Erica, Diani; Carlo Di, Bonaventura; Mecarelli, Oriano; Antonio, Gambardella; Maurizio, Elia; Giorgia, Bovo; Francesca, Bisulli; Federica, Pinardi; Simona, Binelli; Gabriella, Egeo; Barbara, Castellotti; Pasquale, Striano; Salvatore, Striano; Amedeo, Bianchi; Edoardo, Ferlazzo; Valeria, Vianello; Giangennaro, Coppola; Umberto, Aguglia; Paolo, Tinuper; Giallonardo, Anna Teresa; Roberto, Michelucci; Carlo, Nobile. - In: EPILEPSY RESEARCH. - ISSN 0920-1211. - 80:1(2008), pp. 1-8. [10.1016/j.eplepsyres.2008.03.001]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/230819
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