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ARID1B
AT-rich interaction domain 1B
The ARID1B gene encodes a protein that is a crucial component of SWI/SNF protein complexes, which regulate gene expression through chromatin remodelling and are implicated in various developmental processes. The ARID1B gene provides instructions for producing a protein that forms part of SWI/SNF protein complexes.
ARID1B is located on the long (q) arm of chromosome 6, at band 6q25.3. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 6 in the library →Overview
The ARID1B gene, full name AT-rich interaction domain 1B, is integral to cellular function, particularly in the precise regulation of gene expression. It produces a protein that acts as a subunit within SWI/SNF protein complexes, which are central to chromatin remodelling.
Chromatin remodelling is a process that alters the packaging of DNA within chromosomes, influencing how genes are switched on or off. This activity is vital for normal development, DNA repair, and cell cycle control. Pathogenic variants in ARID1B can disrupt these critical processes, leading to various developmental conditions.
What the gene does
The protein encoded by the ARID1B gene functions as a key component of several SWI/SNF protein complexes. These complexes are responsible for chromatin remodelling, a mechanism that changes the structure of chromatin to regulate gene activity. By altering how tightly DNA is packaged, SWI/SNF complexes can increase or decrease gene expression.
This regulation is fundamental to numerous biological processes, including DNA replication, DNA damage repair, and the control of cell growth, division, and maturation. The ARID1B protein itself can bind to DNA, suggesting it helps to guide SWI/SNF complexes to specific chromatin locations that require remodelling. Furthermore, ARID1B, along with other SWI/SNF subunits, is thought to act as a tumour suppressor, preventing uncontrolled cell proliferation.
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Chromosome location
The ARID1B gene is situated on chromosome 6, specifically at position 6q25.3. This genomic location indicates its precise address within the human genome. The gene spans a significant region and provides the blueprint for a protein composed of 2319 amino acids.
Protein structure
The ARID1B protein is 2319 amino acids long and features several distinct domains and motifs. The N-terminal region includes multiple Disordered regions, specifically from amino acids 1-74, 155-306, 321-414, 487-546, 577-1062, 1085-1129, 1230-1334, 1346-1443, 1475-1647, 1782-1852, 1904-1941, and 1954-1973. A key functional element is the ARID domain, located between amino acids 1136-1227. Other notable motifs include an LXXLL motif (amino acids 502-506) and a Nuclear localization signal (amino acids 1441-1460), which are crucial for protein-protein interactions and cellular localisation, respectively.
Key variants
Variants in the ARID1B gene can lead to alterations in the encoded protein, affecting its structure or function. Many pathogenic variants result in a prematurely truncated, non-functional protein, which can reduce the overall amount of functional ARID1B protein. These changes can disrupt the critical roles of ARID1B within SWI/SNF complexes, impacting gene expression regulation and various developmental pathways.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1021C>T | p.Gln341Ter | Pathogenic | ★★☆☆ | Coffin-Siris syndrome 1 |
c.1290_1320del | p.Ala431fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1293_1311del | p.Gly434fs | Pathogenic | ★★☆☆ | not provided |
c.1293_1314del | p.Gly434fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1293_1317del | p.Ala433fs | Pathogenic/Likely pathogenic | ★★☆☆ | Coffin-Siris syndrome 1 |
c.1293_1320del | p.Ala432fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1293_1320dup | p.Tyr441fs | Pathogenic/Likely pathogenic | ★★☆☆ | Coffin-Siris syndrome 1 |
c.1329del | p.Ser444fs | Pathogenic | ★★☆☆ | not provided |
c.1409_1449del | p.Ala470fs | Pathogenic | ★★☆☆ | not provided |
c.1451dup | p.Phe485fs | Pathogenic | ★★☆☆ | Coffin-Siris syndrome 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the ARID1B gene are primarily associated with inherited conditions such as Coffin-Siris syndrome. This autosomal dominant disorder is characterised by developmental delay, distinctive facial features, and abnormalities of the fifth fingers or toes. ARID1B variants have also been identified in individuals with intellectual disability that may present without the full spectrum of Coffin-Siris syndrome features, and some cases of autism spectrum disorder. Somatic variants in ARID1B have also been observed in certain types of cancer, including breast cancer and neuroblastoma, indicating its role as a tumour suppressor.
Inheritance pattern
Conditions caused by pathogenic ARID1B variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
ARID1B is recognised within the NHS Genomic Medicine Service due to its association with several conditions. It is listed on PanelApp for conditions such as DDG2P (developmental disorders), early onset or syndromic epilepsy, foetal anomalies (R21), intellectual disability, and rare syndromic craniosynostosis or isolated multisuture synostosis (R100). This indicates its clinical significance in diagnosing these conditions within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the ARID1B gene?
The ARID1B gene provides instructions for a protein that is a subunit of SWI/SNF protein complexes. These complexes are critical for regulating gene activity by modifying chromatin structure, which influences cell development, division, and repair processes.
What is Coffin-Siris syndrome?
Coffin-Siris syndrome is a genetic condition typically caused by variants in the ARID1B gene. It is characterised by developmental delay, distinctive facial features, and abnormalities affecting the fifth fingers or toes.
Can ARID1B variants cause conditions other than Coffin-Siris syndrome?
Yes, variants in the ARID1B gene have also been linked to intellectual disability without the full set of Coffin-Siris syndrome features, and some cases of autism spectrum disorder. Additionally, somatic variants are associated with certain types of cancer.
References
- D'Gama AM, Pochareddy S, Li M. Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. Neuron. 2015. PMID: 26637798
- Shain AH, Pollack JR. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PloS one. 2013. PMID: 23355908
- Halgren C, Kjaergaard S, Bak M. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B. Clinical genetics. 2012. PMID: 21801163
- Hoyer J, Ekici AB, Endele S. Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability. American journal of human genetics. 2012. PMID: 22405089
- Tsurusaki Y, Okamoto N, Ohashi H. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome. Nature genetics. 2012. PMID: 22426308
- Santen GW, Aten E, Sun Y. Mutations in SWI/SNF chromatin remodeling complex gene ARID1B cause Coffin-Siris syndrome. Nature genetics. 2012. PMID: 22426309
- Santen GW, Kriek M, van Attikum H. SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability. Epigenetics. 2012. PMID: 23010866
- Nord AS, Roeb W, Dickel DE. Reduced transcript expression of genes affected by inherited and de novo CNVs in autism. European journal of human genetics : EJHG. 2011. PMID: 21448237
- Wang X, Nagl NG, Wilsker D. Two related ARID family proteins are alternative subunits of human SWI/SNF complexes. The Biochemical journal. 2004. PMID: 15170388