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ARID1A
AT-rich interaction domain 1A
The ARID1A gene provides instructions for a protein that is a crucial component of SWI/SNF protein complexes, which regulate gene activity by remodelling chromatin. ARID1A, or AT-rich interaction domain 1A, plays a vital role in gene expression regulation and various cellular processes, including DNA repair and cell proliferation.
ARID1A is located on the short (p) arm of chromosome 1, at band 1p36.11. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 1 in the library →Overview
The ARID1A gene encodes a protein that is an essential subunit of SWI/SNF (SWItch/Sucrose NonFermentable) protein complexes. These complexes are critical for controlling gene activity by modifying the structure of chromatin, the tightly packed DNA and protein material within chromosomes. This regulation is fundamental for proper cell development, growth, and repair processes.
What the gene does
The ARID1A protein functions as a key component within SWI/SNF complexes, which regulate gene expression through a process known as chromatin remodelling. Chromatin remodelling alters how DNA is packaged, thereby influencing gene accessibility and activity. The ARID1A subunit specifically binds to DNA, helping to direct SWI/SNF complexes to the correct genomic locations where remodelling is required. This precise targeting is vital for orchestrating numerous cellular functions, including DNA damage repair, DNA replication, and the controlled growth, division, and maturation of cells. Furthermore, ARID1A and other SWI/SNF subunits are understood to act as tumour suppressors, preventing uncontrolled cell proliferation.
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Chromosome location
The ARID1A gene is located on the short arm of chromosome 1, specifically at position 1p36.11. This gene provides the genetic blueprint for a protein consisting of 2285 amino acids.
Protein structure
The ARID1A protein, comprising 2285 amino acids, features several distinct regions and motifs. It contains multiple disordered regions located at amino acids 1-820, 978-1005, 1113-1483, 1539-1603, 1747-1774, and 1859-1907. Key functional motifs include an ARID (AT-rich interaction domain) at amino acids 1017-1108, which is involved in DNA binding. Additionally, there are several LXXLL motifs, found at positions 295-299, 1709-1713, 1967-1971, and 2085-2089, which typically mediate protein-protein interactions. A nuclear localisation signal is present between amino acids 1368-1387, facilitating transport into the cell nucleus.
Key variants
Variants in the ARID1A gene can significantly impact its function, leading to a range of health implications. These genetic changes can result in an abnormally short or non-functional ARID1A protein, compromising its ability to participate in chromatin remodelling and gene regulation. Such variants are associated with both inherited developmental conditions and acquired somatic mutations observed in various cancers.
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.1015del | p.Ala339fs | Pathogenic | ★★☆☆ | Intellectual disability, autosomal dominant 14 |
c.1348C>T | p.Gln450Ter | Pathogenic | ★★☆☆ | Intellectual disability, autosomal dominant 14 |
c.1642C>T | p.Gln548Ter | Pathogenic | ★★☆☆ | Intellectual disability, autosomal dominant 14 |
c.166C>T | p.Gln56Ter | Pathogenic | ★★☆☆ | ARID1A-related BAFopathy |
c.3033G>T | p.Leu1011Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Intellectual disability, autosomal dominant 14 |
c.3067T>C | p.Trp1023Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Intellectual disability, autosomal dominant 14 |
c.31_56del | p.Ser11fs | Pathogenic | ★★☆☆ | Intellectual disability, autosomal dominant 14 |
c.3230C>A | p.Ala1077Glu | Pathogenic/Likely pathogenic | ★★☆☆ | Intellectual disability, autosomal dominant 14 |
c.3287A>G | p.Tyr1096Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Intellectual disability, autosomal dominant 14 |
c.6134_6138del | p.Lys2045fs | Pathogenic | ★★☆☆ | Intellectual disability, autosomal dominant 14 |
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 ARID1A gene are known to cause Coffin-Siris syndrome, a developmental condition characterised by delayed development, distinctive facial features, and abnormalities of the fifth fingers or toes. Additionally, somatic variants in ARID1A are frequently identified in various cancers, including those affecting the ovaries, endometrium, bladder, kidney, stomach, lung, breast, and brain. These somatic mutations are acquired during a person's lifetime and are typically present only within the tumour cells.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic ARID1A variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
ARID1A is included in several UK NHS national genomic testing panels. It is part of the green list for DDG2P (developmental disorders), Foetal anomalies (R21), and Intellectual disability, indicating its established role in these conditions within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ARID1A gene?
The ARID1A gene provides instructions for a protein that is a crucial subunit of SWI/SNF protein complexes. These complexes are responsible for regulating gene activity by modifying the structure of chromatin, which is essential for proper cellular development and function.
What health conditions are associated with ARID1A variants?
Variants in the ARID1A gene are primarily associated with Coffin-Siris syndrome, a developmental disorder. Somatic mutations in ARID1A are also frequently found in various types of cancer, including ovarian, endometrial, and bladder cancers.
Is ARID1A included in UK NHS genetic testing?
Yes, the ARID1A gene is part of several UK NHS national genomic testing panels, specifically for conditions related to developmental disorders, foetal anomalies, and intellectual disability, reflecting its clinical significance.
References
- Shain AH, Pollack JR. The spectrum of SWI/SNF mutations, ubiquitous in human cancers. PloS one. 2013. PMID: 23355908
- 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, Kriek M, van Attikum H. SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability. Epigenetics. 2012. PMID: 23010866
- Wilson BG, Roberts CW. SWI/SNF nucleosome remodellers and cancer. Nature reviews. Cancer. 2011. PMID: 21654818
- 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