Alternative titles; symbols
HGNC Approved Gene Symbol: SIL1
SNOMEDCT: 80734006;
Cytogenetic location: 5q31.2 Genomic coordinates (GRCh38) : 5:138,946,724-139,198,368 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.2 | Marinesco-Sjogren syndrome | 248800 | Autosomal recessive | 3 |
SIL1 is a resident endoplasmic reticulum (ER) glycoprotein that interacts with the ATPase domain of BIP (HSPA5; 138120) and enhances nucleotide exchange.
By searching EST databases for sequences showing similarity to yeast Sil1, Tyson and Stirling (2000) identified human SIL1. The deduced protein contains 461 amino acids.
Using an ATPase-defective rodent Bip mutant as bait in a yeast 2-hybrid screen of a liver cDNA library, followed by database screening, Chung et al. (2002) cloned SIL1, which they called BAP. The deduced 461-amino acid protein contains an N-terminal ER targeting sequence, 2 putative N-glycosylation sites, and a C-terminal ER retention signal. BAP mRNA contains 2 polyadenylation sequences. BAP shares 29% homology with Hsp70-binding protein-1 (HSPBP1; 612939), which inhibits the ATPase activity of Hsp70 (see 140550). Northern blot analysis detected a 1.8-kb transcript in all tissues examined, with highest levels in liver, placenta, and kidney. Immunolocalization found epitope-tagged BAP colocalized with endogenous GRP94 (191175) in the ER of transfected COS-1 cells. Western blot analysis and endoglycosidase treatment revealed that endogenous BAP is an N-linked glycoprotein with an apparent molecular mass of about 54 kD.
Takahata et al. (2010) stated that the SIL1 gene contains 10 exons.
Takahata et al. (2010) noted that the SIL1 gene maps to chromosome 5q31.
Tyson and Stirling (2000) determined that yeast Sil1 interacts directly with the ATPase domain of Bip. They found that upregulation of Sil1 was associated with the constitutively induced unfolded protein response resulting from deletion of Lhs1, an ER resident heat shock protein homologous to ORP150 (HYOU1; 601746).
By Northern blot analysis, Chung et al. (2002) detected expression of BAP in the same tissues that express BIP. In vitro binding assays between BAP, wildtype rodent Bip, and ATPase domain mutants of rodent Bip showed that BAP bound more stably to the mutants than to wildtype Bip. BAP stimulated the ATPase activity of BIP 2-fold, and addition of both BAP and the ER protein ERDJ4 (DNAJB9; 602634) stimulated the ATPase activity of BIP 4-fold. Chung et al. (2002) concluded that BAP is a nucleotide exchange factor for BIP.
Marinesco-Sjogren syndrome (MSS; 248800) is an autosomal recessive disorder characterized by cerebellar ataxia, progressive myopathy, and cataracts. Anttonen et al. (2005) identified mutations in the SIL1 gene in 8 families with MSS. The finding of mutations in the SIL1 gene in affected individuals and the similar spatial and temporal patterns of tissue expression of SIL1 and HSPA5, the heat-shock protein-70 (HSP70) chaperone for which SIL1 is a nucleotide exchange factor, suggested that disturbed SIL1-HSPA5 interaction and protein folding is the primary pathology in Marinesco-Sjogren syndrome.
Senderek et al. (2005) identified the gene encoding the ER resident protein SIL1 in the 2.8-Mb critical region for the MSS phenotype. They noted that SIL1 is ubiquitously expressed, and they confirmed its expression in tissues targeted by MSS. They proceeded to identify homozygous SIL1 coding sequence variants in 3 affected individuals. They also discovered sequence variants on both alleles in 2 additional consanguineous families, in 2 affected sib pairs from 2 nonconsanguineous families, and in an apparently isolated case. Senderek et al. (2005) suggested that there are several reasons why loss of functional SIL1 could lead to a multisystem disorder like MSS. In mammalian cells, most secretory pathway proteins enter the ER cotranslationally through multiprotein complexes called 'translocons.' Chaperone GRP78, also called HSPA5 and BIP, regulates translocon gating at the ER membrane in an ATP-dependent manner. As SIL1 promotes BiP ATP-ADP exchange, reduction of SIL1 levels could affect translocon gating, resulting in decreased ER protein synthesis. Thus, MSS may be a disorder of protein biosynthesis or processing in the ER.
In affected members of 5 families with Marinesco-Sjogren syndrome, Anttonen et al. (2008) identified 4 novel homozygous mutations in the SIL1 gene (see, e.g., 608005.0007 and 608005.0008). All had the classic features of cerebellar atrophy and ataxia, cataracts, mental retardation, and some form of myopathy though severity varied somewhat.
In 3 Japanese sibs with Marinesco-Sjogren syndrome, Takahata et al. (2010) identified compound heterozygosity for 2 deletions in the SIL1 gene: a 5-bp deletion (598delGAAGA; 608005.0009) and a 58-kb deletion (608005.0010) both in exon 6. Each unaffected parent was heterozygous for 1 of the deletions. The 58-kb deletion was not detected by the standard PCR sequencing protocol, and was only found after array comparative genomic hybridization and quantitative PCR analysis. Takahata et al. (2010) suggested that some MSS patients in whom mutations are not found should be screened for larger deletions in the SIL1 gene. All 3 patients had cataracts, ataxia, hypotonia, myopathy, spasticity, mental retardation, and skeletal deformities.
In proteomics studies in fibroblasts from 2 patients with Marinesco-Sjogren syndrome, Hathazi et al. (2021) demonstrated decreased expression of PHGDH (606879) compared to controls. Fibroblasts from the 2 patients showed a 20% increase in cell viability when grown with serine supplementation compared to non-supplemented cells. Hathazi et al. (2021) hypothesized that decreased PHGDH expression is associated with dysregulation in serine metabolism and may contribute to the neurologic phenotype of MSS.
Endoplasmic reticulum chaperones and ER stress have been implicated in the pathogenesis of neurodegenerative disorders, such as Alzheimer (104300) and Parkinson (168600) diseases. Zhao et al. (2005) established a direct in vivo link between ER dysfunction and neurodegeneration. They showed that mice homozygous with respect to the 'woozy' (wz) mutation develop adult-onset ataxia with cerebellar Purkinje cell loss. Affected cells have intracellular protein accumulations reminiscent of protein inclusions in both the ER and the nucleus. In addition, upregulation of the unfolded protein response, suggestive of ER stress, occurs in mutant Purkinje cells. Zhao et al. (2005) reported that the wz mutation disrupts the gene Sil1, which encodes an adenine nucleotide exchange factor of BiP (HSPA5; 138120), a crucial ER chaperone. The finding provided evidence that perturbation of ER chaperone function in terminally differentiated neurons leads to protein accumulation, ER stress, and subsequent neurodegeneration.
Zhao et al. (2010) reported that overexpression of Hyou1 (601746), an exchange factor that works in parallel to Sil1, prevented ER stress and rescued neurodegeneration in Sil1 -/- mice, whereas decreasing expression of Hyou1 exacerbated these phenotypes. In addition, loss of Dnajc3 (601184), a cochaperone that promotes ATP hydrolysis by BiP, ameliorated ER stress and neurodegeneration in Sil1 -/- mice. Zhao et al. (2010) suggested that alterations in the nucleotide exchange cycle of BiP may cause ER stress and neurodegeneration in Sil1 -/- mice.
In all Finnish individuals with Marinesco-Sjogren syndrome (MSS; 248800), Anttonen et al. (2005) found a 4-nucleotide duplication, 506_509dupAAGA, in exon 6 of the SIL1 gene.
In a 5-year-old Turkish male, the offspring of consanguineous parents, with Marinesco-Sjogren syndrome (MSS; 248800), Senderek et al. (2005) found homozygosity for a splice site mutation in intron 6 of the SIL1 gene, 645+1G-A, which resulted in skipping of exon 6. Cataracts had been diagnosed at the age of 4.5 years. Ataxia, hypotonia, short stature, cerebellar atrophy, myopathic EMG, and myopathic biopsy showing membranous structure associated with myonuclei were features. Senderek et al. (2005) generated a putative model of the SIL1-BIP (138120) interaction, which suggested that SIL1 exons 6 and 9 have a key role in associating with BIP. Thus the mutants that lack exons 6 or 9, or both, would be expected to be defective in binding to BIP.
In 2 Swedish individuals with a Finnish paternal ancestor who were affected with Marinesco-Sjogren syndrome (MSS; 248800), Anttonen et al. (2005) found compound heterozygosity for 2 mutations in the SIL1 gene: the universal Finnish mutation (608005.0001) and a donor splice site mutation in intron 6, 645+2T-C. RT-PCR analysis of SIL1 from lymphocyte RNA showed that the duplication mutant transcript was of the expected length, whereas 2 shorter variants were expressed from the splice site mutated allele. In the shorter of these, which was expressed at higher levels, exon 6 was skipped, predicting an in-frame deletion of 64 amino acids. In the longer variant, a cryptic splice site in exon 6 was used, predicting an in-frame deletion of 30 amino acids.
In a 14-year-old Iranian female, the offspring of consanguineous parents, with Marinesco-Sjogren syndrome (MSS; 248800), Senderek et al. (2005) found a homozygous nonsense mutation in the SIL gene, arg111 to stop (R111X), due to a change at nucleotide 331 in exon 4 from C to T. The girl had congenital cataracts, ataxia, hypotonia, psychomotor delay, short stature, skeletal deformities, hypogonadism, elevated serum creatine kinase, cerebellar atrophy, myopathic biopsy and EMG, and membranous structure associated with myonuclei. The R111X mutation was also found in homozygous form in Turkish sisters, aged 38 and 16 years. Cataracts had been diagnosed at the age of 4 years in each of them.
The R111X mutation was described in a Turkish family with MSS by Anttonen et al. (2005).
Aguglia et al. (2000) reported 2 Italian brothers who had MSS and chylomicron retention disease (CMRD; 246700). In these patients, Jones et al. (2003) identified a mutation in the SAR1B gene (607690.0006), responsible for CMRD, and Annesi et al. (2007) identified an R111X mutation in the SIL1 gene, responsible for MSS. The findings indicated that the patients had 2 distinct diseases due to mutations in 2 different genes, rather than defects in a single gene leading to both disorders.
In an 11-year-old Bosnian male, born of consanguineous parents, with Marinesco-Sjogren syndrome (MSS; 248800), Senderek et al. (2005) found homozygosity for a donor splice site mutation of intron 9 of the SIL1 gene, 1029+1G-A, that resulted in skipping of exon 9. Congenital cataracts, ataxia, hypotonia, psychomotor delay, short stature, cerebellar atrophy, and myopathic EMG and biopsy were described.
In 4 affected members of 2 separate sibships in a consanguineous Egyptian family with Marinesco-Sjogren syndrome (MSS; 248800), 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). A curious feature in this family was the lack of cerebellar ataxia in a 25-year-old male and 19-year-old female who were sibs of the mother of 7- and 9-year-old females with full expression of Marinesco-Sjogren syndrome. The older patients had delayed physical and mental development, mental retardation, progressive muscle weakness, hypotonia of legs, and cataract. The male showed hypogonadism.
In 2 Japanese sibs, born of consanguineous parents, with Marinesco-Sjogren syndrome (MSS; 248800), Anttonen et al. (2008) identified a homozygous 1370T-C transition in exon 10 of the SIL1 gene, resulting in a leu457-to-pro (L457P) substitution. One of the affected sibs had a twin brother who died soon after birth. Both brothers showed psychomotor delay and distinct cerebellar symptoms, including limb and truncal ataxia, hypotonia, and dysarthria. They also had congenital cataracts. In transfected COS-1 cells, the L457P mutant protein showed altered subcellular localization compared to the wildtype protein. The mutant protein was observed to form aggregates within the endoplasmic reticulum.
In 2 Japanese sisters with Marinesco-Sjogren syndrome (MSS; 248800), Anttonen et al. (2008) identified a homozygous 1-bp duplication (936_937dupG) in exon 9 of the SIL1 gene, resulting in a frameshift and premature termination (Leu313AlafsTer39). The parents were second cousins once removed. Both sisters had bilateral cataracts, learned to walk but with unstable gait, and lost ambulation around 20 years of age. Other features included short stature, psychomotor delay, hypotonia, and cerebellar atrophy.
Hasegawa et al. (2014) identified a homozygous c.936_397insG mutation in a 14-month-old Japanese boy with MSS. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The patient had mild global developmental delay, nystagmus, cerebellar atrophy, and low serum IgG and IgA in the absence of opportunistic or recurrent infections. Studies of patient-derived lymphoblastoid cells showed markedly decreased SIL1 expression as well as increased phosphorylation of EIF2A (609234), indicating increased ER stress, which Hasegawa et al. (2014) postulated may have hampered proper assembly of immunoglobulins in the ER.
In 3 Japanese sibs with Marinesco-Sjogren syndrome (MSS; 248800), Takahata et al. (2010) identified compound heterozygosity for 2 deletions in the SIL1 gene: a 5-bp deletion (598delGAAGA) in exon 6, and a 58-kb deletion in exon 6 (608005.0010). Each unaffected parent was heterozygous for 1 of the deletions. The 5-bp deletion was not detected in 80 healthy Japanese individuals. The 58-kb deletion was not detected by the PCR sequencing protocol, and was only found after array comparative genomic hybridization and quantitative PCR analysis. The breakpoints of the 58-kb deletion were in a LINE/L1 repetitive sequence in intron 5 and in a unique sequence in intron 7. Takahata et al. (2010) suggested that some MSS patients in whom mutations are not found should be screened for larger deletions in the SIL1 gene. All 3 patients had cataracts, ataxia, hypotonia, myopathy, spasticity, mental retardation, and skeletal deformities.
For discussion of the 58-kb deletion in the SIL1 gene that was found in compound heterozygous state in sibs with Marinesco-Sjogren syndrome (MSS; 248800) by Takahata et al. (2010), see 608005.0009.
Aguglia, U., Annesi, G., Pasquinelli, G., Spadafora, P., Gambardella, A., Annesi, F., Pasqua, A. A., Cavalcanti, F., Crescibene, L., Bagala, A., Bono, F., Oliveri, R. L., Valentino, P., Zappia, M., Quattrone, A. Vitamin E deficiency due to chylomicron retention disease in Marinesco-Sjogren syndrome. Ann. Neurol. 47: 260-264, 2000. [PubMed: 10665502]
Annesi, G., Aguglia, U., Tarantino, P., Annesi, F., De Marco, E. V., Civitelli, D., Torroni, A., Quattrone, A. SIL1 and SARA2 mutations in Marinesco-Sjogren and chylomicron retention disease. (Letter) Clin. Genet. 71: 288-289, 2007. [PubMed: 17309654] [Full Text: https://doi.org/10.1111/j.1399-0004.2007.00759.x]
Anttonen, A.-K., Mahjneh, I., Hamalainen, R. H., Lagier-Tourenne, C., Kopra, O., Waris, L., Anttonen, M., Joensuu, T., Kalimo, H., Paetau, A., Tranebjaerg, L., Chaigne, D., Koenig, M., Eeg-Olofsson, O., Udd, B., Somer, M., Somer, H., Lehesjoki, A.-E. The gene disrupted in Marinesco-Sjogren syndrome encodes SIL1, an HSPA5 cochaperone. Nature Genet. 37: 1309-1311, 2005. [PubMed: 16282978] [Full Text: https://doi.org/10.1038/ng1677]
Anttonen, A.-K., Siintola, E., Tranebjaerg, L., Iwata, N. K., Bijlsma, E. K., Meguro, H., Ichikawa, Y., Goto, J., Kopra, O., Lehesjoki, A.-E. Novel SIL1 mutations and exclusion of functional candidate genes in Marinesco-Sjogren syndrome. Europ. J. Hum. Genet. 16: 961-969, 2008. [PubMed: 18285827] [Full Text: https://doi.org/10.1038/ejhg.2008.22]
Chung, K. T., Shen, Y., Hendershot, L. M. BAP, a mammalian BiP-associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. J. Biol. Chem. 277: 47557-47563, 2002. [PubMed: 12356756] [Full Text: https://doi.org/10.1074/jbc.M208377200]
Hasegawa, S., Imai, K., Yoshida, K., Okuno, Y., Muramatsu, H., Shiraishi, Y., Chiba, K., Tanaka, H., Miyano, S., Kojima, S., Ogawa, S., Morio, T., Mizutani, S., Takagi, M. Whole-exome sequence analysis of ataxia telangiectasia-like phenotype. J. Neurol. Sci. 340: 86-90, 2014. [PubMed: 24631270] [Full Text: https://doi.org/10.1016/j.jns.2014.02.033]
Hathazi, D., Cox, D., D'Amico, A., Tasca, G., Charlton, R., Carlier, R. Y., Baumann, J., Kollipara, L., Zahedi, R. P., Feldmann, I., Deleuze, J. F., Torella, A., and 16 others. INPP5K and SIL1 associated pathologies with overlapping clinical phenotypes converge through dysregulation of PHGDH. Brain 144: 2427-2442, 2021. Note: Erratum: Brain 147: e62, 2024. [PubMed: 33792664] [Full Text: https://doi.org/10.1093/brain/awab133]
Jones, B., Jones, E. L., Bonney, S. A., Patel, H. N., Mensenkamp, A. R., Eichenbaum-Voline, S., Rudling, M., Myrdal, U., Annesi, G., Naik, S., Meadows, N., Quattrone, A., and 9 others. Mutations in a Sar1 GTPase of COPII vesicles are associated with lipid absorption disorders. Nature Genet. 34: 29-31, 2003. [PubMed: 12692552] [Full Text: https://doi.org/10.1038/ng1145]
Karim, M. A., Parsian, A. J., Cleves, M. A., Bracey, J., Elsayed, M. S., Elsobky, E., Parsian, A. A novel mutation in BAP/SIL1 gene causes Marinesco-Sjogren syndrome in an extended pedigree. (Letter) Clin. Genet. 70: 420-423, 2006. [PubMed: 17026626] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00695.x]
Senderek, J., Krieger, M., Stendel, C., Bergmann, C., Moser, M., Breitbach-Faller, N., Rudnik-Schoneborn, S., Blaschek, A., Wolf, N. I., Harting, I., North, K., Smith, J., and 13 others. Mutations in SIL1 cause Marinesco-Sjogren syndrome, a cerebellar ataxia with cataract and myopathy. Nature Genet. 37: 1312-1314, 2005. [PubMed: 16282977] [Full Text: https://doi.org/10.1038/ng1678]
Takahata, T., Yamada, K., Yamada, Y., Ono, S., Kinoshita, A., Matsuzaka, T., Yoshiura,K., Kitaoka, T. Novel mutations in the SIL1 gene in a Japanese pedigree with the Marinesco-Sjogren syndrome. J. Hum. Genet. 55: 142-146, 2010. [PubMed: 20111056] [Full Text: https://doi.org/10.1038/jhg.2009.141]
Tyson, J. R., Stirling, C. J. LHS1 and SIL1 provide a lumenal function that is essential for protein translocation into the endoplasmic reticulum. EMBO J. 19: 6440-6452, 2000. [PubMed: 11101517] [Full Text: https://doi.org/10.1093/emboj/19.23.6440]
Zhao, L., Longo-Guess, C., Harris, B. S., Lee, J.-W., Ackerman, S. L. Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Nature Genet. 37: 974-979, 2005. [PubMed: 16116427] [Full Text: https://doi.org/10.1038/ng1620]
Zhao, L., Rosales, C., Seburn, K., Ron, D., Ackerman, S. L. Alteration of the unfolded protein response modifies neurodegeneration in a mouse model of Marinesco-Sjogren syndrome. Hum. Molec. Genet. 19: 25-35, 2010. [PubMed: 19801575] [Full Text: https://doi.org/10.1093/hmg/ddp464]