SIL1, a causative cochaperone gene of Marinesco-Söjgren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex.
SIL1, a causative cochaperone gene of Marinesco-Söjgren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex.
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DOI：
10.1002/emmm.201303069
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发表时间：
2014-03
影响因子：
11.1
通讯作者：
Nagata, Koh-ichi
中科院分区：
文献类型：
--
作者：
Inaguma, Yutaka;Hamada, Nanako;Tabata, Hidenori;Iwamoto, Ikuko;Mizuno, Makoto;Nishimura, Yoshiaki V.;Ito, Hidenori;Morishita, Rika;Suzuki, Motomasa;Ohno, Kinji;Kumagai, Toshiyuki;Nagata, Koh-ichi
Marinesco-Sjögren 综合征 (MSS) 是一种罕见的常染色体隐性遗传性疾病，伴有智力低下 (MR)。最近，SIL1 基因（编码调节伴侣 HSPA5 的辅助伴侣）的突变被确定为 MSS 的主要原因。我们在这里检查了 SIL1 突变在 MSS 皮质生成异常中的病理生理学意义。 SIL1 沉默导致离体皮质生成过程中神经元迁移延迟。虽然抗 RNAi 的 SIL1 修复了这些缺陷，但测试的三种导致 MSS 的 SIL1 突变体却没有。这些突变体在体外对 HSPA5 的亲和力较低，并且发现 SIL1-HSPA5 相互作用以及 HSPA5 功能对于神经元离体迁移至关重要。此外，延时成像揭示了与 SIL1 缺陷神经元的异常迁移相关的形态紊乱。这些结果表明，这些突变阻止 SIL1 与 HSPA5 相互作用并对其进行调节，从而导致神经元形态和迁移异常。与此一致的是，当一侧半球皮质神经元中的 SIL1 被沉默时，对侧半球的轴突生长就会延迟。总而言之，异常的神经元迁移和半球间轴突发育可能导致 MSS 的 MR。学科类别 遗传学；基因治疗与遗传病；
Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessively inherited disorder with mental retardation (MR). Recently, mutations in the SIL1 gene, encoding a co-chaperone which regulates the chaperone HSPA5, were identified as a major cause of MSS. We here examined the pathophysiological significance of SIL1 mutations in abnormal corticogenesis of MSS. SIL1-silencing caused neuronal migration delay during corticogenesis ex vivo. While RNAi-resistant SIL1 rescued the defects, three MSS-causing SIL1 mutants tested did not. These mutants had lower affinities to HSPA5 in vitro, and SIL1-HSPA5 interaction as well as HSPA5 function was found to be crucial for neuronal migration ex vivo. Furthermore time-lapse imaging revealed morphological disorganization associated with abnormal migration of SIL1-deficient neurons. These results suggest that the mutations prevent SIL1 from interacting with and regulating HSPA5, leading to abnormal neuronal morphology and migration. Consistent with this, when SIL1 was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed. Taken together, abnormal neuronal migration and interhemispheric axon development may contribute to MR in MSS. Subject Categories Genetics; Gene Therapy & Genetic Disease;
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影响因子：
3.3
作者：
Shinoda T;Ito H;Sudo K;Iwamoto I;Morishita R;Nagata K
通讯作者：
Nagata K
影响因子：
2.3
作者：
Sakai, Kenji;Tada, Mari;Kakita, Akiyoshi
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Kakita, Akiyoshi
影响因子：
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作者：
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通讯作者：
Lehesjoki, AE
影响因子：
5.2
作者：
Anttonen, Anna-Kaisa;Siintola, Eija;Lehesjoki, Anna-Elina
通讯作者：
Lehesjoki, Anna-Elina
影响因子：
5.3
作者：
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通讯作者：
Aoe, Tomohiko