Abstract
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;
Highlights
Marinesco–Sjo€gren syndrome (MSS; OMIM 248800) is an autosomal recessive disorder affecting various tissues
Marinesco-Sjo€gren syndrome (MSS)-associated SIL1 mutations are thought to cause functional defects of SIL1 to various degrees that reflect the variety of clinical symptoms in MSS patients (Senderek et al, 2005; Anttonen et al, 2008; Eriguchi et al, 2008; Riazuddin et al, 2009; Takahata et al, 2010; Howes et al, 2012)
Several clinical signs in Case#1 and Case#2 presented more severely than those in Case#4 and Case#6 (Table 1). These differences in clinical severity can be correlated with the type of mutations; the mutations in Case#1 and Case#2 were homozygous and close to and within the armadillo repeats (ARMs) region, respectively, while the mutations in Case#4 and Case#6 were compound heterozygous where one mutation occurred inside the ARM region but the other did not
Summary
Marinesco–Sjo€gren syndrome (MSS; OMIM 248800) is an autosomal recessive disorder affecting various tissues. The clinical features of MSS are cerebellar ataxia, early-onset cataracts, progressive myopathy and mental retardation (MR). Brain magnetic resonance imaging (MRI) studies have revealed general cerebellar atrophy while dysplastic cytoarchitecture in the cerebral cortex was reported by an autopsy in one patient clinically diagnosed as MSS (Reinhold et al, 2003; Sakai et al, 2008). The MSS phenotypes have been found to be caused by mutations in the SIL1 gene on chromosome 5q31, resulting in loss of SIL1 function due to premature termination of translation, abnormal splicing of the transcript or single amino acid substitution (Anttonen et al, 2005, 2008; Senderek et al, 2005; Karim et al, 2006; Eriguchi et al, 2008; Riazuddin et al, 2009; Takahata et al, 2010). SIL1 is an ER-resident glycoprotein harboring an N-terminal endoplasmic reticulum (ER) targeting sequence, four armadillo repeats (ARMs), 2 N-linked glycosylation sites (Asn193 and Asn236) and a C-terminal putative ER retention tetrapeptide (Chung et al, 2002)
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