Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy

Am J Hum Genet. 2015 Jun 4;96(6):992-1000. doi: 10.1016/j.ajhg.2015.04.020.

Emanuela Dazzo ¹, Manuela Fanciulli ², Elena Serioli ¹, Giovanni Minervini ³, Patrizia Pulitano ⁴, Simona Binelli ⁵, Carlo Di Bonaventura ⁴, Concetta Luisi ⁶, Elena Pasini ⁷, Salvatore Striano ⁸, Pasquale Striano ⁹, Giangennaro Coppola ¹⁰, Angela Chiavegato ¹, Slobodanka Radovic ¹¹, Alessandro Spadotto ¹¹, Sergio Uzzau ², Angela La Neve ⁶, Anna Teresa Giallonardo ⁴, Oriano Mecarelli ⁴, Silvio C E Tosatto ¹², Ruth Ottman ¹³, Roberto Michelucci ⁷, Carlo Nobile ¹⁴

Affiliations

1 Section of Padua, Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy.
2 Porto Conte Ricerche, 07041 Alghero, Sassari, Italy.
3 Department of Biomedical Sciences, University of Padua, 35121 Padova, Italy.
4 Department of Neurology and Psychiatry, Sapienza University of Rome, 00185 Roma, Italy.
5 Carlo Besta Foundation Neurological Institute, 20133 Milano, Italy.
6 Neurology Clinic, University of Bari, 70124 Bari, Italy.
7 IRCCS-Institute of Neurological Sciences, Bellaria Hospital, 40139 Bologna, Italy.
8 Department of Neurosciences and Reproductive and Odontostomatological Sciences, School of Medicine, University of Naples Federico II, 80131 Napoli, Italy.
9 Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa and Giannina Gaslini Institute, 16148 Genova, Italy.
10 Child and Adolescent Psychiatry, Faculty of Medicine and Surgery, University of Salerno, 84100 Salerno, Italy.
11 IGA Technology Services, 33100 Udine, Italy.
12 Section of Padua, Institute of Neuroscience, Consiglio Nazionale delle Ricerche, 35121 Padova, Italy; Department of Biomedical Sciences, University of Padua, 35121 Padova, Italy.
13 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.
14 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: [email protected].

PMID: 26046367 DOI: 10.1016/j.ajhg.2015.04.020

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.

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