Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy

Emanuela Dazzo, Manuela Fanciulli, Elena Serioli, Giovanni Minervini, Patrizia Pulitano, Simona Binelli, Carlo Di Bonaventura, Concetta Luisi, Elena Pasini, Salvatore Striano, Pasquale Striano, Giangennaro Coppola, Angela Chiavegato, Slobodanka Radovic, Alessandro Spadotto, Sergio Uzzau, Angela La Neve, Anna T eresa Giallonardo, Oriano Mecarelli, Silvio C E TosattoRuth Ottman, Roberto Michelucci, Carlo Nobile

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)992-1000
Number of pages9
JournalAmerican Journal of Human Genetics
Volume96
Issue number6
DOIs
Publication statusPublished - Jun 4 2015

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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