Article

Craniosynostosis in Alagille syndrome

Division of Gastroenterology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
American Journal of Medical Genetics (Impact Factor: 3.23). 10/2002; 112(2):176-80. DOI: 10.1002/ajmg.10608
Source: PubMed

ABSTRACT Alagille syndrome is a multisystem developmental disorder with primary involvement of the liver, heart, skeleton, eyes and facial structures, and demonstrates highly variable expressivity with respect to all of the involved systems. Alagille syndrome is caused by mutations in the Jagged1 gene. Jagged1 is a ligand in the Notch signaling pathway that has been shown to regulate early cell fate determination. Mutations in Jagged1 have been identified in approximately 80% of patients with Alagille syndrome. We have recently identified two patients with mutation proven Alagille syndrome who also had unilateral coronal craniosynostosis. Both individuals were screened for mutations in fibroblast growth factor receptor 1, 2, 3 and TWIST genes, all associated with various types of craniosynostosis and no mutations were identified. The finding of a conserved form of craniosynostosis in two unrelated patients with Alagille syndrome and mutations in Jagged1 may indicate that Jagged1 plays a role in cranial suture formation.

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Available from: Catherine A Stolle, Oct 30, 2014
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    • "We sought to test the role of the Notch pathway in craniosynostosis and in the formation of a compartment boundary in the coronal suture. Our focus was the Notch ligand, Jagged1, because of its function in boundary formation and Alagille syndrome, which has craniosynostosis as a feature (Kamath et al., 2002). Here, by means of conditional targeting, we show that inactivation of Jagged1 in the coronal suture results in craniosynostosis. "
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    ABSTRACT: The Notch pathway is crucial for a wide variety of developmental processes including the formation of tissue boundaries. That it may function in calvarial suture development and figure in the pathophysiology of craniosynostosis was suggested by the demonstration that heterozygous loss of function of JAGGED1 in humans can cause Alagille syndrome, which has craniosynostosis as a feature. We used conditional gene targeting to examine the role of Jagged1 in the development of the skull vault. We demonstrate that Jagged1 is expressed in a layer of mesoderm-derived sutural cells that lie along the osteogenic-non-osteogenic boundary. We show that inactivation of Jagged1 in the mesodermal compartment of the coronal suture, but not in the neural crest compartment, results in craniosynostosis. Mesodermal inactivation of Jagged1 also results in changes in the identity of sutural cells prior to overt osteogenic differentiation, as well as defects in the boundary between osteogenic and non-osteogenic compartments at the coronal suture. These changes, surprisingly, are associated with increased expression of Notch2 and the Notch effector, Hes1, in the sutural mesenchyme. They are also associated with an increase in nuclear β-catenin. In Twist1 mutants, Jagged1 expression in the suture is reduced substantially, suggesting an epistatic relationship between Twist1 and Jagged1. Consistent with such a relationship, Twist1-Jagged1 double heterozygotes exhibit a substantial increase in the severity of craniosynostosis over individual heterozygotes. Our results thus suggest that Jagged1 is an effector of Twist1 in coronal suture development.
    Developmental Biology 11/2010; 347(2):258-70. DOI:10.1016/j.ydbio.2010.08.010 · 3.64 Impact Factor
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    • "Alagille syndrome (Krantz et al., 1998; Crosnier et al., 1999), which can cause unilateral coronal craniosynostosis in patients (Kamath et al., 2002). This correlation between a CeTwist target and craniosynostosis further validates that new genes identified in the CeTwist pathway could be good candidates for other craniosynostotic syndromes. "
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    ABSTRACT: Twist, a basic helix-loop-helix (bHLH) transcription factor, plays an important role in mesoderm development in many organisms, including C. elegans where CeTwist is required to direct cell fate specifications of a subset of mesodermal cells. Although several target genes of CeTwist have been identified, how this protein accomplishes its function is unclear. In addition, several human genes whose mutations cause different syndromes of craniosynostosis (premature fusion of cranial sutures) have homologues in the CeTwist pathway. Identification of novel target genes of CeTwist will shed more light on the functions of CeTwist in mesoderm development, and the corresponding human homologues will be good candidates for related syndromes with unidentified mutated genes. In our study, both CeTwist and its heterodimeric partner, CeE/DA, were overexpressed from the inducible heat-shock promoter, and potential target genes were detected with Affymetrix oligonucleotide microarrays. Using transcriptional GFP reporters, we found 11 genes were expressed in cells coincident with known CeTwist target gene products. Based on subsequent validation experiments, 9 genes were defined as novel CeTwist and CeE/DA targets. Human homologues of two of these genes might be involved in craniofacial diseases, which further validates C. elegans as a good model organism for providing insights into these disorders.
    Developmental Biology 06/2006; 293(2):486-98. DOI:10.1016/j.ydbio.2005.10.011 · 3.64 Impact Factor
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    ABSTRACT: The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in organisms as diverse as insects, nematodes, echinoderms and mammals. Disruptions in conserved developmental pathways frequently result in inherited congenital anomalies in humans. Mutations in genes encoding Notch pathway components underlie three inherited human diseases: Alagille syndrome, spondylocostal dysostosis, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Mouse models for these three diseases have been developed, and are leading to novel insights into the pathology of these diseases in humans.
    Human Molecular Genetics 05/2003; 12 Spec No 1(90001):R9-13. DOI:10.1093/hmg/ddg052 · 6.68 Impact Factor
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