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DDX11
DEAD/H-box helicase 11
The DDX11 gene encodes the ChlR1 helicase enzyme, which is critical for DNA replication, repair, and maintaining genomic stability within cells. DDX11 provides the blueprint for a protein called ChlR1, a type of helicase.
DDX11 is located on the short (p) arm of chromosome 12, at band 12p11.21. Arm ratio per GRCh38 - banding schematic.
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Overview
The DDX11 gene, also known as DEAD/H-box helicase 11, produces an enzyme named ChlR1. This enzyme functions as a helicase, a class of proteins responsible for separating the two strands of the DNA double helix. This unwinding action is fundamental for processes like DNA replication and repair, ensuring the accurate transmission of genetic information during cell division.
The ChlR1 enzyme's involvement in these critical cellular mechanisms means that its proper function is essential for maintaining the stability of a cell's genetic material. Alterations in the DDX11 gene can therefore impact cellular processes and are associated with certain inherited conditions.
What the gene does
The DDX11 gene directs the production of the ChlR1 enzyme, a DNA helicase. Helicases unwind the DNA double helix, which is a necessary step for DNA replication, where the genetic material is copied before cell division. ChlR1 attaches to DNA and temporarily separates its strands, allowing the cellular machinery to access the genetic code for copying.
Beyond replication, ChlR1 is also involved in the repair of errors that can arise during DNA copying, helping to correct any mistakes to maintain genomic integrity. Furthermore, this enzyme plays a role in organising chromosomes prior to cell division. It assists in keeping sister chromatids - identical DNA structures formed after replication - together until they are ready to separate into new cells, ensuring accurate distribution of genetic material. Through these functions, the ChlR1 enzyme is crucial for maintaining the stability of a cell's genetic information.
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Chromosome location
The DDX11 gene is situated on the short (p) arm of chromosome 12 at position 11.21, denoted as 12p11.21. This specifies its precise address within the human genome.
Protein structure
The DDX11 gene encodes a protein consisting of 970 amino acids. Key functional regions within this protein include a Helicase ATP-binding domain spanning amino acids 9-445, which is crucial for energy transduction. A Disordered region is found between amino acids 289-312, and another Disordered region is located from amino acids 818-849. The protein also contains a DEAH box motif at amino acids 393-396, which is characteristic of a subfamily of helicases.
Key variants
Variants in the DDX11 gene can lead to changes in the ChlR1 enzyme's structure or function. These genetic alterations can range from single base pair changes to larger deletions or insertions, potentially affecting the enzyme's ability to unwind DNA, repair errors, or manage chromosome segregation during cell division. The specific impact of a variant depends on its nature and location within the gene.
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.1403dup | p.Ser469fs | Pathogenic/Likely pathogenic | ★★☆☆ | Warsaw breakage syndrome |
c.1591C>T | p.Gln531Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Warsaw breakage syndrome |
c.1672C>T | p.Arg558Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Warsaw breakage syndrome |
c.1763-1G>C | - | Pathogenic | ★★☆☆ | Warsaw breakage syndrome |
c.1947T>A | p.Cys649Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Warsaw breakage syndrome |
c.1949-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Warsaw breakage syndrome |
c.2230C>T | p.Gln744Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Warsaw breakage syndrome |
c.223C>T | p.Arg75Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.788G>A | p.Arg263Gln | Pathogenic/Likely pathogenic | ★★☆☆ | Warsaw breakage syndrome |
g.31087936AG[1] | - | Pathogenic | ★☆☆☆ | not provided |
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 changes in the DDX11 gene are known to cause Warsaw breakage syndrome. This condition is characterised by a range of developmental abnormalities, including impaired growth, distinct facial features, hearing difficulties, and heart malformations. Variants linked to Warsaw breakage syndrome typically result in a significant reduction or complete loss of the ChlR1 enzyme's activity, impairing its essential DNA-binding functions.
No disease links recorded for this gene in our reference set.
UK clinical status
The DDX11 gene is recognised within several UK NHS Genomic Medicine Service pathways. It is listed as 'green' in DDG2P, Foetal anomalies (R21), Intellectual disability, and Severe microcephaly (R88) panels. A 'green' status indicates there is strong evidence for a gene's association with a particular condition, supporting its inclusion in diagnostic testing panels.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the DDX11 gene?
The DDX11 gene provides instructions for making the ChlR1 enzyme, which functions as a DNA helicase. Its main role is to unwind DNA for replication and to help repair errors in DNA, thereby maintaining the stability of a cell's genetic information.
What is Warsaw breakage syndrome?
Warsaw breakage syndrome is a genetic condition caused by mutations in the DDX11 gene. It is characterised by growth impairment, distinctive facial features, hearing loss, and heart defects, resulting from reduced or absent ChlR1 enzyme activity.
How does DDX11 help maintain healthy cells?
DDX11 helps maintain healthy cells by ensuring accurate DNA replication and repair. Its encoded enzyme, ChlR1, unwinds DNA so it can be copied correctly and fixes mistakes that occur during this process, which is crucial for preventing genetic instability.
References
- Capo-Chichi JM, Bharti SK, Sommers JA. Identification and biochemical characterization of a novel mutation in DDX11 causing Warsaw breakage syndrome. Human mutation. 2013. PMID: 23033317
- Shah N, Inoue A, Woo Lee S. Roles of ChlR1 DNA helicase in replication recovery from DNA damage. Experimental cell research. 2013. PMID: 23797032
- Inoue A, Hyle J, Lechner MS. Mammalian ChlR1 has a role in heterochromatin organization. Experimental cell research. 2011. PMID: 21854770
- van der Lelij P, Chrzanowska KH, Godthelp BC. Warsaw breakage syndrome, a cohesinopathy associated with mutations in the XPD helicase family member DDX11/ChlR1. American journal of human genetics. 2010. PMID: 20137776