Alternative titles; symbols
HGNC Approved Gene Symbol: DLL3
SNOMEDCT: 61367005;
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:39,498,947-39,508,469 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Spondylocostal dysostosis 1, autosomal recessive | 277300 | Autosomal recessive | 3 |
Mutation in the mouse delta-like-3 gene (Dll3), which is homologous to the Notch-ligand delta in Drosophila, results in the mouse 'pudgy' phenotype (Kusumi et al., 1998). On the basis of the similarity of human autosomal recessive spondylocostal dysostosis (SCDO1; 277300) and the mouse 'pudgy' phenotype (see later) and the homologous regions of the 2 chromosomes, Bulman et al. (2000) hypothesized that a human Dll3 ortholog would be a candidate for the SCDO1 locus. They cloned the human DLL3 gene and confirmed its localization to 19q13. Several cDNA clones representing exons 2 through 10 of human DLL3 were identified. A comparison of the predicted amino acid sequence showed 79% identity to mouse Dll3 with EGF repeat 5 varying by only 1 residue.
Bulman et al. (2000) demonstrated that the intron/exon junctions within the predicted amino acid sequences were identical between human and mouse Dll3, with the exception of the terminal exon, which corresponds to a fusion of mouse exons 9 and 10. This difference would result in the human protein having 32 additional amino acids.
The human DLL3 gene was identified within a critical interval, mapped in 2 consanguineous Arab-Israeli and Pakistani SCDO1 pedigrees, of 7.8 cM at 19q13.1-q13.3 between D19S570 and D19S908 (Bulman et al., 2000). The Dll3 gene is located on chromosome 7 of the mouse (Kusumi et al., 1998).
Bettenhausen et al. (1995) demonstrated transient and restricted expression during mouse embryogenesis of Dll1, a murine gene closely related to Drosophila 'delta.' Dunwoodie et al. (1997) presented results suggesting that mouse Dll3 may complement the function of other delta homologs during early pattern formation in the mouse embryo. Wong et al. (1997) demonstrated that presenilin-1 (PS1; 104311) is required for Notch1 (190198) and Dll1 expression in the paraxial mesoderm.
Pourquie and Kusumi (2001) discussed errors in body segmentation. They cited work in fish, chick, and mouse embryos indicating that segmentation of the embryonic body relies on a molecular oscillator, called the segmentation clock, that requires Notch signaling for its proper functioning. In humans, the fact that mutations in genes required for oscillation, such as DLL3, result in abnormal segmentation of the vertebral column suggests that the segmentation clock also acts during human embryonic development. Disruption of the Notch pathway occurs in Alagille syndrome (see 118450), a disorder that has vertebral abnormalities, i.e., 'butterfly vertebrae,' as a feature in about two-thirds of patients.
Gridley (2003) provided a brief review of human disorders due to defects in the Notch signaling pathway: Alagille syndrome, spondylocostal dysostosis, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL; 125310).
Matsuda et al. (2020) used human induced pluripotent stem cells for in vitro induction of presomitic mesoderm and its derivatives to model human somitogenesis, with a focus on the human segmentation clock. The authors observed oscillatory expression of core segmentation clock genes, including HES7 (608059) and DKK1 (605189), determined the period of the human segmentation clock to be around 5 hours, and demonstrated the presence of dynamic traveling wave-like gene expression in in vitro-induced human presomitic mesoderm. Identification and comparison of oscillatory genes in human and mouse presomitic mesoderm derived from pluripotent stem cells revealed species-specific and shared molecular components and pathways associated with the putative mouse and human segmentation clocks. Knockout of genes mutated in patients with segmentation defects of vertebrae, including HES7, LFNG (602576), DLL3, and MESP2 (605195), followed by analysis of patient-like and patient-derived induced pluripotent stem cells revealed gene-specific alterations in oscillation, synchronization, or differentiation properties.
Bulman et al. (2000) sequenced the coding region and splice sites of DLL3 in patients with SCDO1 and identified a unique mutation in DLL3 in each of 3 pedigrees. In pedigree 1, there was a 5-bp insertion in exon 5 (602768.0001), predicted to truncate the protein in the Delta-Serrate-Lag2 domain before EGF repeat 1. In pedigree 2, there was a 2-bp deletion in the fourth EGF repeat domain that predicted a truncation immediately after EGF repeat 3 (602768.0002). In pedigree 3, there was a missense mutation in which aspartic acid replaced glycine in EGF repeat 5 (602768.0003). This residue is highly conserved in Delta proteins from Drosophila to humans, and the substitution of a charged polar for a nonpolar residue may disrupt the conformation of the DLL3 protein. Testing of all available family members in each pedigree confirmed that affected SCDO1 individuals were homozygous and obligate carriers heterozygous for the mutation. Clinical examination did not identify any neurologic abnormalities in SCDO1 individuals, and none had mental retardation.
Gassner and Grabs (1982) reported a cluster of 8 individuals affected by spondylocostal dysostosis in 4 nuclear families indigenous to a village in eastern Switzerland. After the relationship of spondylocostal dysostosis to the DLL3 gene was demonstrated, they tested the presumption that the molecular basis of this cluster was segregation of a single mutation in the DLL3 gene. Bonafe et al. (2003) showed that marker haplotypes around the DLL3 locus contradicted this hypothesis, as 3 different haplotypes were seen in affected individuals and sequence analysis showed that 3 previously unreported DLL3 mutations were segregating: a duplication of 17 bp in exon 8 (1285-1301dup; 602768.0004), a single-nucleotide deletion in exon 5 (615delC; 602768.0005), and an R238X (602768.0006) nonsense mutation in exon 6. Recessive mutations in the DLL3 gene were present in all affected individuals. Homozygosity for 1285-1301dup, a presumed founder mutation, was found in 2 of 4 families. In the other 2 families, this founder mutation was present in compound heterozygous state with one or the other of the 'new' mutations. Despite the mutation heterogeneity, the phenotype was homogeneous with severe and characteristic vertebral changes, but relatively little associated morbidity and mortality. Affected individuals were recognized at birth by virtue of the shortening of the neck and trunk. However, they did not have respiratory insufficiency after birth, and did not have neurologic signs from compression of the spinal cord or nerves. The vertebral and costal defects were readily recognizable on 'babygrams,' and involved the whole spine and usually multiple ribs.
Turnpenny et al. (2003) sequenced the DLL3 gene in a series of spondylocostal dysostosis patients from 14 families and identified 12 mutations, 2 of which occurred twice. The patients represented diverse ethnic backgrounds and 6 came from traditionally consanguineous communities. In all affected individuals, the radiologic phenotype was abnormal segmentation throughout the entire vertebral column with smooth outlines to the vertebral bodies in childhood, for which Turnpenny et al. (2003) suggested the term 'pebble beach sign.' This appeared to be a very consistent phenotype-genotype correlation.
Shen et al. (1997) found skeletal and CNS defects in mice homozygous for disruption of the presenilin-1 gene.
'Pudgy' (pu) homozygous mice exhibit clear patterning defects at the earlier stages of somitogenesis, resulting in adult mice with severe vertebral and rib deformities. By positional cloning and complementation, Kusumi et al. (1998) determined that the pu phenotype is caused by mutation in the delta-like-3 gene (Dll3), which is homologous to the Notch-ligand delta in Drosophila. Histologic and molecular marker analyses showed that the pu mutation disrupts the proper formation of morphologic borders in early somite formation and of rostral-caudal compartment boundaries within somites. Viability analysis also indicated an important role in early development. Overall, the results pointed to a key role for the Notch-signaling pathway in the initiation of patterning of vertebrate paraxial mesoderm.
In a consanguineous Arab-Israeli family segregating autosomal recessive spondylocostal dysostosis (SCDO1; 277300), Bulman et al. (2000) identified a 5-bp insertion (GCGGT) resulting in a frameshift mutation in exon 5 of the DLL3 gene. This mutation was found in homozygous state in all affected individuals.
In a family from Rawalpindi, Pakistan segregating autosomal recessive spondylocostal dysostosis (SCDO1; 277300), Bulman et al. (2000) identified a 2-bp deletion (AT) resulting in a frameshift in exon 7 of the DLL3 gene. As expected, this mutation was found in homozygous state in all affected individuals.
In a consanguineous Kashmiri family segregating autosomal recessive spondylocostal dysostosis (SCDO1; 277300), Bulman et al. (2000) identified a G-to-A transition at nucleotide 1154 resulting in a gly385-to-asp (G385D) substitution in exon 8 of the DLL3 gene. As expected, all affected individuals were homozygous. Glycine at position 5 is in the fifth epidermal growth factor repeat and is highly conserved in delta proteins from Drosophila to humans. In addition, the substitution replaced a nonpolar residue with a charged polar residue.
Bonafe et al. (2003) identified a duplication of 17 bp (nucleotides 1285-1301) in exon 8 of the DLL3 gene as a founder mutation in a village in eastern Switzerland in a founder population. The mutation causes spondylocostal dysostosis (SCDO1; 277300) when present in homozygous state or present in compound heterozygous state with 615delC (602768.0005) or R238X (602768.0006).
For discussion of the 1-bp deletion in the DLL3 gene (615delC) that was found in compound heterozygous state in affected individuals from Switzerland with spondylocostal dysostosis (SCDO1; 277300) by Bonafe et al. (2003), see 602768.0004.
For discussion of the arg238-to-ter (R238X) mutation in the DLL3 gene that was found in compound heterozygous state in affected individuals from Switzerland with spondylocostal dysostosis (SCDO1; 277300) by Bonafe et al. (2003), see 602768.0004.
In 2 affected sibs of a family with spondylocostal dysostosis (SCDO1; 277300), originally reported by Floor et al. (1989), Whittock et al. (2004) identified compound heterozygosity for 2 mutations in exon 8 of the DLL3 gene: a 1-bp deletion (1440delG) and a 1511G-A transition. The deletion is predicted to result in a 68-amino acid C-terminal peptide and premature termination at codon 547, with loss of the transmembrane domain; the 1511G-A transition results in a gly504-to-asp substitution (G504D; 602768.0008) within the predicted transmembrane domain. The family was initially believed to represent autosomal dominant inheritance (see Floor et al. (1989)), but haplotype analysis by Whittock et al. (2004) suggested linkage to DLL3 in a pseudodominant manner with segregation of 2 distinct disease alleles. Direct sequencing revealed that the affected father was homozygous and all 4 sibs were heterozygous for the 1440delG mutation, whereas the unaffected mother and 2 affected sibs were heterozygous for the G504D substitution.
For discussion of the gly504-to-asp (G504D) mutation in the DLL3 gene that was found in compound heterozygous state in 2 sibs with spondylocostal dysostosis (SCDO1; 277300) by Whittock et al. (2004), see 602768.0007.
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Bonafe, L., Giunta, C., Gassner, M., Steinmann, B., Superti-Furga, A. A cluster of autosomal recessive spondylocostal dysostosis caused by three newly identified DLL3 mutations segregating in a small village. Clin. Genet. 64: 28-35, 2003. [PubMed: 12791036] [Full Text: https://doi.org/10.1034/j.1399-0004.2003.00085.x]
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Turnpenny, P. D., Whittock, N., Duncan, J., Dunwoodie, S., Kusumi, K., Ellard, S. 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: 333-339, 2003. [PubMed: 12746394] [Full Text: https://doi.org/10.1136/jmg.40.5.333]
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Wong, P. C., Zheng, H., Chen, H., Becher, M. W., Sirinathsinghji, D. J., Trumbauer, M. E., Chen, H. Y., Price, D. L., Van der Ploeg, L. H., Sisodia, S. S. Presenilin 1 is required for Notch1 and Dll1 expression in the paraxial mesoderm. Nature 387: 288-292, 1997. [PubMed: 9153393] [Full Text: https://doi.org/10.1038/387288a0]