SIL1, a causative cochaperone gene of Marinesco‐Sjögren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex. Issue 3 (29th January 2014)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: EMBO molecular medicine. Volume 6:Issue 3(2014:Mar.)
• Page Start: 414
• Page End: 429
• Publication Date: 2014-01-29
• Subjects: Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.1002/emmm.201303069
• Languages: English
• ISSNs: 1757-4676

Abstract

<abstract abstract-type="main" id="emmm201303069-abs-0001"> <title>Abstract</title> <p>Marinesco‐Sjögren syndrome (MSS) is a rare autosomal recessively inherited disorder with mental retardation (MR). Recently, mutations in the <italic>SIL1</italic> 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 <italic>ex vivo</italic>. While RNAi‐resistant SIL1 rescued the defects, three MSS‐causing SIL1 mutants tested did not. These mutants had lower affinities to HSPA5 <italic>in vitro</italic>, and SIL1‐HSPA5 interaction as well as HSPA5 function was found to be crucial for neuronal migration <italic>ex vivo</italic>. 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.</p> </abstract>