Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy
Heterozygous Reelin Mutations Cause Autosomal-Dominant Lateral Temporal Epilepsy
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DOI：
10.1016/j.ajhg.2015.04.020
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发表时间：
2015-06-04
影响因子：
9.8
通讯作者：
Nobile, Carlo
中科院分区：
文献类型：
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作者：
Dazzo, Emanuela;Fanciulli, Manuela;Nobile, Carlo
常染色体显性颞侧癫痫（ADLTE）是一种遗传性癫痫综合征，临床特征为局灶性癫痫发作并伴有突出的听觉症状。 ADLTE 具有遗传异质性，LGI1 突变仅占受影响家族的不到 50%。在这里，我们报告了七个受 ADLTE 影响但没有 LGI1 突变的家族中 reelin (RELN) 因果突变的鉴定。我们最初通过进行 SNP 阵列连锁分析和全外显子组测序研究了 13 个受 ADLTE 影响的家族，并鉴定了与该综合征共分离的三个杂合错义突变。随后对 15 个受 ADLTE 影响的小家族进行的分析揭示了另外 4 个错义突变。 3D 建模预测所有突变都会对蛋白质结构域折叠产生结构影响。总体而言，RELN 突变发生在 7/40 (17.5%) ADLTE 影响的家庭中。 RELN 编码一种分泌蛋白 Reelin，它在发育中和成人大脑中具有重要功能，并且也存在于血清中。我们发现 ADLTE 相关突变显着降低 Reelin 的血清水平，表明突变对蛋白质分泌具有抑制作用。我们还表明 Reelin 和 LGI1 共定位于大鼠大脑神经元的子集中，支持这两种蛋白参与 ADLTE 的共同分子途径。已知纯合 RELN 突变会导致无脑畸形伴小脑发育不全。我们的研究结果扩展了与 RELN 突变相关的神经系统疾病的范围，并建立了 RELN 和 LGI1 之间的联系，它们在发育中和成人大脑中发挥着关键的调节作用。
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.