Autosomal dominant lateral temporal epilepsy: absence of mutations in ADAM22 and Kv1 channel genes encoding LGI1-associated proteins.
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.
Diani
Erica
E
CNR-Institute of Neurosciences, Section of Padua, Padova, Italy.
Di Bonaventura
Carlo
C
Mecarelli
Oriano
O
Gambardella
Antonio
A
Elia
Maurizio
M
Bovo
Giorgia
G
Bisulli
Francesca
F
Pinardi
Federica
F
Binelli
Simona
S
Egeo
Gabriella
G
Castellotti
Barbara
B
Striano
Pasquale
P
Striano
Salvatore
S
Bianchi
Amedeo
A
Ferlazzo
Edoardo
E
Vianello
Valeria
V
Coppola
Giangennaro
G
Aguglia
Umberto
U
Tinuper
Paolo
P
Giallonardo
Anna T
AT
Michelucci
Roberto
R
Nobile
Carlo
C
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*
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