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RAD21
RAD21 cohesin complex component
The RAD21 gene provides instructions for a protein that is a key component of the cohesin complex, essential for proper chromosome structure and DNA repair during cell division. The RAD21 gene encodes a protein integral to the cohesin complex, which plays a vital role in maintaining the structural integrity of chromosomes.
RAD21 is located on the long (q) arm of chromosome 8, at band 8q24.11. Arm ratio per GRCh38 - banding schematic.
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Overview
The RAD21 gene, also known as SCC1 or KIAA0078, codes for the RAD21 protein. This protein is a central part of the cohesin complex, which is a group of proteins important for holding sister chromatids together after DNA replication. This function is essential for the accurate distribution of genetic material to new cells during cell division.
Beyond its role in keeping sister chromatids connected, the RAD21 protein is also involved in other key cellular processes. It helps stabilise the cell's genetic information, aids in DNA repair mechanisms, and influences the activity of specific genes vital for normal growth and development. Issues with the RAD21 gene or its protein can lead to various health concerns, particularly those affecting development and the stability of the genome.
What the gene does
The RAD21 protein serves as an essential subunit of the cohesin complex, a ring-like assembly that encircles chromosomal DNA. Within this structure, RAD21 enables the physical attachment between sister chromatids-the duplicate copies generated when DNA replicates-preventing their premature separation during the cell cycle. Maintaining this attachment is fundamental to distributing a complete chromosome set to each daughter cell.
When chromosomes duplicate ahead of cell division, cohesin containing RAD21 establishes links between the newly formed sister chromatids. These links persist through the early phases of mitosis until anaphase, when cohesin is cleaved, releasing the chromatids to migrate toward opposite cellular poles. Accurate timing of this separation prevents chromosomal imbalances that might trigger developmental abnormalities or malignancy.
The RAD21 protein also participates in maintaining genomic stability through its contributions to DNA damage response pathways. When double-strand breaks occur, RAD21 helps coordinate the recruitment of repair machinery to injury sites. Additionally, the protein influences how chromatin adopts its three-dimensional architecture, which in turn affects whether genes are accessible for transcription. Specific protein interaction surfaces enable these diverse roles: residues 154-171 mediate binding to NIPBL, whilst the 362-403 segment facilitates association with STAG1, both interactions being integral to cohesin function.
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Chromosome location
The RAD21 gene is found on chromosome 8, specifically at position 8q24.11. This indicates it is located on the long arm of chromosome 8, within band 24, sub-band 11. The gene provides the instructions for creating a protein made up of 631 amino acids. This genomic position places RAD21 in an area known to be associated with various genetic conditions when deletions or alterations occur.
Protein structure
The RAD21 protein is made up of 631 amino acids and features a modular structure that is crucial for its roles within the cohesin complex and other cellular processes. Important interaction domains include a region from amino acids 126-282, which is necessary for interaction with SMARCA5, a protein involved in remodelling chromatin. A specific domain that interacts with NIPBL, another factor related to cohesin, is located between amino acids 154-171.
The protein also contains several intrinsically disordered regions. One notable disordered segment spans amino acids 258-285, another is found between 423-489, and a third from 517-558. These flexible regions often play roles in protein-protein interactions and modifications after protein synthesis. Additionally, the protein has a region from amino acids 287-403 which is involved in interactions with WAPL and PDS5B, components that regulate how cohesin binds to DNA. Within this segment, amino acids 362-403 specifically facilitate interaction with STAG1, another subunit of the cohesin complex.
Key variants
Variants in the RAD21 gene, also referred to as mutations, have been identified in individuals with Cornelia de Lange syndrome. In some cases, deletions involving the RAD21 gene on chromosome 8 are associated with Trichorhinophalangeal syndrome type II.
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.1222G>T | p.Gly408Ter | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 4 |
c.1306C>T | p.Gln436Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cornelia de Lange syndrome 4 |
c.1432C>T | p.Arg478Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cornelia de Lange syndrome 4 |
c.144+1G>A | - | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 4 |
c.1635del | p.Gly547fs | Pathogenic | ★★☆☆ | Cornelia de Lange syndrome 4 |
c.1774_1776del | p.Gln592del | Pathogenic/Likely pathogenic | ★★☆☆ | Cornelia de Lange syndrome 4 |
c.193C>T | p.Arg65Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Cornelia de Lange syndrome 4 |
c.1045dup | p.Thr349fs | Pathogenic | ★☆☆☆ | Cornelia de Lange syndrome 4 |
c.1142G>A | p.Trp381Ter | Pathogenic | ★☆☆☆ | not provided |
c.1161+1G>A | - | Pathogenic | ★☆☆☆ | Cornelia de Lange syndrome 4 |
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
Genetic alterations involving the RAD21 gene have been connected to rare developmental disorders. These include Cornelia de Lange syndrome, a condition characterised by distinctive facial features, intellectual disability, and developmental delays. Although RAD21 variants are an uncommon cause, they have been identified in affected individuals.
Furthermore, deletions on chromosome 8 that include the RAD21 gene are associated with Trichorhinophalangeal syndrome type II (TRPS II). This syndrome manifests with bone and joint malformations, characteristic facial features, intellectual disability, and abnormalities of the skin, hair, and teeth.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic RAD21 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
In the UK, the RAD21 gene is included in several NHS Genomic Medicine Service national testing panels, indicating its clinical importance for diagnostic purposes. It is currently categorised with a 'green' status on panels related to Clefting, Developmental Disorders Gene (DDG2P), Foetal anomalies, Haematological malignancies cancer susceptibility, Holoprosencephaly, Intellectual disability, Intrauterine growth restriction (IUGR) and Insulin-like Growth Factor (IGF) abnormalities, and Severe microcephaly. This inclusion highlights its relevance across a range of developmental and cancer-related conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle supports overall genomic integrity. This often includes a balanced diet rich in antioxidants, regular physical activity, and avoiding environmental toxins known to damage DNA. While these general health recommendations are beneficial, there is no specific lifestyle intervention known to prevent or directly lessen the effects of genetic variants in the RAD21 gene. These are general population observations, not personalised medical advice.
Supplement considerations
Currently, there is no conclusive scientific evidence indicating that any specific supplement can prevent, treat, or directly alleviate symptoms associated with RAD21-related conditions. Individuals considering supplements should consult with a healthcare professional, as some supplements can interact with medications or have unintended side effects. It is important to rely on evidence-based medicine for managing health conditions.
Frequently asked questions
What is the primary function of the RAD21 gene?
The RAD21 gene provides instructions for making a protein that is a key component of the cohesin complex. This complex is vital for holding sister chromatids together during cell division, ensuring accurate distribution of genetic material to daughter cells.
What happens if there is a variant in the RAD21 gene?
Variants in the RAD21 gene can disrupt the normal function of the RAD21 protein, affecting chromosome organisation, DNA repair, and gene regulation. This can lead to various developmental disorders, such as Cornelia de Lange syndrome and Trichorhinophalangeal syndrome type II.
Is RAD21-related disease inherited?
Conditions associated with RAD21 variants follow an autosomal recessive inheritance pattern, meaning two copies of an altered gene (one from each parent) are typically needed for the condition to manifest.
What is the cohesin complex and RAD21's role in it?
The cohesin complex is a multi-protein structure that encircles DNA to hold sister chromatids together after replication. The RAD21 protein acts as a crucial subunit within this complex, helping to maintain the physical connection between chromatids until they need to separate during cell division.
Can diet or lifestyle influence RAD21-related conditions?
While a healthy lifestyle generally supports overall genomic health, there is no specific diet or lifestyle intervention known to prevent or directly treat conditions caused by RAD21 gene variants. Any health decisions should be discussed with a healthcare professional.
References
- Maas SM, Shaw AC, Bikker H. Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome. European journal of medical genetics. 2015. PMID: 25792522
- Minor A, Shinawi M, Hogue JS. Two novel RAD21 mutations in patients with mild Cornelia de Lange syndrome-like presentation and report of the first familial case. Gene. 2014. PMID: 24378232
- Deardorff MA, Wilde JJ, Albrecht M. RAD21 mutations cause a human cohesinopathy. American journal of human genetics. 2012. PMID: 22633399
- Sonoda E, Matsusaka T, Morrison C. Scc1/Rad21/Mcd1 is required for sister chromatid cohesion and kinetochore function in vertebrate cells. Developmental cell. 2001. PMID: 11740938
- McKay MJ, Troelstra C, van der Spek P. Sequence conservation of the rad21 Schizosaccharomyces pombe DNA double-strand break repair gene in human and mouse. Genomics. 1996. PMID: 8812457