title: Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy.
abstract: Autosomal-dominant lateral temporal epilepsy (ADLTE) is a genetic epilepsy syndrome clinically characterized by focal seizures with prominent auditory symptoms. ADLTE is genetically heterogeneous, and mutations in LGI1 account for fewer than 50% of affected families. Here, we report the identification of causal mutations in reelin (RELN) in seven ADLTE-affected families without LGI1 mutations. We initially investigated 13 ADLTE-affected families by performing SNP-array linkage analysis and whole-exome sequencing and identified three heterozygous missense mutations co-segregating with the syndrome. Subsequent analysis of 15 small ADLTE-affected families revealed four additional missense mutations. 3D modeling predicted that all mutations have structural effects on protein-domain folding. Overall, RELN mutations occurred in 7/40 (17.5%) ADLTE-affected families. RELN encodes a secreted protein, Reelin, which has important functions in both the developing and adult brain and is also found in the blood serum. We show that ADLTE-related mutations significantly decrease serum levels of Reelin, suggesting an inhibitory effect of mutations on protein secretion. We also show that Reelin and LGI1 co-localize in a subset of rat brain neurons, supporting an involvement of both proteins in a common molecular pathway underlying ADLTE. Homozygous RELN mutations are known to cause lissencephaly with cerebellar hypoplasia. Our findings extend the spectrum of neurological disorders associated with RELN mutations and establish a link between RELN and LGI1, which play key regulatory roles in both the developing and adult brain.
authors.affiliation: Section of Padua, Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Dazzo
authors.affiliation: Porto Conte Ricerche, 07041 Alghero, Sassari, Italy.
authors.forename: Manuela
authors.initials: M
authors.lastname: Fanciulli
authors.affiliation: Section of Padua, Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Serioli
authors.affiliation: Department of Biomedical Sciences, University of Padua, 35121 Padova, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Minervini
authors.affiliation: Department of Neurology and Psychiatry, Sapienza University of Rome, 00185 Roma, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Pulitano
authors.affiliation: Carlo Besta Foundation Neurological Institute, 20133 Milano, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Binelli
authors.affiliation: Department of Neurology and Psychiatry, Sapienza University of Rome, 00185 Roma, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Di Bonaventura
authors.affiliation: Neurology Clinic, University of Bari, 70124 Bari, Italy.
authors.forename: Concetta
authors.initials: C
authors.lastname: Luisi
authors.affiliation: IRCCS-Institute of Neurological Sciences, Bellaria Hospital, 40139 Bologna, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Pasini
authors.affiliation: Department of Neurosciences and Reproductive and Odontostomatological Sciences, School of Medicine, University of Naples Federico II, 80131 Napoli, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Striano
authors.affiliation: Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa and Giannina Gaslini Institute, 16148 Genova, Italy.
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.affiliation: Child and Adolescent Psychiatry, Faculty of Medicine and Surgery, University of Salerno, 84100 Salerno, Italy.
authors.forename: Giangennaro
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Section of Padua, Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: Chiavegato
authors.affiliation: IGA Technology Services, 33100 Udine, Italy.
authors.forename: Slobodanka
authors.initials: S
authors.lastname: Radovic
authors.affiliation: IGA Technology Services, 33100 Udine, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Spadotto
authors.affiliation: Porto Conte Ricerche, 07041 Alghero, Sassari, Italy.
authors.forename: Sergio
authors.initials: S
authors.lastname: Uzzau
authors.affiliation: Neurology Clinic, University of Bari, 70124 Bari, Italy.
authors.forename: Angela
authors.initials: A
authors.lastname: La Neve
authors.affiliation: Department of Neurology and Psychiatry, Sapienza University of Rome, 00185 Roma, Italy.
authors.forename: Anna Teresa
authors.initials: AT
authors.lastname: Giallonardo
authors.affiliation: Department of Neurology and Psychiatry, Sapienza University of Rome, 00185 Roma, Italy.
authors.forename: Oriano
authors.initials: O
authors.lastname: Mecarelli
authors.affiliation: Section of Padua, Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy; Department of Biomedical Sciences, University of Padua, 35121 Padova, Italy.
authors.forename: Silvio C E
authors.initials: SC
authors.lastname: Tosatto
authors.affiliation: Departments of Epidemiology and Neurology and the Gertrude H. Sergievsky Center, Columbia University, New York, NY 10032, USA; Division of Epidemiology, New York State Psychiatric Institute, New York, NY 10032, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Ottman
authors.affiliation: IRCCS-Institute of Neurological Sciences, Bellaria Hospital, 40139 Bologna, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Michelucci
authors.affiliation: Section of Padua, Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy; Department of Biomedical Sciences, University of Padua, 35121 Padova, Italy. Electronic address: nobile@bio.unipd.it.
authors.forename: Carlo
authors.initials: C
authors.lastname: Nobile
mesh_terms: D000818:Animals; D001483:Base Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002874:Chromosome Mapping; D017034:Epilepsy, Frontal Lobe / Q000235:genetics* / Q000473:pathology*; D059472:Exome; D016326:Extracellular Matrix Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D040461:Gene Components; D006801:Humans; D015151:Immunoblotting; D036341:Intercellular Signaling Peptides and Proteins; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011487:Protein Conformation; D017510:Protein Folding; D011506:Proteins / Q000378:metabolism; D051381:Rats; D000091042:Reelin Protein; D017422:Sequence Analysis, DNA; D012697:Serine Endopeptidases / Q000097:blood / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D012893:Sleep Wake Disorders / Q000235:genetics* / Q000473:pathology*
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; C513865:Lgi1 protein, rat; D009419:Nerve Tissue Proteins; D011506:Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; C000717127:RELN protein, human; D012697:Serine Endopeptidases