Alternative titles; symbols
HGNC Approved Gene Symbol: ARID2
Cytogenetic location: 12q12 Genomic coordinates (GRCh38) : 12:45,729,706-45,908,037 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q12 | Coffin-Siris syndrome 6 | 617808 | Autosomal dominant | 3 |
ARID2 is a subunit of the PBAF chromatin-remodeling complex (see BAF180; 606083), which facilitates ligand-dependent transcriptional activation by nuclear receptors (Yan et al., 2005).
By sequencing clones obtained from a size-fractionated fetal brain cDNA library, Nagase et al. (2000) cloned ARID2, which they designated KIAA1557. RT-PCR ELISA detected ARID2 expression in all tissues and specific brain regions examined, with highest expression in ovary and lowest expression in spinal cord.
Mohrmann et al. (2004) identified ARID2 by searching for sequences similar to Drosophila Bap170. The human and Drosophila proteins contain an N-terminal ARID domain, followed by several LLxxLL motifs and C-terminal canonical and variant C2H2-type zinc finger motifs.
Yan et al. (2005) purified ARID2, which they called BAF200, from PFAB complexes isolated from HeLa cell nuclear extracts. By mass spectrometry, database analysis, and PCR, they obtained full-length ARID2 cDNA. The deduced protein contains 1,835 amino acids. Yan et al. (2005) noted that all domains are conserved between human ARID2 and Drosophila Bap170, including central proline- and glutamine-rich regions.
By Western blot analysis, Yan et al. (2005) determined that ARID2 is an integral component of PBAF. ARID2 interacted directly with BAF180 in the absence of DNA. However, ARID2 was able to form a complex in cells lacking BAF180, and suppression of ARID2 by small interfering RNA in these cells reduced both basal and IFN-alpha (147660)-induced IFITM1 (604456) expression.
Nagase et al. (2000) stated that the ARID2 gene maps to chromosome 12.
Coffin-Siris Syndrome 6
In 4 unrelated patients with Coffin-Siris syndrome (CSS6; 617808), Shang et al. (2015) identified heterozygous frameshift or nonsense mutations in the ARID2 gene (609539.0001-609539.0004). The mutations were confirmed to be de novo in 3 of the families; in the fourth family, the parents were unavailable for testing. The mutations were identified by whole-exome sequencing of 970 patients with intellectual disability. None of the mutations were found in public variant databases.
In 2 unrelated patients with CSS6, Bramswig et al. (2017) identified de novo heterozygous frameshift mutations in the ARID2 gene (609539.0005-609539.0006).
In a 3-year 11-month-old girl with CSS6, Van Paemel et al. (2017) identified a de novo heterozygous deletion in the ARID2 gene (609539.0007).
Association with Cancer
Li et al. (2011) performed exome sequencing of 10 hepatitis C virus (HCV)-associated hepatocellular carcinomas (HCCs; 114550) and matched normal tissue from 10 patients and a subsequent evaluation of additional affected individuals, and discovered novel inactivating mutations of ARID2 in 4 major subtypes of HCC (HCV-associated HCC, hepatitis B virus (HBV)-associated HCC, alcohol-associated HCC, and HCC with no known etiology). Notably, 18.2% of individuals with HCV-associated HCC in the United States and Europe harbored ARID2 inactivating mutations, suggesting that ARID2 is a tumor suppressor gene that is relatively commonly mutated in this tumor subtype.
Biankin et al. (2012) performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort of 142 patients with early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumors identified substantial heterogeneity with 2,016 nonsilent mutations and 1,628 copy number variations. Biankin et al. (2012) defined 16 significantly mutated genes, reaffirming known mutations and uncovering novel mutated genes including additional genes involved in chromatin modification (EPC1, 610999 and ARID2), DNA damage repair (ATM; 607585), and other mechanisms (ZIM2 (see 601483); MAP2K4, 601335; NALCN, 611549; SLC16A4, 603878; and MAGEA6, 300176). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signaling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. Biankin et al. (2012) also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO (see 603742) signaling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
In a 15-year-old female with Coffin-Siris syndrome (CSS6; 617808), Shang et al. (2015) identified a de novo heterozygous 1-bp deletion (c.2536delG, ENST00000334344) in the ARID2 gene, resulting in a frameshift and a premature termination codon (Val846LeufsTer3). The mutation was predicted to disrupt ARID2 proximal to the 2 highly conserved zinc finger motifs. No functional studies were performed, but the authors suggested haploinsufficiency as the pathogenic mechanism. The variant was not found in the ExAC, dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
In an 8-year-old female with Coffin-Siris syndrome-6 (617808), Shang et al. (2015) identified a heterozygous c.1028T-A transversion (c.1028T-A, ENST00000334344), resulting in a leu343-to-ter (L343X) substitution. The child's parents were unavailable for testing. The mutation was predicted to disrupt ARID2 proximal to the 2 highly conserved zinc finger motifs. No functional studies were performed, but the authors suggested haploinsufficiency as the pathogenic mechanism. The variant was not found in the ExAC, dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
In a 6-year-old male with Coffin-Siris syndrome-6 (CSS6; 617808), Shang et al. (2015) identified a de novo heterozygous 1-bp deletion (c.4441delC, ENST00000334344) in the ARID2 gene, resulting in a frameshift and premature termination (His1481IlefsTer4). The mutation was predicted to disrupt ARID2 proximal to the 2 highly conserved zinc finger motifs. No functional studies were performed, but the authors suggested haploinsufficiency as the pathogenic mechanism. The variant was not found in the ExAC, dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
In an 8-year-old girl with Coffin-Siris syndrome-6 (CSS6; 617808), Shang et al. (2015) identified a de novo heterozygous c.4318C-T transition in the ARID2 gene, resulting in a gln1440-to-ter (Q1440X) substitution. The mutation was predicted to disrupt ARID2 proximal to the 2 highly conserved zinc finger motifs. No functional studies were performed, but the authors suggested haploinsufficiency as the pathogenic mechanism. The variant was not found in the ExAC, dbSNP, 1000 Genomes Project, or Exome Variant Server databases.
In a 7-year-old boy with Coffin-Siris syndrome-6 (CSS6; 617808), Bramswig et al. (2017) identified a de novo heterozygous 2-bp deletion (c.3411_3412delAG, NM_152641.2) in the ARID2 gene, resulting in a frameshift and premature termination (Gly1139SerfsTer20). The variant was not found in the ExAC database.
In a 4.5-year-old boy with Coffin-Siris syndrome-6 (CSS6; 617808), Bramswig et al. (2017) identified a de novo heterozygous 1-bp deletion (c.156delC, NM_152641.2) in the ARID2 gene, resulting in a frameshift and premature termination (Arg53GlufsTer5). The variant was not found in the ExAC database.
In a female, aged 3 years, 11 months, with Coffin-Siris syndrome-6 (CSS6; 617808), Van Paemel et al. (2017) identified a de novo heterozygous 105-kb deletion (12q12(46125066-46230365)x1, GRCh37) encompassing exons 3-5 of the ARID2 gene.
Biankin, A. V., Waddell, N., Kassahn, K. S., Gingras, M.-C., Muthuswamy, L. B., Johns, A. L., Miller, D. K., Wilson, P. J., Patch, A.-M., Wu, J., Chang, D. K., Cowley, M. J., and 116 others. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature 491: 399-405, 2012. [PubMed: 23103869] [Full Text: https://doi.org/10.1038/nature11547]
Bramswig, N. C., Caluseriu, O., Ludecke, H.-J., Bolduc, F. V., Noel, N. C. L., Wieland, T., Surowy, H. M., Christen, H.-J., Engels, H., Strom, T. M., Wieczorek, D. Heterozygosity for ARID2 loss-of-function mutations in individuals with a Coffin-Siris syndrome-like phenotype. Hum. Genet. 136: 297-305, 2017. [PubMed: 28124119] [Full Text: https://doi.org/10.1007/s00439-017-1757-z]
Li, M., Zhao, H., Zhang, X., Wood, L. D., Anders, R. A., Choti, M. A., Pawlik, T. M., Daniel, H. D., Kannangai, R., Offerhaus, G. J. A., Velculescu, V. E., Wang, L., Zhou, S., Vogelstein, B., Hruban, R. H., Papadopoulos, N., Cai. J., Torbenson, M. S., Kinzler, K. W. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nature Genet. 43: 828-829, 2011. [PubMed: 21822264] [Full Text: https://doi.org/10.1038/ng.903]
Mohrmann, L., Langenberg, K., Krijgsveld, J., Kal, A. J., Heck, A. J. R., Verrijzer, C. P. Differential targeting of two distinct SWI/SNF-related Drosophila chromatin-remodeling complexes. Molec. Cell. Biol. 24: 3077-3088, 2004. [PubMed: 15060132] [Full Text: https://doi.org/10.1128/MCB.24.8.3077-3088.2004]
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 273-281, 2000. [PubMed: 10997877] [Full Text: https://doi.org/10.1093/dnares/7.4.271]
Shang, L., Cho, M. T., Retterer, K., Folk, L., Humberson, J., Rohena, L., Sidhu, A., Salignan, S., Iglesias, A., Vitazka, P., Juusola, J., O'Donnell-Luria, A. H., Shen, H., Chung, W. K. Mutations in ARID2 are associated with intellectual disabilities. Neurogenetics 16: 307-314, 2015. [PubMed: 26238514] [Full Text: https://doi.org/10.1007/s10048-015-0454-0]
Van Paemel, R., De Bruyne, P., van der Straaten, S., D'hondt, M., Frankel, U., Dheedene, A., Menten, B., Callewaert, B. Confirmation of an ARID2 defect in SWI/SNF-related intellectual disability. Am. J. Med. Genet. 173A: 3104-3108, 2017. [PubMed: 28884947] [Full Text: https://doi.org/10.1002/ajmg.a.38407]
Yan, Z., Cui, K., Murray, D. M., Ling, C., Xue, Y., Gerstein, A., Parsons, R., Zhao, K., Wang, W. PBAF chromatin-remodeling complex requires a novel specificity subunit, BAF200, to regulate expression of selective interferon-responsive genes. Genes Dev. 19: 1662-1667, 2005. [PubMed: 15985610] [Full Text: https://doi.org/10.1101/gad.1323805]