Novel mutation in DLL3, a somitogenesis gene encoding a ligand for the Notch signaling pathway of abnormal vertebral segmentation in spondylocostal dysostosis

The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States
Journal of Medical Genetics (Impact Factor: 6.34). 06/2003; 40(5):333-9. DOI: 10.1136/jmg.40.5.333
Source: PubMed


The spondylocostal dysostoses (SCD) are a group of disorders characterised by multiple vertebral segmentation defects and rib anomalies. SCD can either be sporadic or familial, and can be inherited in either autosomal dominant or recessive modes. We have previously shown that recessive forms of SCD can be caused by mutations in the delta-like 3 gene, DLL3. Here, we have sequenced DLL3 in a series of SCD cases and identified 12 mutations in a further 10 families. These include 10 novel mutations in exons 4-8, comprising nonsense, missense, frameshift, splicing, and in frame insertion mutations that are predicted to result in either the truncation of the mature protein in the extracellular domain, or affect highly conserved amino acid residues in the epidermal growth factor-like repeats of the protein. The affected cases represent diverse ethnic backgrounds and six come from traditionally consanguineous communities. In all affected subjects, the radiological phenotype is abnormal segmentation throughout the entire vertebral column with smooth outlines to the vertebral bodies in childhood, for which we suggest the term "pebble beach sign". This is a very consistent phenotype-genotype correlation and we suggest the designation SCD type 1 for the AR form caused by mutations in the DLL3 gene.

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Available from: Sally L Dunwoodie
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    • "DLL3 is expressed throughout the presomitic mesoderm and is localized to the rostral somatic compartments. Homozygous disruptions of Notch1 and DLL3 result in severe abnormalities in somitogenesis (17–19) and mutations in the human DLL3 homolog cause recessive skeletal abnormalities in spondylocostal dysostosis (20–22). The role of DLL3 in carcinogenesis has not been reported. "
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    ABSTRACT: The genetic and epigenetic events of hepato-carcinogenesis are relatively poorly understood. By analyzing genes from human hepatocellular carcinoma (HCC) with restriction landmark genomic scanning, several aberrantly methylated genes, including Delta-like 3 (DLL3), have been isolated. In this study, we investigated the function of DLL3 in hepatocarcinogenesis. Methylation of the DLL3 gene in HCC cell lines was investigated with methylation-specific PCR and expression of DLL3 mRNA in HCC cells was examined by RT-PCR. Reactivation of DLL3 expression by treatment with a demethylating agent was examined in methylation-silenced HuH2 cells. Human DLL3 cDNA was cloned and DLL3 function was examined by restoring DLL3 expression in HuH2 cells. The effects of DLL3 on cell growth were evaluated by colony formation assay. Induction of cell death by overexpression of DLL3 was examined by flow cytometric assay using Annexin V and PI. Apoptotic cells were detected by TUNEL staining and the amount of single-stranded DNA was measured by ELISA. As a result, the promoter region of the DLL3 gene was methylated in four of ten HCC cell lines. This aberrant methyl-ation correlated well with the suppression of RNA expression and a demethylating agent reactivated DLL3 expression in methylation-silenced HCC cells. Interestingly, the restoration of DLL3 in the methylation-silenced HuH2 cells led to growth suppression on colony formation assay. Flow cytometric assay with Annexin V and PI showed that this growth suppression by DLL3 expression is associated with the induction of apoptosis. Furthermore, these apoptotic effects were confirmed by TUNEL staining and measurement of single-stranded DNA. These results suggest that DLL3 was silenced by methylation in human HCC and that it negatively regulates the growth of HCC cells.
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    • "Mutations in Notch signaling pathway genes, including MESP2 [60], LFNG [61], and HES7, have subsequently been identified [62]. The term “pebble beach” sign refers to morphologically abnormal vertebral bodies characterized by a smooth, round contour, usually associated with the presence of a DLL3 mutation [63]. Hypoplasia of the left vertebral artery has been reported in one affected individual with a compound heterozygous mutation in HES7 (158D/V186Y). "
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    ABSTRACT: Congenital and idiopathic scoliosis represent disabling conditions of the spine. While congenital scoliosis (CS) is caused by morphogenic abnormalities in vertebral development, the cause(s) for idiopathic scoliosis is (are) likely to be varied, representing alterations in skeletal growth, neuromuscular imbalances, disturbances involving communication between the brain and spine, and others. Both conditions are characterized by phenotypic and genetic heterogeneities, which contribute to the difficulties in understanding their genetic basis that investigators face. Despite the differences between these two conditions there is observational and experimental evidence supporting common genetic mechanisms. This paper focuses on the clinical features of both CS and IS and highlights genetic and environmental factors which contribute to their occurrence. It is anticipated that emerging genetic technologies and improvements in phenotypic stratification of both conditions will facilitate improved understanding of the genetic basis for these conditions and enable targeted prevention and treatment strategies.
    Full-text · Article · Dec 2012
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    • "Axial skeletal defects have been reported when abnormalities of this pathway are present, due in part to the fact that somite segmentation relies on boundary formation. Both core Notch signalling components and modifiers are required for normal somite formation and anteroposterior somite polarity.6,7,14 "
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    ABSTRACT: The aim of this study was to perform a detailed tomographic analysis of the skull base, craniocervical junction, and the entire spine in seven patients with spondylocostal dysostosis syndrome. Detailed scanning images have been organized in accordance with the most prominent clinical pathology. The reasons behind plagiocephaly, torticollis, short immobile neck, scoliosis and rigid back have been detected. Radiographic documentation was insufficient modality. Detailed computed tomography scans provided excellent delineation of the osseous abnormality pattern in our patients. This article throws light on the most serious osseous manifestations of spondylocostal dysostosissyndrome.
    Full-text · Article · Oct 2010 · Clinics (São Paulo, Brazil)
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