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DLL3
delta like canonical Notch ligand 3
The DLL3 gene provides instructions for a protein crucial in the Notch signalling pathway, which is vital for proper embryonic development, particularly the formation of the spine and ribs. The DLL3 gene encodes Delta-like canonical Notch ligand 3, a protein that regulates cell-to-cell communication.
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, or delta like canonical Notch ligand 3, is an important gene involved in the Notch signalling pathway. This pathway plays a critical role in embryonic development, guiding the proper formation and separation of structures that will eventually become the vertebrae and ribs.
Disruptions to the normal function of the DLL3 gene can lead to developmental abnormalities, particularly affecting the skeletal system.
What the gene does
The DLL3 protein is a key regulator within the Notch signalling pathway, an intricate system of cell-to-cell communication essential during embryogenesis. Specifically, DLL3 is involved in the process of somite segmentation, where future vertebrae are separated from one another.
The DLL3 protein regulates the activity of other proteins in the Notch pathway, such as NOTCH1. It functions by binding to and either sequestering inactive NOTCH1 protein or marking it for degradation, thereby preventing its activation. This regulatory role ensures the precise oscillation of Notch pathway activity required for proper vertebral development.
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Chromosome location
The DLL3 gene is located on chromosome 19, specifically at position 19q13.2. This genomic location refers to the long (q) arm of chromosome 19, within band 13.2.
Protein structure
The DLL3 protein consists of 618 amino acids. It features several distinct domains that contribute to its function. These include a DSL domain, located from amino acids 176-215, which is typically involved in ligand binding.
Following the DSL domain are several 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 present, spanning amino acids 546-566.
Key variants
Variants within the DLL3 gene can impact the structure and function of the DLL3 protein. These genetic changes can range from small alterations in the DNA sequence to larger deletions or insertions, potentially affecting how the protein interacts within the Notch pathway. Such variants may lead to a non-functional or abnormally short protein, disrupting critical developmental processes.
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 | ★★☆☆ | Hemivertebrae |
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 associated with spondylocostal dysostosis, particularly type 1. This condition is characterised by abnormal development of bones in the spine and ribs, leading to various skeletal abnormalities. The effect of these variants is often due to the production of an altered or non-functional DLL3 protein, which impairs its regulatory role in embryonic development.
No disease links recorded for this gene in our reference set.
UK clinical status
The DLL3 gene is included in several expert-curated panels within the NHS Genomic Medicine Service's PanelApp. It is listed in the DDG2P (Developmental Disorders Genotype-Phenotype) panel, the Foetal Anomalies panel (R21), and the Skeletal Dysplasia panel (R104), all with a 'green' status, indicating strong evidence for its gene-disease association in these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the function of the DLL3 gene?
The DLL3 gene provides instructions for a protein that is a key regulator in the Notch signalling pathway. This pathway is essential during embryonic development, particularly for the proper segmentation of somites, which form the spine and ribs.
What condition is associated with variants in the DLL3 gene?
Variants in the DLL3 gene are associated with spondylocostal dysostosis, type 1. This condition is characterised by abnormal development of the bones in the spine and ribs.
How does the DLL3 protein affect other proteins?
The DLL3 protein regulates the activity of other Notch pathway proteins, such as NOTCH1. It does this by binding to and either sequestering inactive NOTCH1 or marking it for degradation, preventing its activation and ensuring proper developmental signalling.
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