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DLL3
delta like canonical Notch ligand 3
The *DLL3* gene provides instructions for a protein crucial in embryonic development, particularly for vertebral formation, and is associated with spondylocostal dysostosis. The *DLL3* gene encodes Delta-like canonical Notch ligand 3, a protein that plays a key role in regulating the Notch signalling pathway during embryonic development.
DLL3 is located on the long (q) arm of chromosome 19, at band 19q13.2. Arm ratio per GRCh38 - banding schematic.
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Overview
The *DLL3* gene, also known as delta like canonical Notch ligand 3, is vital for correct embryonic development. It provides the genetic blueprint for a protein that helps regulate the Notch signalling pathway, a critical process involved in the formation of the spine and ribs.
Disruptions in *DLL3* can lead to conditions characterised by abnormal skeletal development, such as spondylocostal dysostosis. Understanding this gene's role is important for comprehending the genetic basis of such congenital conditions.
What the gene does
The *DLL3* gene produces a protein that acts as a regulator within the Notch signalling pathway. This pathway is fundamental during embryonic development, especially for the intricate process of somite segmentation, where future vertebrae separate from each other. While the precise mechanisms are still being elucidated, the process requires specific on-and-off cycling of several Notch pathway proteins, including NOTCH1.
The DLL3 protein influences the activity of NOTCH1 by binding to the inactive NOTCH1 protein. This interaction can either sequester NOTCH1, preventing its activation, or mark it for degradation. By controlling NOTCH1, DLL3 ensures the precise regulation required for proper vertebral development.
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Chromosome location
The *DLL3* gene is situated on chromosome 19, specifically at position 19q13.2. This location refers to the long (q) arm of chromosome 19, within region 13 and sub-band 2.
Protein structure
The DLL3 protein comprises 618 amino acids. Its structure includes several distinct domains critical for its function. These include a DSL domain, located between amino acids 176-215, which is characteristic of Notch ligands. Additionally, there are multiple EGF-like domains: EGF-like 1 (amino acids 216-249), EGF-like 2 (amino acids 274-310), EGF-like 3 (amino acids 312-351), EGF-like 4 (amino acids 353-389), EGF-like 5 (amino acids 391-427), and EGF-like 6 (amino acids 429-465). A disordered region is also identified between amino acids 546-566.
Key variants
Variations within the *DLL3* gene can alter the protein's structure and function. These changes can range from small alterations in the DNA sequence to larger deletions or insertions. Such genetic variations can impact how the DLL3 protein regulates the Notch pathway, potentially leading to developmental abnormalities.
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.1036C>T | p.Gln346Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Spondylocostal dysostosis 1, autosomal recessive |
c.1136G>A | p.Cys379Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | Spondylocostal dysostosis 1, autosomal recessive |
c.1392_1393del | p.Cys464_Glu465delinsTer | Pathogenic | ★★☆☆ | Spondylocostal dysostosis 1, autosomal recessive |
c.366_378del | p.Ile123fs | Pathogenic/Likely pathogenic | ★★☆☆ | Spondylocostal dysostosis 1, autosomal recessive |
c.395del | p.Gly132fs | Pathogenic | ★★☆☆ | Spondylocostal dysostosis 1, autosomal recessive |
c.661C>T | p.Arg221Ter | Pathogenic | ★★☆☆ | Rib fusion |
c.712C>T | p.Arg238Ter | Pathogenic | ★★☆☆ | Spondylocostal dysostosis 1, autosomal recessive |
c.945_946del | p.Ala317fs | Pathogenic/Likely pathogenic | ★★☆☆ | Spondylocostal dysostosis 1, autosomal recessive |
c.1165_1196del | p.Glu389fs | Pathogenic | ★☆☆☆ | not provided |
c.1365_1381del | p.Cys455fs | Pathogenic | ★☆☆☆ | Inborn genetic diseases |
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 *DLL3* gene are primarily associated with spondylocostal dysostosis type 1. This condition is characterised by malformations of the bones in the spine and ribs. Most known variants in *DLL3* linked to this disorder either prevent the production of the DLL3 protein entirely or result in a shortened, non-functional protein, disrupting its crucial role in vertebral development.
No disease links recorded for this gene in our reference set.
UK clinical status
The *DLL3* gene is included in several NHS Genomic Medicine Service clinical panels in the UK, indicating its relevance in diagnosing specific conditions. It is listed on the DDG2P panel, the Foetal anomalies panel (R21), and the Skeletal dysplasia panel (R104), all with a 'green' status, signifying that there is sufficient evidence for its use in routine clinical sequencing.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the DLL3 gene?
The *DLL3* gene provides instructions for a protein that helps regulate the Notch signalling pathway, which is essential for proper embryonic development, particularly the segmentation and formation of vertebrae in the spine.
What condition is associated with variants in the DLL3 gene?
Variants in the *DLL3* gene are primarily associated with spondylocostal dysostosis type 1, a condition that results in abnormal development of the bones in the spine and ribs.
How does the DLL3 protein affect the Notch pathway?
The DLL3 protein regulates the Notch pathway by binding to and inhibiting the NOTCH1 protein. This action helps to control the precise timing and activity of Notch signalling required for correct vertebral formation during development.
References
- Serth K, Schuster-Gossler K, Kremmer E. O-fucosylation of DLL3 is required for its function during somitogenesis. PloS one. 2015. PMID: 25856312
- Chapman G, Sparrow DB, Kremmer E. Notch inhibition by the ligand DELTA-LIKE 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis. Human molecular genetics. 2011. PMID: 21147753
- Oginuma M, Takahashi Y, Kitajima S. The oscillation of Notch activation, but not its boundary, is required for somite border formation and rostral-caudal patterning within a somite. Development (Cambridge, England). 2010. PMID: 20335362
- Gibb S, Maroto M, Dale JK. The segmentation clock mechanism moves up a notch. Trends in cell biology. 2010. PMID: 20724159
- Ferjentsik Z, Hayashi S, Dale JK. Notch is a critical component of the mouse somitogenesis oscillator and is essential for the formation of the somites. PLoS genetics. 2009. PMID: 19779553
- Sparrow DB, Chapman G, Turnpenny PD. Disruption of the somitic molecular clock causes abnormal vertebral segmentation. Birth defects research. Part C, Embryo today : reviews. 2007. PMID: 17600782
- Ladi E, Nichols JT, Ge W. The divergent DSL ligand Dll3 does not activate Notch signaling but cell autonomously attenuates signaling induced by other DSL ligands. The Journal of cell biology. 2005. PMID: 16144902
- Turnpenny PD, Whittock N, Duncan J. Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis. Journal of medical genetics. 2003. PMID: 12746394
- Dunwoodie SL, Clements M, Sparrow DB. Axial skeletal defects caused by mutation in the spondylocostal dysplasia/pudgy gene Dll3 are associated with disruption of the segmentation clock within the presomitic mesoderm. Development (Cambridge, England). 2002. PMID: 11923214
- Bulman MP, Kusumi K, Frayling TM. Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nature genetics. 2000. PMID: 10742114
- Adam MP, Bick S, Mirzaa GM. Spondylocostal Dysostosis, Autosomal Recessive. 1993. PMID: 20301771