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Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy

The American Journal of Human Genetics, ISSN: 0002-9297, Vol: 96, Issue: 6, Page: 992-1000
2015
  • 94
    Citations
  • 0
    Usage
  • 129
    Captures
  • 1
    Mentions
  • 1
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    94
  • Captures
    129
  • Mentions
    1
    • References
      1
      • 1
  • Social Media
    1
    • Shares, Likes & Comments
      1
      • Facebook
        1

Article Description

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.

Bibliographic Details

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

Elsevier BV

Biochemistry, Genetics and Molecular Biology; Medicine

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