DLL3 as a candidate for vertebral malformations

ArticleinAmerican Journal of Medical Genetics Part A 140(22):2447-53 · November 2006with9 Reads
DOI: 10.1002/ajmg.a.31509 · Source: PubMed
Investigations have not identified a major locus for congenital vertebral malformations. Based on observations in mice, we hypothesized that mutations in DLL3, a member of the notch-signaling pathway, might contribute to human vertebral malformations. We sequenced the DLL3 gene in 50 patients with congenital vertebral malformations. A Caucasian male patient with VACTERL manifestations including a T5-T6 block vertebrae was heterozygous for a "G" to "A" missense mutation changing glycine to arginine at codon 269. This residue is conserved in mammals, including chimpanzee, mouse, dog, and rat. Additional testing in the patient did not show evidence of chromosome abnormalities. The patient's asymptomatic mother was also heterozygous for the missense mutation. Since this mutation was not observed in a control population and leads to an amino acid change, it may be clinically significant. The mutation was not found in a control population of 87 anonymous individuals. Several established mechanisms could explain the mutation in both the patient and his asymptomatic mother (susceptibility allele requiring additional environmental factors, somatic mosaicism, multigenic inheritance). Documenting the absence of the mutation in a larger control population or the presence of the mutation in additional affected patients, or documenting a functional difference in DLL3 would provide further evidence supporting its causal role.
    • "In general, we have observed a remarkable consistency in the radiological phenotype in mutation-positive cases (Turnpenny et al., 2003), and with experience, scrutiny of the radiograph is usually possible to identify those patients who will prove to have DLL3 mutations. Importantly, DLL3 mutations have not been found in the wide variety of more common, although diverse, phenotypes that include MVSD and abnormal ribs (Maisenbacher et al., 2005; Giampietro et al., 2006). Therefore, there is remarkably little clinical heterogeneity for the axial skeletal malformation due to mutated DLL3, which has significant implications for the application of genetic testing in the clinical setting. "
    [Show abstract] [Hide abstract] ABSTRACT: Abnormal vertebral segmentation (AVS) in man is a relatively common congenital malformation but cannot be subjected to the scientific analysis that is applied in animal models. Nevertheless, some spectacular advances in the cell biology and molecular genetics of somitogenesis in animal models have proved to be directly relevant to human disease. Some advances in our understanding have come through DNA linkage analysis in families demonstrating a clustering of AVS cases, as well as adopting a candidate gene approach. Only rarely do AVS phenotypes follow clear Mendelian inheritance, but three genes—DLL3, MESP2, and LNFG—have now been identified for spondylocostal dysostosis (SCD). SCD is characterized by extensive hemivertebrae, trunkal shortening, and abnormally aligned ribs with points of fusion. In familial cases clearly following a Mendelian pattern, autosomal recessive inheritance is more common than autosomal dominant and the genes identified are functional within the Notch signaling pathway. Other genes within the pathway cause diverse phenotypes such as Alagille syndrome (AGS) and CADASIL, conditions that may have their origin in defective vasculogenesis. Here, we deal mainly with SCD and AGS, and present a new classification system for AVS phenotypes, for which, hitherto, the terminology has been inconsistent and confusing. Developmental Dynamics 236:1456–1474, 2007. © 2007 Wiley-Liss, Inc.
    Full-text · Article · Jun 2007
    • "Currently, the Shh gene represents the closest known gene and best candidate for a keystone defect creating the VACTERL complex although it is clearly not alone. Recently a missense mutation in the DLL gene resulting in an altered amino acid in the sequence was found in a VACTERL patient with vertebral anoma- lies [10]. This sequence is conserved among mammals and defects within have been previously found in mice with vertebral defects [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: The VACTERL complex refers to anomalies of the bony spinal column (V), atresias in the gastrointestinal tract (A), congenital heart lesions (C), tracheoesophageal defects (TE), renal and distal urinary tract anomalies (R) and limb lesions (L). The incidence of each of these components has not been precisely quantified in the recent literature and the full array of anomalies within each systemic class of the VACTERL complex has not been well described. Therefore, we reviewed our most recent 20-year experience of patients born with esophageal atresia to comprehensively delineate and accurately describe the type and incidence of associated lesions. A retrospective review was then conducted on all patients diagnosed with esophageal atresia between 1985 and 2005. Patient demographics recorded included gestational age, weight and gender. The specific types of lesions were carefully cataloged. The outcome measure recorded was survival. One hundred and twelve patients were diagnosed with esophageal atresia were identified during the study period. The gestational age range was 28-41 weeks with an average of 36.5 weeks. Average birth weight was 2,557 g (range 1,107-3,890). A male predominance was seen with 62 males and 50 females. The overall survival was 92.9%. The categorical breakdown of anomalies were vertebral (24.1%), atresia (14.3%), cardiac (32.1%), tracheoesophageal fistula (95.5%), urinary (17.0%), skeletal (16.1%) and other (10.8%). VACTERL anomalies are common in patients with esophageal atresia, however, they appear to have little impact on overall survival.
    Full-text · Article · May 2007
    • "Evidence for genetically heterogeneous etiologies of vertebral malformations includes the identification of mutations in DLL3 in patients with spondylocostal dysostosis [14,15] and mutations identified in JAG 1 in patients with Alagille syndrome [16]. Recently, a few DNA coding sequence alterations with uncertain clinical significance in PAX1 and DLL3 have been identified in a cohort of patients with phenotypically characterized vertebral mal- formations17181920. Our inability to detect mutations in WNT3A, as well as other candidate genes studied, may reflect differences in the regulation of somitogenesis in humans as compared to mice. "
    [Show abstract] [Hide abstract] ABSTRACT: Prior investigations have not identified a major locus for vertebral malformations, providing evidence that there is genetic heterogeneity for this condition. WNT3A has recently been identified as a negative regulator of Notch signaling and somitogenesis. Mice with mutations in Wnt3a develop caudal vertebral malformations. Because congenital vertebral malformations represent a sporadic occurrence, linkage approaches to identify genes associated with human vertebral development are not feasible. We hypothesized that WNT3A mutations might account for a subset of congenital vertebral malformations. A pilot study was performed using a cohort of patients with congenital vertebral malformations spanning the entire vertebral column was characterized. DNA sequence analysis of the WNT3A gene in these 50 patients with congenital vertebral malformations was performed. A female patient of African ancestry with congenital scoliosis and a T12-L1 hemivertebrae was found to be heterozygous for a missense variant resulting in the substitution of alanine by threonine at codon 134 in highly conserved exon 3 of the WNT3A gene. This variant was found at a very low prevalence (0.35%) in a control population of 443 anonymized subjects and 1.1% in an African population. These data suggest that WNT3A does not contribute towards the development of congenital vertebral malformations. Factors such as phenotypic and genetic heterogeneity may underlie our inability to detect mutations in WNT3A in our patient sample.
    Full-text · Article · Feb 2007
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