Alternative titles; symbols
HGNC Approved Gene Symbol: SMARCC2
Cytogenetic location: 12q13.2 Genomic coordinates (GRCh38) : 12:56,162,359-56,189,483 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q13.2 | Coffin-Siris syndrome 8 | 618362 | Autosomal dominant | 3 |
The SMARCC2 gene encodes BAF170, the 170-kD subunit of the SWI/SNF chromatin remodeling complex (Wang et al., 1996).
See also BAF60a (601735), -b (601736), and -c (601737), other subunits in this complex.
Chromatin is actively remodeled during development. Chromatin remodeling of certain genes appears to precede their transcriptional activation. In yeast, the multisubunit SWI/SNF complex is thought to be responsible for chromatin remodeling. Wang et al. (1996) isolated an analogous SWI/SNF complex from the human YT cell line. They found that the resultant complexes are composed of 9 to 12 polypeptides, which they termed BAFs (for BRG1-associated factors). The BAF170 subunit encodes a polypeptide of 1,213 amino acids and is homologous both to the yeast SWI3 gene and to BAF155 (601732). SWI3, BAF155, and BAF170 all contain a predicted leucine zipper region (a dimerization motif for a variety of transcription factors) and a myb-like tryptophan-repeat domain. Western blot analysis and EST database analysis revealed that BAF170 is expressed in many tissues.
By immunohistochemical analysis of adult mouse hippocampus, Tuoc et al. (2017) found that Baf170 was expressed in cell types involved in the sequential steps of adult neurogenesis, including radial glial-like (RGL) cells, mature astrocytes, immature neurons, and mature neurons.
By PCR of a somatic cell hybrid panel and radiation hybrid analysis, Ring et al. (1998) mapped the SMARCC2 gene to chromosome 12q13-q14.
Using transgenic mice, Tuoc et al. (2013) found that Baf170 regulated cortical size and thickness by controlling the direct or indirect mode of cortical neuronal output, thereby influencing the composition of lower and upper layer laminae. Baf170 interacted with Pax6 (607108) and suppressed expression of Pax6 target genes, including those that regulate generation of intermediate and late cortical progenitors, by directly recruiting the REST (600571)-corepressor (RCOR; 607675) complex to their promoters. Baf155 and Baf170 competed with one another within the SWI/SNF complex in cortical radial glial cells, and the balance between Baf170 and Baf155 affected chromatin modifications and modulated binding of the Pax6/REST-corepressor complex to Pax6 target promoters. Tuoc et al. (2013) concluded that BAF170 acts within a precise time window to repress indirect cortical neurogenesis and control cortical size.
In 15 patients with Coffin-Siris syndrome-8 (CSS8; 618362), Machol et al. (2019) detected 13 heterozygous mutations in the SMARCC2 gene, 12 of which occurred de novo. Three mutations affected splicing, 1 resulted in frameshift, 1 caused a premature termination codon, 7 were missense, and 1 was an in-frame single amino acid deletion. Two mutations were recurrent. All 7 missense mutations occurred in highly conserved amino acids and were predicted to be deleterious by various in silico tools. The mutations clustered in the SWIRM and SANT domains of the protein, and the presence of a majority of missense and splice site mutations suggested a dominant-negative mechanism.
Tuoc et al. (2013) found that Baf170-null mice died shortly after birth. Conditional knockout of Baf170 in developing cortex of transgenic mice promoted indirect neurogenesis and resulted in an enlarged cortex, whereas conditional overexpression of Baf170 in developing cortex induced direct neurogenesis and resulted in a smaller cortex.
Tuoc et al. (2017) found that conditional deletion of Baf170 in developing and postnatal mouse hippocampus affected positioning and proliferation of RGL cells in subgranular zone (SGZ) of dentate gyrus (DG). Baf170-deleted RGL cells underwent premature differentiation predominantly into astrocytes rather than generating neuronal progenitors and neurons, resulting in depletion of the RGL cell pool in SGZ of DG. Deletion of Baf170 in the SGZ of DG in adult mouse brain also affected generation and maintenance of RGL progenitors, which seemed to differentiate into astrocytes prematurely. Ablation of Baf170 during late and postnatal hippocampus neurogenesis impaired the accuracy of place responding and reversal learning. In contrast, deletion of Baf170 in adult mouse brain impaired spatial learning during late stages, but impairment of hidden platform task and reduction of proactive memory interference during early stages was only moderate.
In a 7-year-old boy with Coffin-Siris syndrome-8 (CSS8; 618362) from a nonconsanguineous family (trio 74), Zhu et al. (2015) detected heterozygosity for a c.1833+2T-C transition in the SMARCC2 gene that disrupted a canonical splice site.
Machol et al. (2019) included the patient of Zhu et al. (2015) in their report as patient 10, and additionally found the c.1833+2T-C mutation (c.1833+2T-C, NM_003075.3) in a 2.5-year-old boy (patient 9). The authors showed that the mutation occurred de novo in both cases. Machol et al. (2019) noted that the mutation occurred in intron 19 in the highly conserved SANT domain, which has DNA-binding activity and functions as a histone tail-binding module.
In a female patient (patient 36) with Coffin-Siris syndrome-8 (CSS8; 618362), Martinez et al. (2017) reported a de novo heterozygous c.1311-3C-G transversion (c.1311-3C-G, NM_003075.3) in the SMARCC2 gene that was predicted to result in aberrant splicing.
Machol et al. (2019) reported the patient of Martinez et al. (2017) as patient 4, and gave her age as 17 years. The c.1311-3C-G mutation in intron 14 occurs in the SWIRM domain of the protein, which interacts with DNA, binds dinucleosome structures, and mediates specific protein-protein interactions. Quantitative RT-PCR in lymphocytes from patient 4 demonstrated an approximately 50% decrease in SMARCC2 mRNA compared to a control, suggesting haploinsufficiency through nonsense-mediated decay (NMD).
In 2 unrelated individuals (patients 6 and 7) with Coffin-Siris syndrome-8 (CSS8; 618362), Machol et al. (2019) reported a heterozygous de novo c.1829T-C transition (c.1829T-C, NM_003075.3) in exon 19 of the SMARCC2 gene, resulting in a leucine-to-proline substitution at codon 610 (L610P). Patient 6 was an 18-year-old female, and patient 7 was an 11-year-old male. The L610P mutation occurs in the SANT domain of the protein, which has DNA-binding activity and functions as a histone tail-binding module.
In a 3-year-old boy (patient 2) and his affected father with Coffin-Siris syndrome-8 (CSS8; 618362), Machol et al. (2019) identified a heterozygous de novo c.723G-A transition (c.723G-A, NM_003075.3) in exon 9 of the SMARCC2 gene, resulting in a tryptophan-to-termination substitution at codon 241 (W241X). Both the patient and his father had a mild phenotype. Neither RNA nor cells from the patient were available to test for NMD.
In an 8-year-old male (patient 13) with Coffin-Siris syndrome-8 (CSS8; 618362), Machol et al. (2019) reported a heterozygous de novo c.2686A-G transition (c.2686A-G, NM_003075.3) in exon 25 of the SMARCC2 gene, resulting in a met896-to-val substitution (M896V).
Machol, K., Rousseau, J., Ehresmann, S., Garcia, T., Nguyen, T. T. M., Spillmann, R. C., Sullivan, J. A., Shashi, V., Jiang, Y., Stong, N., Fiala, E., Willing, M., and 34 others. Expanding the spectrum of BAF-related disorders: de novo variants in SMARCC2 cause a syndrome with intellectual disability and developmental delay. Am. J. Hum. Genet. 104: 164-178, 2019. [PubMed: 30580808] [Full Text: https://doi.org/10.1016/j.ajhg.2018.11.007]
Martinez, F., Caro-Llopis, A., Rosello, M., Oltra, S., Mayo, S., Monfort, S., Orellana, C. High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. J. Med. Genet. 54: 87-92, 2017. [PubMed: 27620904] [Full Text: https://doi.org/10.1136/jmedgenet-2016-103964]
Ring, H. Z., Vameghi-Meyers, V., Wang, W., Crabtree, G. R., Francke, U. Five SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin (SMARC) genes are dispersed in the human genome. Genomics 51: 140-143, 1998. [PubMed: 9693044] [Full Text: https://doi.org/10.1006/geno.1998.5343]
Tuoc, T. C., Boretius, S., Sansom, S. N., Pitulescu, M.-E., Frahm, J., Livesey, F. J., Stoykova, A. Chromatin regulation by BAF170 controls cerebral size and thickness. Dev. Cell 25: 256-269, 2013. [PubMed: 23643363] [Full Text: https://doi.org/10.1016/j.devcel.2013.04.005]
Tuoc, T., Dere, E., Radyushkin, K., Pham, L., Nguyen, H., Tonchev, A. B., Sun, G., Ronnenberg, A., Shi, Y., Staiger, J. F., Ehrenreich, H., Stoykova, A. Ablation of BAF170 in developing and postnatal dentate gyrus affects neural stem cell proliferation, differentiation, and learning. Molec. Neurobiol. 54: 4618-4635, 2017. [PubMed: 27392482] [Full Text: https://doi.org/10.1007/s12035-016-9948-5]
Wang, W., Xue, Y., Zhou, S., Kuo, A., Cairns, B. R., Crabtree, G. R. Diversity and specialization of mammalian SWI/SNF complexes. Genes Dev. 10: 2117-2130, 1996. [PubMed: 8804307] [Full Text: https://doi.org/10.1101/gad.10.17.2117]
Zhu, X., Petrovski, S., Xie, P., Ruzzo, E. K., Lu, Y.-F., McSweeney, K. M., Ben-Zeev, B., Nissenkorn, A., Anikster, Y., Oz-Levi, D., Dhindsa, R. S., Hitomi, Y., and 15 others. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet. Med. 17: 774-781, 2015. [PubMed: 25590979] [Full Text: https://doi.org/10.1038/gim.2014.191]