Low penetrance and effect on protein secretion of LGI1 mutations causing autosomal dominant lateral temporal epilepsy *Carlo Di Bonaventura, yFrancesca F. Operto, zGiorgia Busolin, *xGabriella Egeo, yAlfredo D’Aniello, {Libero Vitello, {Gessica Smaniotto, zSandra Furlan, zErica Diani, #Roberto Michelucci, *Anna Teresa Giallonardo, yGiangennaro Coppola, and zCarlo Nobile *Department of Neurological Sciences, University of Rome ‘‘Sapienza,’’ Roma, Italy; yClinic of Child Neuropsychiatry, Second University of Naples, Napoli, Italy; zCNR-Institute of Neurosciences, Section of Padua, Padova, Italy; xIRCCS San Raffaele Pisana, Roma, Italy; {Department of Biology, University of Padua, Padova, Italy; and #Department of Neurosciences, Bellaria Hospital, Bologna, Italy SUMMARY Purpose: To describe the clinical and genetic findings of four families with autosomal dominant lateral temporal epilepsy. Methods: A personal and family history was obtained from each affected and unaffected subject along with a physical and neurologic examination. Routine electroen- cephalography and magnetic resonance imaging (MRI) studies were performed in almost all patients. DNAs from family members were screened for LGI1 mutations. The effects of mutations on Lgi1 protein secretion were determined in transfected culture cells. Key Findings: The four families included a total of 11 patients (two deceased), six of whom had lateral tempo- ral epilepsy with auditory aura. Age at onset was in the second decade of life; seizures were well controlled by antiepileptic treatment and MRI studies were normal. We found two pathogenic LGI1 mutations with uncom- monly low penetrance: the R136W mutation, previously detected in a sporadic case with telephone-induced par- tial seizures, gave rise to the epileptic phenotype in three of nine mutation carriers in one family; the novel C179R mutation caused epilepsy in an isolated patient from a family where the mutation segregated. Another novel pathogenic mutation, I122T, and a nonsynonymous variant, I359V, were found in the two other families. Pro- tein secretion tests showed that the R136W and I122T mutations inhibited secretion of the mutant proteins, whereas I359V had no effect on protein secretion; C179R was not tested, because of its predictable effect on pro- tein folding. Significance: These findings suggest that some LGI1 muta- tions may have a weak penetrance in families with com- plex inheritance pattern, or isolated patients, and that the protein secretion test, together with other predictive cri- teria, may help recognize pathogenic LGI1 mutations. KEY WORDS: Autosomal dominant lateral temporal epi- lepsy, LGI1, Mutation, Low penetrance, Protein secre- tion. Autosomal dominant lateral temporal epilepsy (ADLTE; OMIM 600512), also named autosomal dominant partial epilepsy with auditory features (ADPEAF), is a well- defined condition characterized by onset in adolescence or early adulthood, lateral temporal seizures with prominent auditory or aphasic auras, normal MRI, and overall benign outcome (Ottman et al., 1995). Seizures in ADLTE/AD- PEAF are sometimes triggered by sensory (usually acoustic) stimuli (Michelucci et al., 2003, 2004). Mutations associ- ated with ADLTE/ADPEAF are found in the leucine rich, glioma inactivated 1 (LGI1) gene (Kalachikov et al., 2002; Morante-Redolat et al., 2002). To date, more than 25 LGI1 mutations have been identified in families with a rather homogeneous phenotype and autosomal dominant inheritance pattern (Nobile et al., 2009; Heiman et al., 2010; Kawamata et al., 2010). Overall, LGI1mutations- account for about 50% of ADLTE/ADPEAF families (Michelucci et al., 2003; Ottman et al., 2004). LGI1 does not encode an ion channel subunit. The struc- ture of its protein product consists of an N-terminal domain composed of four leucine rich repeats (LRRs; Buchanan & Gay, 1996) and a C-terminal 7-repeat domain named EPTP (beta-propeller; Staub et al., 2002), both of which mediate Accepted February 22, 2011; Early View publication April 19, 2011. Address correspondence to Carlo Nobile, Istituto di Neuroscienze del CNR, Sede di Padova, C/o Dipartimento di Scienze Biomediche Sperimen- tali, Università di Padova, viale G. Colombo 3, 35121 Padova, Italy. E-mail: nobile@bio.unipd.it Wiley Periodicals, Inc. ª 2011 International League Against Epilepsy Epilepsia, 52(7):1258–1264, 2011 doi: 10.1111/j.1528-1167.2011.03071.x FULL-LENGTH ORIGINAL RESEARCH 1258