The SIL1 gene encodes the nucleotide exchange factor SIL1 for the endoplasmic reticulum resident heat-shock protein 70 chaperone BiP (also known as GRP78). As a nucleotide exchange factor, SIL1 induces ADP release and ATP binding of BiP. BiP is encoded by the HSPA5 gene; it functions in protein translocation, synthesis, and quality control and senses and responds to stressful cellular conditions.
The SIL1 gene is located on the long arm of chromosome 5 at 5q31. It has 10 exons and encodes a protein that is 461-amino acid long and weights 52,085 Da. SIL1 can be alternatively spliced; a variant missing exon 6 is present in multiple tissues at low levels and another variant with an additional 5' non-coding exon is present at least in placental tissue. The SIL1 protein is N-linked glycoprotein with an N-terminal ER targeting sequence, two putative N-glycosylation sites, and a C-terminal ER retention signal.
More than a dozen mutations in the SIL1 gene have been identified as a major cause of Marinesco-Sjogren syndrome (MSS). Most of these mutations result in truncating the production or inactivation of the activity of this protein. Defective SIL1 protein cannot release ADP from BiP. BiP is then unable to bind to ATP and re-start the protein folding process. A disruption in protein folding impairs protein transport and causes proteins to accumulate in the endoplasmic reticulum. This accumulation likely damages and destroys cells in many different tissues, leading to poor coordination, muscle weakness, and the other features of Marinesco-Sjögren syndrome.
In four affected members of two separate sibships in a consanguineous Egyptian family with Marinesco-Sjogren syndrome, Karim et al. (2006) found a homozygous C-to-T transition at nucleotide 1312 in exon 10 of the SIL1 gene, resulting in a glutamine to stop codon change at position 438 (Q438X).
Anazi et al. (2016) described the effectiveness of genomic tools in diagnosing Intellectual Disability (ID) cases compared to standard clinical evaluations. 337 ID affected patients were recruited and subjected to molecular karyotyping, exome sequencing and sequencing by a multi-gene panel comprised of neurologically associated genes. This helped uncover a homozygous mutation (c.1030-9G>A) in the SIL1 gene of one patient, suggesting a diagnosis of Marinesco–Sjogren syndrome. However, it was noted that the patient’s MRI exhibited features typical of Joubert syndrome.
Nair et al. (2016) described a 12-year-old Emirati male, from a consanguineous family, presenting with developmental and speech delay, ataxia and bilateral cataracts. The patient also suffered from subtle facial dysmorphia, cerebellar atrophy, intention tremor, dysmetria, dysdiadochokinesia, pectus carinatum, mild kyphosis, bilateral clinodactyly of the fifth fingers and flat feet. Based on a tentative diagnosis of MSS, the patient’s SIL1 gene was analyzed. The authors identified a homozygous deletion from the 5’ untranslated region (UTR c.-197) to exon 1 (c.90) and the insertion of a base of unclear origin (C) and 20 bases from intron 1 (c.-197_90delin sCTGTACTTTCTCAGTTCACT). Both parents were found to be heterozygous for the indel mutation. Further, the variant was not found in the ExAC browser or the GALAXCTM Allele Frequency Database. It was postulated that the resulting mutant protein would remain in the cytosol due to the absence of its ER targeting sequence and hence would be unable to carry out its chaperoning activities.
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