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
- 94Citations
- 129Captures
- 1Mentions
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations94
- Citation Indexes94
- 94
- CrossRef30
- Captures129
- Readers129
- 129
- Mentions1
- References1
- 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
http://www.sciencedirect.com/science/article/pii/S0002929715001573; http://dx.doi.org/10.1016/j.ajhg.2015.04.020; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85005917703&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/26046367; https://linkinghub.elsevier.com/retrieve/pii/S0002929715001573; http://www.cell.com/ajhg/abstract/S0002-9297(15)00157-3
Elsevier BV
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