Mutations in Capillary Morphogenesis Gene-2 Result in the Allelic Disorders Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis

Department of Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 11/2003; 73(4):957-66. DOI: 10.1086/378781
Source: PubMed

ABSTRACT Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive syndromes of unknown etiology characterized by multiple, recurring subcutaneous tumors, gingival hypertrophy, joint contractures, osteolysis, and osteoporosis. Both are believed to be allelic disorders; ISH is distinguished from JHF by its more severe phenotype, which includes hyaline deposits in multiple organs, recurrent infections, and death within the first 2 years of life. Using the previously reported chromosome 4q21 JHF disease locus as a guide for candidate-gene identification, we identified and characterized JHF and ISH disease-causing mutations in the capillary morphogenesis factor-2 gene (CMG2). Although CMG2 encodes a protein upregulated in endothelial cells during capillary formation and was recently shown to function as an anthrax-toxin receptor, its physiologic role is unclear. Two ISH family-specific truncating mutations, E220X and the 1-bp insertion P357insC that results in translation of an out-of-frame stop codon, were generated by site-directed mutagenesis and were shown to delete the CMG-2 transmembrane and/or cytosolic domains, respectively. An ISH compound mutation, I189T, is predicted to create a novel and destabilizing internal cavity within the protein. The JHF family-specific homoallelic missense mutation G105D destabilizes a von Willebrand factor A extracellular domain alpha-helix, whereas the other mutation, L329R, occurs within the transmembrane domain of the protein. Finally, and possibly providing insight into the pathophysiology of these diseases, analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Capillary morphogenesis gene 2 (CMG2) is a receptor of anthrax toxin and plays an important role in angiogenesis. It has been shown to be involved in the cell adhesion and motility of various cell types, including epithelia and endothelia. The present study aimed to examine the therapeutic potential of targeting CMG2 to prevent tumour‑related new vasculature. The full-length coding sequence of the human CMG2 gene and different fragments of the CMG2 vWA domain were amplified and constructed into a mammalian expression plasmid vector. The effect of CMG2 and its vWA domain on endothelial cells and angiogenesis was assessed using relevant in vitro, ex vivo and in vivo models. The overexpression of CMG2 enhanced the adhesion of endothelial cells to extracellular matrix, but was negatively associated with cell migration. Overexpression of CMG2 and the vWA domain fragments inhibited the tubule formation and migration of endothelial cells. Small peptides based on the amino acid sequence of the CMG2 vWA domain fragments potently inhibited in vitro tubule formation and ex vivo angiogenesis. One of the polypeptides, LG20, showed an inhibitory effect on in vivo tumour growth of cancer cells which were co-inoculated with the vascular endothelial cells. CMG2 is a potential target for treating tumour‑related angiogenesis. The polypeptides based on the CMG2 vWA domain can potently inhibit in vitro and ex vivo angiogenesis, which may contribute to the inhibitory effect on in vivo tumour growth. Further investigations are required to shed light on the machinery and may provide a novel therapeutic approach for inhibition of angiogenesis in cancer management.
    International Journal of Oncology 07/2014; 45(4). DOI:10.3892/ijo.2014.2533 · 2.77 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Capillary morphogenesis gene 2 (CMG2), also known as anthrax toxin receptor 2, has been indicated in the formation of new vasculature and in the internalisation of the anthrax toxin. Anti-angiogenesis therapy that targets this molecule has been investigated. However, our recent studies of this molecule have indicated that this gene may also play certain roles in cancer cells. The present study aimed to examine the expression of CMG2 in prostate cancer tissues and cell lines, and also its impact on cellular functions. The expression of CMG2 was detectable in normal and prostate cancer tissues. The prostate cancer cell lines appeared to have relatively high expression compared with the prostatic epithelial cells. Knockdown of CMG2 impaired the adherence of the prostate cancer cells. CMG2 overexpression resulted in decreasing invasiveness, while the knockdown of CMG2 contrastingly enhanced this ability. The altered expression of CMG2 in the prostate cancer cells did not affect the in vitro or in vivo growth of the cells. Taken together, these results show that CMG2 is expressed in prostatic epithelia and cancer cells. In addition to its role in the angiogenesis and the internalisation of anthrax toxin, CMG2 also plays an important role in regulating the adhesion and invasion of prostate cancer cells.
    Oncology letters 06/2014; 7(6):2149-2153. DOI:10.3892/ol.2014.2038 · 0.99 Impact Factor
  • Frontiers in Bioscience 01/2009; Volume(14):2335. DOI:10.2741/3382 · 4.25 Impact Factor

Full-text (2 Sources)

Available from
Jun 5, 2014