Alternative titles; symbols
HGNC Approved Gene Symbol: SMARCE1
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38) : 17:40,624,962-40,647,818 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | {Meningioma, familial, susceptibility to} | 607174 | Autosomal dominant | 3 |
| Coffin-Siris syndrome 5 | 616938 | Autosomal dominant | 3 |
The SWI/SNF complex in S. cerevisiae and Drosophila is thought to facilitate transcriptional activation of specific genes by antagonizing chromatin-mediated transcriptional repression. The complex contains an ATP-dependent nucleosome disruption activity that can lead to enhanced binding of transcription factors. The BRG1/brm (603254)-associated factors, or BAF, complex in mammals is functionally related to SWI/SNF and consists of 9 to 12 subunits, some of which are homologous to SWI/SNF subunits. See 601732. A 57-kD BAF subunit, BAF57, is present in higher eukaryotes, but not in yeast.
Wang et al. (1998) purified BAF57 from extracts of a human cell line and obtained a partial protein sequence. Based on the peptide sequences, they identified cDNAs encoding BAF57. The predicted 411-amino acid protein contains an HMG domain adjacent to a kinesin-like region. RNase protection studies and Western blot analysis revealed that BAF57 is expressed ubiquitously.
Wang et al. (1998) showed that both recombinant BAF57 and the whole BAF complex bind 4-way junction (4WJ) DNA, which is thought to mimic the topology of DNA as it enters or exits the nucleosome. The BAF57 DNA-binding activity has characteristics similar to those of other HMG proteins. However, Wang et al. (1998) found that complexes with mutations in the BAF57 HMG domain retain their DNA-binding and nucleosome-disruption activities. They suggested that the mechanism by which mammalian SWI/SNF-like complexes interact with chromatin may involve recognition of higher-order chromatin structure by 2 or more DNA-binding domains.
Coffin-Siris Syndrome 5
In a Japanese patient with Coffin-Siris syndrome-5 (CSS5; 616938), Tsurusaki et al. (2012) identified a de novo heterozygous missense mutation in the SMARCE1 gene (Y73C; 603111.0001). The mutation was found by exome sequencing; functional studies of the variant were not performed.
Wieczorek et al. (2013) identified a de novo heterozygous missense mutation affecting the same codon as the mutation identified by Tsurusaki et al. (2012) (Y73S; 603111.0006) in a 3-year-old girl with CSS5. The mutation was found by whole-exome sequencing; functional studies of the variant were not performed. The patient was 1 of 46 individuals with a clinical diagnosis of CSS who underwent sequencing, suggesting that SMARCE1 mutations are not common in this disorder.
Susceptibility to Familial Meningioma
In 6 patients from 4 unrelated families with spinal meningiomas (607174), Smith et al. (2013) identified 4 different heterozygous loss-of-function mutations in the SMARCE1 gene (603111.0002-603111.0005). The first 2 mutations were identified by exome sequencing, and the second 2 were found by Sanger sequencing of the SMARCE1 gene in 6 additional patients with spinal meningiomas. The age at onset was between 15 and 30 years, and 5 of the patients were female. Three of the woman developed the tumors during pregnancy, suggesting a hormonal influence on penetrance. One unaffected father was heterozygous for the mutation, indicating incomplete penetrance. All spinal tumors were clear-cell type, and all tumors studied showed loss of the SMARCE1 protein, consistent with a tumor suppressor mechanism. However, only 1 of 3 tumors analyzed showed loss of heterozygosity for wildtype SMARCE1. Sequencing SMARCE1 in 34 individuals with multiple cranial meningiomas did not identify any mutations, suggesting that the mutations are specific for spinal tumors. Smith et al. (2013) postulated that loss of SMARCE1 activity may lead to the uncoupling of apoptotic control.
Chi et al. (2002) generated transgenic mice expressing dominant-negative mutants of Baf57 lacking the N terminus, including the HMG and proline-rich domains, or bearing a point mutation, lys112 to ile (K112I), that disrupted DNA binding. T-cell-specific expression of these mutants gave rise to complexes specifically deficient in HMG-mediated functions. Flow cytometric analysis demonstrated a compromise in CD4 (186940) silencing, indicated by premature CD4 expression at double-negative stage 3 (DN3) and the absence of a DN4 stage, and impaired CD8 (see 186910) expression. Heterozygous Brg (603254) deletions indicated that CD8 expression was inhibited at the immature single-positive and double-positive stages independently of CD4 derepression. Mutational and flow cytometric analyses showed that CD4 silencer mutations and the Baf57 dominant-negative transgene each partially derepressed CD4 on DN3 cells. Immunoprecipitation analysis confirmed that Baf57 and Brg interacted with the CD4 silencer, but not with the CD8 enhancers III or IV. Chi et al. (2002) noted that the alterations in CD4 and CD8 expression during thymic development were not associated with changes in CD4/CD8 coreceptor expression in mature T cells, which were relatively normal. The authors concluded that BRG is a major regulator of CD8 expression. They suggested that chromatin remodeling is dependent on the DNA-bending activity unique to the HMG domain and that other DNA/chromatin-binding domains exist in BAF complexes.
In a Japanese patient (subject 24) with Coffin-Siris syndrome-5 (CSS5; 616938), Tsurusaki et al. (2012) detected a heterozygous A-to-G transition at nucleotide 218 of the SMARCE1 gene that resulted in a tyr-to-cys substitution at codon 73 (Y73C). The mutation occurred as a de novo event and was not observed in any of 368 Japanese controls, in the dbSNP (build 132), 1000 Genomes Project, or NHLBI Exome Sequencing Project databases. Functional studies of the variant were not performed.
In a mother and daughter with clear-cell spinal meningiomas (607174), Smith et al. (2013) identified a heterozygous c.715C-T transition in exon 9 of the SMARCE1 gene, resulting in an arg239-to-ter (R239X) substitution, predicted to result in nonsense-mediated mRNA decay. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, was not found in several large control exome databases.
In a mother and daughter who developed clear-cell spinal meningiomas (607174) during pregnancy, Smith et al. (2013) identified a heterozygous T-to-C transition in exon 5 of the SMARCE1 gene (c.237+2T-C), resulting in 2 abnormal transcripts: an insertion of the first 18 bases of intron 5, which introduces an in-frame premature stop codon after 3 codons and is predicted to lead to nonsense mediated decay (Lys79_Val80insTer), and a less-abundant transcript containing an in-frame deletion of exon 5 (Ala53_Lys79del). Skipping of exon 5 is predicted to remove the start of the high mobility group (HMG) domain. The mutation, which was identified by exome sequencing and confirmed by Sanger sequencing, was not found in several large control exome databases. Immunohistochemical studies showed absence of the SMARCE1 protein in tumor tissue.
In a 26-year-old man with 2 clear-cell spinal meningiomas (607174), Smith et al. (2013) identified a heterozygous c.311G-A transition in exon 6 of the SMARCE1 gene, resulting in a trp104-to-ter (W104X) substitution. The mutation was not found in several large control databases. One of the tumors showed loss of heterozygosity of SMARCE1.
In a 17-year-old girl who presented with a clear-cell spinal meningioma (607174) at the foramen magnum during pregnancy, Smith et al. (2013) identified a heterozygous 1-bp insertion (c.572insC) in exon 8 of the SMARCE1 gene, resulting in a frameshift and premature termination (Thr191ThrfsTer14). The tumor did not show loss of heterozygosity for SMARCE1, but immunohistochemical studies showed absence of the SMARCE1 protein. The patient's unaffected father also carried the mutation, which was not found in several large control databases.
In a 3-year-old girl (patient K2442) with Coffin-Siris syndrome-5 (CSS5; 616938), Wieczorek et al. (2013) identified a de novo heterozygous c.218A-C transversion (c.218A-C, NM_003079.4) in exon 5 of the SMARCE1 gene, resulting in a tyr73-to-ser (Y73S) substitution at a highly conserved residue in the HMG box domain. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP (build 135) database or in 105 in-house controls. A different mutation at the same codon (Y73C; 603111.0001) had been reported in another patient with CSS5. Functional studies of the variant were not performed. The patient was 1 of 46 individuals with a clinical diagnosis of CSS who underwent sequencing.
Chi, T. H., Wan, M., Zhao, K., Taniuchi, I., Chen, L., Littman, D. R., Crabtree, G. R. Reciprocal regulation of CD4/CD8 expression by SWI/SNF-like BAF complexes. Nature 418: 195-199, 2002. [PubMed: 12110891] [Full Text: https://doi.org/10.1038/nature00876]
Smith, M. J., O'Sullivan, J., Bhaskar, S. S., Hadfield, K. D., Poke, G., Caird, J., Sharif, S., Eccles, D., Fitzpatrick, D., Rawluk, D., du Plessis, D., Newman, W. G., Evans, D. G. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nature Genet. 45: 295-298, 2013. [PubMed: 23377182] [Full Text: https://doi.org/10.1038/ng.2552]
Tsurusaki, Y., Okamoto, N., Ohashi, H., Kosho, T., Imai, Y., Hibi-Ko, Y., Kaname, T., Naritomi, K., Kawame, H., Wakui, K., Fukushima, Y., Homma, T., and 19 others. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nature Genet. 44: 376-378, 2012. [PubMed: 22426308] [Full Text: https://doi.org/10.1038/ng.2219]
Wang, W., Chi, T., Xue, Y., Zhou, S., Kuo, A., Crabtree, G. R. Architectural DNA binding by a high-mobility-group/kinesin-like subunit in mammalian SWI/SNF-related complexes. Proc. Nat. Acad. Sci. 95: 492-498, 1998. [PubMed: 9435219] [Full Text: https://doi.org/10.1073/pnas.95.2.492]
Wieczorek, D., Bogershausen, N., Beleggia, F., Steiner-Haldenstatt, S., Pohl, E., Li, Y., Milz, E., Martin, M., Thiele, H., Altmuller, J., Alanay, Y., Kayserili, H., and 44 others. A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling. Hum. Molec. Genet. 22: 5121-5135, 2013. [PubMed: 23906836] [Full Text: https://doi.org/10.1093/hmg/ddt366]