DLL3 explained

Delta-like 3 (Drosophila), also known as DLL3, is a protein which in humans is encoded by the DLL3 gene.^[1] Two transcript variants encoding distinct isoforms have been identified for this gene.

Function

This gene encodes a member of the delta protein ligand family. This family functions as Notch ligands that are characterized by a DSL domain, EGF repeats, and a transmembrane domain.^[2] Expression of DLL3 is highest in fetal brain. It plays a key role in somitogenesis within the paraxial mesoderm.^[3]

Clinical significance

Mutations in this gene cause the autosomal recessive genetic disorder Jarcho-Levin syndrome.^[4] Expression of the gene occurs in Neuroendocrine tumors, which has been targeted as a potential pathway for treatment.^[5]

Experimental drugs targetting DLL3 have been investigated as a possible treatment for lung cancer including Tarlatamab and rovalpituzumab tesirine.^[6]

External links

• GeneReviews/NIH/NCBI/UW entry on Spondylocostal Dysostosis, Autosomal Recessive

Further reading

• Turnpenny PD, Bulman MP, Frayling TM . A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3. . Am. J. Hum. Genet. . 65 . 1 . 175–82 . 1999 . 10364530 . 10.1086/302464 . 1378088 . etal.
• Bulman MP, Kusumi K, Frayling TM . Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. . Nat. Genet. . 24 . 4 . 438–41 . 2000 . 10742114 . 10.1038/74307 . 9284439 . etal.
• 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 . 129 . 7 . 1795–806 . 2002 . 10.1242/dev.129.7.1795 . 11923214 . 7550276 . etal.
• Strausberg RL, Feingold EA, Grouse LH . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proc. Natl. Acad. Sci. U.S.A. . 99 . 26 . 16899–903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . etal. free .
• 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. . J. Med. Genet. . 40 . 5 . 333–9 . 2003 . 12746394 . 10.1136/jmg.40.5.333 . 1735475 . etal.
• Bonafé L, Giunta C, Gassner M . A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village. . Clin. Genet. . 64 . 1 . 28–35 . 2004 . 12791036 . 10.1034/j.1399-0004.2003.00085.x . 45791073 . etal. free .
• Whittock NV, Ellard S, Duncan J . Pseudodominant inheritance of spondylocostal dysostosis type 1 caused by two familial delta-like 3 mutations. . Clin. Genet. . 66 . 1 . 67–72 . 2005 . 15200511 . 10.1111/j.0009-9163.2004.00272.x . 46448881 . etal.
• Gerhard DS, Wagner L, Feingold EA . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Res. . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 . etal.
• Maisenbacher MK, Han JS, O'brien ML . Molecular analysis of congenital scoliosis: a candidate gene approach. . Hum. Genet. . 116 . 5 . 416–9 . 2005 . 15717203 . 10.1007/s00439-005-1253-8 . 21481013 . etal.
• Otsuki T, Ota T, Nishikawa T . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries. . DNA Res. . 12 . 2 . 117–26 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . etal. free .

Notes and References

1. Turnpenny PD, Bulman MP, Frayling TM, Abu-Nasra TK, Garrett C, Hattersley AT, Ellard S . A gene for autosomal recessive spondylocostal dysostosis maps to 19q13.1-q13.3 . Am. J. Hum. Genet. . 65 . 1 . 175–82 . July 1999 . 10364530 . 1378088 . 10.1086/302464 .
2. Web site: DLL3 delta like canonical Notch ligand 3 [Homo sapiens (human) ]].
3. Chapman G, Sparrow DB, Kremmer E, Dunwoodie SL . Notch inhibition by the ligand Delta-Like 3 defines the mechanism of abnormal vertebral segmentation in spondylocostal dysostosis . Human Molecular Genetics . 20 . 5 . 438–41 . March 2011 . 21147753 . 10.1093/hmg/ddq529 . free .
4. Bulman MP, Kusumi K, Frayling TM, McKeown C, Garrett C, Lander ES, Krumlauf R, Hattersley AT, Ellard S, Turnpenny PD . Mutations in the human delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis . Nat. Genet. . 24 . 4 . 438–41 . April 2000 . 10742114 . 10.1038/74307 . 9284439 .
5. Saunders LR, Bankovich AJ, Anderson WC, Aujay MA, Bheddah S, Black K, Desai R, Escarpe PA, Hampl J, Laysang A, Liu D, Lopez-Molina J, Milton M, Park A, Pysz MA, Shao H, Slingerland B, Torgov M, Williams SA, Foord O, Howard P, Jassem J, Badzio A, Czapiewski P, Harpole DH, Dowlati A, Massion PP, Travis WD, Pietanza MC, Poirier JT, Rudin CM, Stull RA, Dylla SJ . A DLL3-targeted antibody-drug conjugate eradicates high-grade pulmonary neuroendocrine tumor-initiating cells in vivo . Sci. Transl. Med. . 7 . 302 . 302 . August 2015 . 26311731 . 10.1126/scitranslmed.aac9459 . 4934375.
6. Web site: Rovalpituzumab tesirine - Stemcentrx - AdisInsight.