Alternative titles; symbols
HGNC Approved Gene Symbol: SMARCA4
Cytogenetic location: 19p13.2 Genomic coordinates (GRCh38) : 19:10,961,030-11,062,273 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19p13.2 | ?Otosclerosis 12 | 620792 | Autosomal dominant | 3 |
| {Rhabdoid tumor predisposition syndrome 2} | 613325 | Autosomal dominant | 3 | |
| Coffin-Siris syndrome 4 | 614609 | Autosomal dominant | 3 |
The SMARCA4 gene encodes a catalytic subunit of SWI/SNF complexes, which function as regulators of gene expression by remodeling chromatin to alter nucleosome conformation, making it more accessible to transcriptional activation (summary by Jelinic et al., 2014).
The S. cerevisiae SNF2/SWI2 protein is required for transcription of a number of genes under differential regulation. See BAF57 (603111). The Drosophila 'brahma' (brm) protein is a SWI2 homolog that activates homeotic genes. By screening a HeLa cell library with a brm cDNA, Khavari et al. (1993) isolated cDNAs encoding a protein that they designated BRG1 (brm/SWI2-related gene-1). The predicted 1,613-amino acid protein has 4 domains that are highly related to those found in brm, including a proline-rich domain, 6 sequence motifs characteristic of some DNA-dependent ATPases, and a bromodomain. BRG1 and brm share 52% protein sequence identity. Antibodies against BRG1 detected a 205-kD protein in various human tissues and cell cultures. The protein was found in nuclear but not cytoplasmic extracts of T cells. Northern blot analysis revealed that BRG1 is expressed as a 5-kb mRNA in human T cells. The authors reported a corrected version of the published sequence in GenBank (U29175).
Chiba et al. (1994) isolated cDNAs encoding SMARCA2 (600014) and BRG1, which they called SNF2-alpha and SNF2-beta, respectively.
Using chromatography, Khavari et al. (1993) demonstrated that, like SWI2 in yeast, BRG1 is part of a protein complex in human cells. A chimeric SWI2 protein containing the BRG1 DNA-dependent ATPase motif restored normal mitotic growth and capacity for transcriptional activation to yeast swi2 mutant cells. Point mutation of a conserved ATP binding site residue in BRG1 generated a transcriptional dominant-negative in human cells. Khavari et al. (1993) suggested that the dominant-negative effect is due to formation of nonfunctional activator complexes at specific promoter sites.
Using a combination of affinity- and conventional chromatographic techniques, Bochar et al. (2000) isolated a predominant form of a multiprotein BRCA1 (113705)-containing complex from human cells displaying chromatin-remodeling activity. Mass spectrometric sequencing of components of this complex indicated that BRCA1 is associated with a SWI/SNF-related complex, and the authors showed that BRCA1 can directly interact with the BRG1 subunit of the SWI/SNF complex. Moreover, p53 (TP53; 191170)-mediated stimulation of transcription by BRCA1 was completely abrogated by either a dominant-negative mutant of BRG1 (Khavari et al., 1993) or the cancer-causing deletion of exon 11 of BRCA1 (Xu et al., 1999). These findings revealed a direct function for BRCA1 in transcriptional control through modulation of chromatin structure.
Otsuki et al. (2001) used yeast 2-hybrid analysis and immunofluorescence to identify an interaction between the Fanconi anemia protein, FANCA (607139) and BRG1. The authors suggested that FANCA may recruit the SWI/SNF complex to target genes, thereby enabling coupled nuclear functions such as transcription and DNA repair.
Using recombinant human proteins, Aalfs et al. (2001) showed that both SNF2H (603375) and BRG1 were nucleosome-stimulated ATPases. BRG1 ATPase activity was also stimulated by naked DNA, whereas SNF2H activity was not. Both proteins remodeled nucleosomes and increased accessibility of restriction sites within a defined nucleosomal array with similar specific activities and rates. However, SNF2H only remodeled a subset of templates within the total population, and the prevalence of this subset varied from assembly to assembly, whereas BRG1 remodeled nearly all templates regardless of assembly conditions. Moreover, unlike BRG1, SNF2H did not display detectable remodeling activity on mononucleosomes, and it did not introduce topologic changes in circular chromatin.
Huang et al. (2002) determined that BRG1 interacts with STAT2 (600556) and mediates the expression of 2 interferon-alpha (IFNA; see 147660)-induced genes, IFITM1 (604456) and IFI27 (600009). Expression of these genes was impaired in human adrenocortical carcinoma and cervical carcinoma cell lines lacking expression of BRG1 protein. Expression of IFITM1 and IFI27 was restored in the adrenocortical carcinoma cells following transfection with wildtype BRG1, but not with an ATPase-defective BRG1 mutant and not with 2 BRG1 deletion mutants that were defective in STAT2 binding. The expression of 4 other IFNA-induced target genes was independent of BRG1 expression.
Kadam and Emerson (2003) showed that BRG1 and BRM associate with different promoters during cellular proliferation and differentiation, and in response to specific signaling pathways by preferential interaction with certain classes of transcription factors. BRG1 binds to zinc finger proteins through a unique N-terminal domain that is not present in BRM. BRM interacts with 2 ankyrin repeat proteins that are critical components of Notch signal transduction. The authors concluded that BRG1 and BRM complexes may direct distinct cellular processes by recruitment to specific promoters through protein-protein interactions that are unique to each ATPase.
Medina et al. (2005) restored BRG1 in H1299 lung cancer cells and used cDNA microarray analysis to identify changes in gene expression. Forty-three transcripts became activated, whereas 2 were repressed. Both CYP3A4 (124010) and ZNF185 (300381) promoters recruited BRG1; BRG1 recruitment was specific to the CYP3A4 promoter and did not involve the CYP3A5 (605325) or CYP3A7 (605340) family members. In 7 additional lung cancer cell lines, CYP3A4 was undetectable. In contrast, the amount of ZNF185 transcript clearly varied among lung cancer cell lines and severely reduced levels were observed in BRG1-deficient cells, except A427 cells. In lung primary tumours, real-time RT-PCR revealed that 4 of 27 and 14 of 27 tumors had BRG1 and ZNF185 downregulation, respectively, when compared with normal lung. No significant correlation between reduced levels of BRG1 and ZNF185 was observed. Medina et al. (2005) concluded that transcriptional activation of ZNF185 and CYP3A4 is mediated by direct association of BRG1 with their promoters, and that a decreased level of ZNF185 is a common feature of lung tumors and may be of biologic relevance in lung carcinogenesis.
In cellular studies, Bilodeau et al. (2006) demonstrated that BRG1 was essential for glucocorticoid-induced transrepression of the POMC gene (176830) in the negative feedback regulation mechanism. BRG1 was required to stabilize interactions between the glucocorticoid receptor (GCCR; 138040) and NGFIB (139139) or HDAC2 (605164). In 17 (47%) of 36 human corticotroph adenomas, which are found in Cushing disease (219090) and associated with glucocorticoid resistance, Bilodeau et al. (2006) found altered expression and/or subcellular localization of either BRG1 (12 tumors) or HDAC2 (5 tumors) compared to adjacent normal pituitary tissue. Bilodeau et al. (2006) concluded that BRG1 acts as a scaffold required to form a ligand- and GCCR-dependent repression machinery that inhibits transcription.
Park et al. (2009) demonstrated that telomerase directly modulates Wnt/beta-catenin (see 116806) signaling by serving as a cofactor in a beta-catenin transcriptional complex. The telomerase protein component TERT (187270) interacts with BRG1, a SWI/SNF-related chromatin remodeling protein, and activates Wnt-dependent reporters in cultured cells and in vivo. TERT serves an essential role in formation of the anterior-posterior axis in Xenopus laevis embryos, and this defect in Wnt signaling manifests as homeotic transformations in the vertebrae of Tert-null mice. Chromatin immunoprecipitation of the endogenous TERT protein from mouse gastrointestinal tract showed that TERT physically occupies gene promoters of Wnt-dependent genes such as AXIN2 (604025) and MYC (190080). Park et al. (2009) concluded that their data revealed an unanticipated role for telomerase as a transcriptional modulator of the Wnt/beta-catenin signaling pathway.
In mice, adult cardiomyocytes primarily express alpha-myosin heavy chain (alpha-MHC, also known as Myh6; 160710), whereas embryonic cardiomyocytes express beta-MHC (also known as Myh7; 160760). Cardiac stress triggers adult hearts to undergo hypertrophy and a shift from alpha-MHC to fetal beta-MHC expression. Hang et al. (2010) showed that BRG1, a chromatin remodeling protein, has a critical role in regulating cardiac growth, differentiation, and gene expression. In embryos, Brg1 promotes myocyte proliferation by maintaining Bmp10 (608748) and suppressing p57(kip2) (600856) expression. It preserves fetal cardiac differentiation by interacting with histone deacetylases and poly(ADP ribose) polymerase (PARP; 173870) to repress alpha-MHC and activate beta-MHC. In adults, Brg1 is turned off in cardiomyocytes. It is reactivated by cardiac stresses and forms a complex with its embryonic partners, HDAC and PARP, to induce a pathologic alpha-MHC-to-beta-MHC shift. Preventing Brg1 reexpression decreases hypertrophy and reverses this MHC switch. BRG1 is activated in certain patients with hypertrophic cardiomyopathy, its level correlating with disease severity and MHC changes. Hang et al. (2010) concluded that their studies showed that BRG1 maintains cardiomyocytes in an embryonic state, and demonstrated an epigenetic mechanism by which 3 classes of chromatin-modifying factors, BRG1, HDAC, and PARP, cooperate to control developmental and pathologic gene expression.
Dykhuizen et al. (2013) showed that BRG1-associated factor (BAF) complexes decatenate newly replicated sister chromatids, a requirement for proper chromosome segregation during mitosis. Dykhuizen et al. (2013) found that deletion of Brg1 in mouse cells, as well as the expression of BRG1 point mutations identified in human tumors, leads to anaphase bridge formation (in which sister chromatids are linked by catenated strands of DNA) and a G2/M-phase block characteristic of the decatenation checkpoint. Endogenous BAF complexes interact directly with endogenous topoisomerase II-alpha (TOP2A; 126430) through BAF250a (603024) and are required for the binding of TOP2A to approximately 12,000 sites across the genome. Dykhuizen et al. (2013) concluded that TOP2A chromatin binding is dependent on the ATPase activity of BRG1, which is compromised in oncogenic BRG1 mutants. They further concluded that the ability of TOP2A to prevent DNA entanglement at mitosis requires BAF complexes and suggested that this activity contributes to the role of BAF subunits as tumor suppressors.
Han et al. (2014) found that mouse Brg1 did not bind to the naked DNA of the Myh6 promoter, but that it readily bound to the in vitro-chromatinized Myh6 promoter.
Fillmore et al. (2015) demonstrated that EZH2 (601573) inhibition has differential effects on the TopoII inhibitor response of nonsmall-cell lung cancers in vitro and in vivo. EGFR (131550) and BRG1 mutations are genetic biomarkers that predict enhanced sensitivity to TopoII inhibitor in response to EZH2 inhibition. BRG1 loss-of-function mutant tumors respond to EZH2 inhibition with increased S phase, anaphase bridging, apoptosis, and TopoII inhibitor sensitivity. Conversely, EGFR and BRG1 wildtype tumors upregulate BRG1 in response to EZH2 inhibition and ultimately become more resistant to TopoII inhibitor. EGFR gain-of-function mutant tumors are also sensitive to dual EZH2 inhibition and TopoII inhibitor, because of genetic antagonism between EGFR and BRG1.
SMARCA4-containing BAF complexes oppose the activity of polycomb repressive complexes (PRC; see EZH1, 601674). Stanton et al. (2017) found that knockdown of Smarca4 in mouse embryonic stem cells, or inactivating mutations within the ATPase domain of SMARCA4 in human cells, increased genomewide deposition of PRC on chromatin and increased PRC activity, particularly trimethylation of histone 3 lys4 (H3K4me3) on CpG-rich bivalent promoters. Inactivation of SMARCA4 also elevated H3K27me3 approximately 2 kb away from PRC1 (603484) occupancy. Wildtype BAF interacted directly with PRC1, and incubation with ATP dissociated the complex. ATPase domain mutations in SMARCA4 reduced direct binding between BAF complex and PRC1. A chemical-induced proximity assay revealed that wildtype BAF directly evicted Polycomb factors within minutes of its chromatin occupancy. Stanton et al. (2017) concluded that ATPase activity of SMARCA4 directly evicts PRC from chromatin, permitting gene expression.
Cryoelectron Microscopy
He et al. (2020) reported the 3.7-angstrom resolution cryoelectron microscopy structure of human BRG1 (SMARCA4)/BRM-associated factor (BAF) complex 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 (601607), 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 (601732) serve as a structural core and scaffold in the base module organization, respectively.
Rhabdoid Tumor Predisposition Syndrome 2
By candidate gene sequencing in 2 German sisters with rhabdoid tumor predisposition syndrome-2 (RTPS2; 613325), Schneppenheim et al. (2010) identified a heterozygous germline truncating mutation in the SMARCA4 gene (R1189X; 603254.0001). The girls' unaffected father was heterozygous for the germline R1189X mutation, indicating reduced penetrance. Analysis of tumor tissue showed complete loss of SMARCA4 expression and loss of heterozygosity at the SMARCA4 locus. SNP array analysis indicated that partial uniparental disomy of the paternal allele was the cause of LOH in the tumors. Schneppenheim et al. (2010) noted both SMARCA4 and the tumor suppressor SMARCB1 (601607), which is mutant in RTPS1 (609322), are members of the ATP-dependent SWI/SNF chromatin-remodeling complex.
In a mother and daughter with RTPS2, Witkowski et al. (2013) identified a germline heterozygous truncating mutation in the SMARCA4 gene (W1178X; 603254.0008). The mutation was found by whole-exome sequencing. Tumor tissue from both patients also carried a somatic truncating mutation in the SMARCA4 gene, consistent with the '2-hit' hypothesis of tumorigenesis.
In affected members of 4 unrelated families with RTPS2 presenting as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), Witkowski et al. (2014) identified 4 different germline heterozygous mutations in the SMARCA4 gene (603254.0009-603254.0012). The mutations in the first 3 families were found by whole-exome sequencing and resulted in complete loss of the SMARCA4 protein. Tumor tissue, when available, showed either a somatic inactivating SMARCA4 mutation or loss of heterozygosity at the SMARCA4 locus. Whole-exome or Sanger sequencing identified at least 1 germline or somatic SMARCA4 mutation in 24 of 26 additional cases of SCCOHT as well as in the BIN-67 cell line. Six of 12 apparently nonfamilial cases for which nontumor tissue was available carried a deleterious germline SMARCA4 mutation, indicating that hereditary cases are more common than previously thought. Immunohistochemical studies showed loss of SMARCA4 expression in 38 of 43 SCCOHT tumors; 3 of those that retained SMARCA4 expression were later recategorized as non-SCCOHT. Witkowski et al. (2014) concluded that SCCOHT falls within the category of extracranial rhabdoid tumors, to which it is more similar than to other types of ovarian carcinoma.
Jelinic et al. (2014) identified biallelic inactivating somatic mutations in the SMARCA4 gene in 100% of 12 SCCOHT samples. The mutations were found by exome sequencing of 279 cancer-related genes in these tumors and were confirmed by Sanger sequencing. Four tumors carried 2 inactivating mutations, whereas 8 carried a single inactivating mutation accompanied by loss of heterozygosity at the SMARCA4 locus. No missense mutations were identified. Immunohistochemical studies of 9 cases with available tissue showed clear loss of SMARCA4 protein expression in 7 cases; the remaining 2 cases showed expression of a catalytically inactive truncated protein and equivocal protein expression, respectively. In 1 case, a patient carried a heterozygous germline truncating mutation associated with loss of heterozygosity in the tumor sample and decreased protein expression in the tumor, suggesting that there may be a hereditary component. Expression of SMARCA4 in SMARCA4-null lung adenocarcinoma cells resulted in a dose-dependent suppression of cell growth. The findings were consistent with SMARCA4's role as a tumor suppressor gene.
Using whole-exome or whole-genome sequencing, Ramos et al. (2014) identified somatic inactivating mutations in the SMARCA4 gene in 6 of 9 SCCOHT tumors and in the SCCOHT cell line BIN-67. Two tumors carried 2 mutations each, indicating biallelic inactivation. Most of the mutations affected the ATPase domain and were expected to result in truncated proteins. Heterozygous germline truncating SMARCA4 mutations were found in 2 of 7 affected girls who were studied, but tumor DNA was not available from these 2 patients. Immunohistochemical studies showed that all tumor samples with a SMARCA4 mutation lacked SMARCA4 protein expression. Loss of SMARCA4 was highly specific to SCCOHT; SMARCA4 protein loss was found in only 0.4% (2 of 485) of primary ovarian epithelial, sex cord stromal, and germ cell tumors. The findings indicated that loss of normal SWI/SNF complex function may represent a key tumorigenic step in SCCOHT formation.
Coffin-Siris Syndrome 4
Tsurusaki et al. (2012) identified 5 missense mutations (603254.0003-603254.0007) and an in-frame deletion (603254.0002) in the SMARCA4 gene in patients with Coffin-Siris syndrome (CSS4; 614609). Whereas germline heterozygous truncating mutations in SMARCA4 have been reported in individuals with rhabdoid tumor predisposition syndrome-2 (613325), all mutations in the CSS4 patients were nontruncating, implying that they exert gain-of-function or dominant-negative effects.
Otosclerosis 12
In 6 affected members of a 2-generation family with otosclerosis (OTSC12; 620792), Drabkin et al. (2024) identified heterozygosity for a missense mutation in the SMARCA4 gene (E1610K; 603254.0013). The pedigree showed incomplete penetrance, with obligate carrier parents reporting normal hearing.
Bultman et al. (2000) generated Brg1-null mice by gene targeting. Brg1 -/- mice died during the periimplantation stage. Furthermore, blastocyst outgrowth studies indicated that neither the inner cell mass nor trophectoderm survived. Experiments with other cell types, however, demonstrated that Brg1 is not a general cell survival factor. Brg1 +/- mice were predisposed to exencephaly (5 of 36) and tumors (3 of 20 displayed large subcutaneous tumors localized to the neck or inguinal regions). These results provided evidence that biochemically similar chromatin-remodeling complexes have dramatically different functions during mammalian development.
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 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.
Using Cre/loxP methodologies, Gebuhr et al. (2003) ablated Brg1 function in mouse T lymphocytes. These mice had gross thymic abnormalities and CD4 derepression at the double-negative stage with no transition to the double-positive stage. Brg1 deficiency did not lead to increased cancer incidence, but there was an increase in death associated with rectal prolapse and endogenous Helicobacter infection. Gebuhr et al. (2003) concluded that chromatin-remodeling complexes are important at different stages in development of the T-cell lineage and the immune response.
Zygotic genome activation (ZGA) is a nuclear reprogramming event that transforms the genome from transcriptional quiescence at fertilization to transcriptional activity shortly thereafter. In order to study the role of Brg1 in ZGA in mice, Bultman et al. (2006) conditionally deleted the Brg1 gene in oocytes. In conditionally mutant females, Brg1-depleted oocytes were meiotically competent and capable of being fertilized, but embryos conceived from depleted eggs exhibited a ZGA defect. Development was arrested at the 2- to 4-cell stage, and transcriptional activity was reduced for about 30% of genes expressed at this stage. Genes involved in transcription, RNA processing, and cell cycle regulation were particularly affected. Examination of covalent histone modification in maternally depleted embryos implicated maternal Brg1 in establishing chromatin structure and transcriptional competence at the 2-cell stage.
Using CRISPR/Cas9, Drabkin et al. (2024) created transgenic mice carrying the human E1610K mutation in the mouse ortholog. Heterozygous mutant mice showed no overt morphologic or behavioral abnormalities compared to their wildtype littermates, and had no gross anatomic anomalies on whole-body X-rays. However, acoustic startle response testing in awake 4-month-old mutant mice revealed hearing impairment, with significantly reduced startle amplitudes at almost all tested stimulus volumes, compared to wildtype mice. Auditory brainstem response testing showed modest but consistently elevated thresholds in the mutant mice, both to pure tone stimuli across all tested frequencies and to broadband (click) stimuli. The authors also studied auditory bullae (the equivalent of the otic capsule in humans) from the mutant mice and observed malformations in the auditory ossicles. Detailed dissection revealed abnormal incus bones, with a malformed lentiform process showing thickening of the distal part of the long crus, as well as a hypoplastic short crus. Micro-CT 3D-reconstructed images of the auditory ossicles confirmed the results, demonstrating a highly irregular structure of the incus bone involving both the incudomalleolar and incudostapedial joints.
In 2 German sisters with early-onset fatal rhabdoid tumors (RTPS2; 613325), Schneppenheim et al. (2010) identified a heterozygous germline 3565C-T transition in the SMARCA4 gene, resulting in an arg1189-to-ter (R1189X) substitution that was found to undergo nonsense-mediated decay. Their unaffected father was heterozygous for the mutation. Examination of tumor tissue showed complete loss of SMARCA4 expression and loss of heterozygosity at the SMARCA4 locus that resulted from partial uniparental disomy of the paternal allele.
In Patient 9 with Coffin-Siris syndrome (CSS4; 614609), Tsurusaki et al. (2012) identified a heterozygous 3-bp deletion in the SMARCA4 gene (1636_1638delAAG)m, resulting in deletion of lysine-546 (lys546del). This mutation occurred as a de novo event and was not identified in 350 Japanese control chromosomes.
In Patient 7 with Coffin-Siris syndrome (CSS4; 614609), Tsurusaki et al. (2012) identified a heterozygous C-to-T transition at nucleotide 2576 of the SMARCA4 gene, resulting in a thr-to-met substitution at codon 859 (T859M). This mutation occurred as a de novo event and was not identified in 368 Japanese control chromosomes.
In Patient 5 with Coffin-Siris syndrome (CSS4; 614609), Tsurusaki et al. (2012) identified a heterozygous C-to-T transition at nucleotide 2653 of the SMARCA4 gene, resulting in an arg-to-cys substitution at codon 885 (R885C). This mutation occurred as a de novo event and was not identified in 368 Japanese control chromosomes.
In Patient 16 with Coffin-Siris syndrome (CSS4; 614609), Tsurusaki et al. (2012) identified a heterozygous C-to-T transition at nucleotide 2761 of the SMARCA4 gene, resulting in a leu-to-phe substitution at codon 921 (L921F). This mutation occurred as a de novo event and was not identified in 368 Japanese control chromosomes.
In Patient 25 with Coffin-Siris syndrome (CSS4; 614609), Tsurusaki et al. (2012) identified a heterozygous T-to-C transition at nucleotide 3032 of the SMARCA4 gene, resulting in a met-to-thr substitution at codon 1011 (M1011T). Parental DNA was not available to determine if this mutation was a de novo event. This mutation was not identified in 372 Japanese control chromosomes.
In Patient 17 with Coffin-Siris syndrome (CSS4; 614609), Tsurusaki et al. (2012) identified a heterozygous C-to-G transversion at nucleotide 3469 of the SMARCA4 gene, resulting in an arg-to-gly substitution at codon 1157 (R1157G). This mutation occurred as a de novo event and was not seen in 368 Japanese control chromosomes.
In a mother and daughter with rhabdoid tumor predisposition syndrome-2 (RTPS2; 613325), Witkowski et al. (2013) identified a germline heterozygous c.3533G-A transition in the SMARCA4 gene, predicted to result in a trp1178-to-ter (W1178X) substitution and nonsense-mediated mRNA decay. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in the dbSNP or Exome Variant Server databases or in 160 in-house control exomes. It was also absent from the mother's parents, suggesting that it occurred de novo in the mother. Tumor tissue from each patient carried different somatic truncating sMARCA4 mutations (Ile759AsnfsTer10 and R1077X in the mother and daughter, respectively), consistent with the '2-hit' hypothesis of tumorigenesis. Immunostaining of the tumor in the fetus showed loss of SMARCA4 expression. The patients were originally reported by Poremba et al. (1993) as having immature teratomas; the report of Witkowski et al. (2013) resulted in reclassification of the tumors as malignant rhabdoid tumors.
In a young mother and daughter with rhabdoid tumor predisposition syndrome-2 (RTPS2; 613325) presenting as fatal small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) (McDonald et al., 2012), Witkowski et al. (2014) identified a germline heterozygous G-to-A transition in intron 29 of the SMARCA4 gene (c.4071+1G-A), resulting in a splice site mutation. Tumor tissue from the mother showed a somatic 1-bp deletion (c.1027delG), resulting in a frameshift and premature termination (Val343CysfsTer68), and tumor tissue from the daughter showed loss of heterozygosity at the SMARCA4 locus. The germline mutations were found by whole-exome sequencing and confirmed by Sanger sequencing.
In a mother and daughter with rhabdoid tumor predisposition syndrome-2 (RTPS2; 613325) presenting as yolk sac tumor of the ovary in the mother and SCCOHT in the daughter, Witkowski et al. (2014) identified a germline heterozygous c.643C-T transition in exon 4 of the SMARCA4 gene, resulting in a gln215-to-ter (Q215X) substitution. Tumor tissue from the daughter carried a somatic heterozygous frameshift mutation, resulting in premature termination (Asn563GlyfsTer82); tumor tissue from the mother was unavailable. The germline mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. The germline mutation was shown to result in a transcript subject to nonsense-mediated decay, and tumor cells showed a complete loss of SMARCA4 protein.
In a mother and daughter with rhabdoid tumor predisposition syndrome-2 (RTPS2; 613325) presenting as SCCOHT (Martinez-Borges et al., 2009), Witkowski et al. (2014) identified a germline heterozygous C-to-G transversion in intron 18 of the SMARCA4 gene (c.2617-3C-G), resulting in a transcript subjected to nonsense-mediated mRNA decay. The germline mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. Tumor tissue from the daughter showed loss of heterozygosity at the SMARCA4 locus.
In a mother and daughter with rhabdoid tumor predisposition syndrome-2 (RTPS2; 613325) presenting as SCCOHT, Witkowski et al. (2014) identified a germline heterozygous c.3239G-A transition in the SMARCA4 gene, resulting in a gly1080-to-asp (G1080D) substitution. The mother's tumor showed loss of heterozygosity at the SMARCA4 locus but retained protein staining, whereas the daughter's tumor contained a somatic truncating SMARCA4 mutation and showed loss of protein staining.
In 6 affected members of a 2-generation family with otosclerosis (OTSC12; 620792), including the proband (IV:1) and his affected maternal aunt (III:1) and uncle (III:2), as well as his second cousin (IV:2) and her affected paternal uncles (III:6 and III:7), Drabkin et al. (2024) identified heterozygosity for a c.4828G-A transition (c.4828G-A, NM_001128849.3) in the SMARCA4 gene, resulting in a glu1610-to-lys (E1610K) substitution at a highly conserved residue near the BROMO domain. The variant was not found in the gnomAD database. The pedigree showed incomplete penetrance, with obligate carrier parents and grandparents reporting normal hearing.
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