Alternative titles; symbols
HGNC Approved Gene Symbol: SMARCC1
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:47,585,269-47,781,893 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | {Hydrocephalus, congenital, 5, susceptibility to} | 620241 | Autosomal dominant | 3 |
The SMARCC1 gene encodes BAF155, the 155-kD subunit of the SWI/SNF chromatin remodeling complex (Wang et al., 1996). See also BAF60a (601735), -b (601736), and -c (601373), other subunits in this complex.
SMARCC1 is an ATP-dependent chromatin remodeler that regulates gene expression required for neural stem cell proliferation, differentiation, and survival during telencephalon development (summary by Jin et al., 2020).
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 human YT cells. They found that the resultant complexes are composed of 9 to 12 polypeptides, which they termed BAFs (for BRG1-associated factors). Wang et al. (1996) isolated BAF155 from a human Jurkat T-cell cDNA library. This gene encodes a polypeptide of 1,104 amino acids, and is homologous both to the yeast SWI3 gene and to BAF170, another of the proteins in this chromatin remodeling complex (601734). 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 BAF155 is expressed in many tissues.
Furey et al. (2018) noted that Smarcc1 is highly expressed in ciliated cells of the neuroepithelium and ventricular zone of the developing mouse brain, with lesser expression later in brain development.
Cryoelectron Microscopy
He et al. (2020) reported the 3.7-angstrom resolution cryoelectron microscopy structure of human BRG1 (SMARCA4; 603254)/BRM-associated factor complex, including SMARCC, bound to the nucleosome. The structure revealed that the nucleosome is sandwiched by the base and the ATPase modules, which are bridged by the actin-related protein (ARP) module, composed of an ACTL6A (604958)-ACTB (102630) heterodimer and the long alpha helix of the helicase-SANT-associated region (HSA) of SMARCA4. The ATPase motor is positioned proximal to nucleosomal DNA and, upon ATP hydrolysis, engages with and pumps DNA along the nucleosome. The C-terminal alpha helix of SMARCB1, enriched in positively charged residues frequently mutated in cancers, mediates interactions with an acidic patch of the nucleosome. ARID1A (603024) and the SWI/SNF complex subunit SMARCC serve as a structural core and scaffold in the base module organization, respectively.
By PCR of a somatic cell hybrid panel and radiation hybrid analysis, Ring et al. (1998) mapped the SMARCC1 gene to chromosome 3p23-p21.
In 2 unrelated children with congenital hydrocephalus-5 (HYC5; 620241), Furey et al. (2018) identified heterozygous variants in the SMARCC1 gene (601732.0001 and 601732.0002). The variants were identified by exome sequencing and confirmed by Sanger sequencing. One of the variants (a missense variant) occurred de novo in the patient, whereas the other (a frameshift variant) was inherited from an unaffected father. Three additional heterozygous putative loss-of-function variants in the SMARCC1 gene were identified in 3 additional probands with HYC5. However, in 2 cases, the variant was inherited from an unaffected parent; parental studies were not performed in the third. None of the variants were present in the gnomAD database. Functional studies of the variants and studies of patient cells were not performed. All 5 individuals had aqueductal stenosis. Overall, these findings were consistent with incomplete penetrance and variable expressivity. Based on the expression pattern of SMARCC1, the authors suggested that this form of hydrocephalus is related to impaired or disrupted neurogenesis rather than active CSF accumulation. The patients were part of a cohort of 88 probands with communicating hydrocephalus and 89 probands with hydrocephalus associated with aqueductal stenosis who underwent whole-exome sequencing.
In 6 patients from 5 unrelated families with HYC5, Jin et al. (2020) identified heterozygous putative loss-of-function variants in the SMARCC1 gene (see, e.g., 601732.0003 and 601732.0004). The variants were found by exome sequencing and confirmed by Sanger sequencing. One of the variants occurred de novo, 3 were inherited from unaffected parents, and the inheritance pattern in 1 individual could not be determined. These findings were consistent with incomplete penetrance and variable expressivity. Functional studies of the variants and studies of patient cells were not performed. Clinical details were not provided.
In a boy (family Hydro106) with congenital hydrocephalus-5 (HYC5; 620241) due to aqueductal stenosis, Furey et al. (2018) identified a heterozygous 1-bp deletion (delA) in the SMARCC1 gene, predicted to result in a frameshift and premature termination (Lys891fsTer4). The variant, which was found by exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected father in whom it occurred de novo. Two sibs of the proband were diagnosed prenatally with congenital hydrocephalus with aqueductal stenosis resulting in death; DNA was not available from these individuals. Another unaffected sib of the proband also carried the variant, indicating incomplete penetrance. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function. The variant was not present in the gnomAD database.
In a girl (family Hydro105) with congenital hydrocephalus-5 (HYC5; 620241) associated with aqueductal stenosis, Furey et al. (2018) identified a de novo heterozygous his526-to-pro (H526P) substitution in the SMARCC1 gene in a conserved position in the SWIRM domain, which mediates BAF complex subunit interactions. The mutation was found by exome sequencing and confirmed by Sanger sequencing; it was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
In 2 boys (family KCHYD363) with congenital hydrocephalus-5 (HYC5; 620241), Jin et al. (2020) identified a heterozygous gln575-to-ter (Q575X) substitution in the SMARCC1 gene. The variant was found by exome sequencing and confirmed by Sanger sequencing. It was inherited from the unaffected mother and also present in another unaffected sib, indicating incomplete penetrance and variable expressivity. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
In a girl with congenital hydrocephalus-5 (HYC5; 620241), Jin et al. (2020) identified a de novo heterozygous G-to-A transition (c.1571+1G-A) in the SMARCC1 gene, predicted to disrupt a splice site. The variant was found by exome sequencing and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed, but it was predicted to result in a loss of function.
Furey, C. G., Choi, J., Jin, S. C., Zeng, X., Timberlake, A. T., Nelson-Williams, C., Mansuri, M. S., Lu, Q., Duran, D., Panchagnula, S., Allocco, A., Karimy, J. K., and 33 others. De novo mutation in genes regulating neural stem cell fate in human congenital hydrocephalus. Neuron 99: 302-314, 2018. [PubMed: 29983323] [Full Text: https://doi.org/10.1016/j.neuron.2018.06.019]
He, S., Wu, Z., Tian, Y., Yu, Z., Yu, J., Wang, X., Li, J., Liu, B., Xu, Y. Structure of nucleosome-bound human BAF complex. Science 367: 875-881, 2020. [PubMed: 32001526] [Full Text: https://doi.org/10.1126/science.aaz9761]
Jin, S. C., Dong, W., Kundishora, A. J., Panchagnula, S., Moreno-De-Luca, A., Furey, C. G., Allocco, A. A., Walker, R. L., Nelson-Williams, C., Smith, H., Dunbar, A., Conine, S., and 49 others. Exome sequencing implicates genetic disruption of prenatal neuro-gliogenesis in sporadic congenital hydrocephalus. Nature Med. 26: 1754-1765, 2020. [PubMed: 33077954] [Full Text: https://doi.org/10.1038/s41591-020-1090-2]
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]
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]