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: 10.93). 11/2003; 73(4):957-66. DOI: 10.1086/378781
Source: PubMed


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.

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Available from: Valerie Grum-Tokars
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    • "The CMG2 gene, located on chromosome 4q, encodes a protein of 489 amino acids with a putative signal peptide and extracellular, transmembrane and cytoplasmic domains (6). Mutations of the CMG2 gene have been identified in hyaline fibromatosis syndrome (HFS), including juvenile hyaline fibromatosis and infantile systemic hyalinosis, which are autosomal recessive syndromes characterized by multiple, recurring subcutaneous tumours, gingival hypertrophy, joint contractures, osteolysis and osteoporosis (8,9). Different natural variants encoded by alternatively spliced mRNA transcripts have been reported. "
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    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.
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    • "Patient HFS Zygocity Variant DNA DNA Alias Protein Protein Alias Exon References 1 Infantile Homozygote c.1073 1074insC c.1073dup insC p.A359CfsX13 ANTXR2 insC 13 Deuquet et al. (2011) 2 Infantile Compound c.566T>C c.566T>C p.I189T 7 Dowling et al. (2003) Heterozygote c.1073 1074insC c.1073dup "
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    ABSTRACT: Hyaline Fibromatosis Syndrome (HFS) is an autosomal recessive disease caused by mutations in ANTXR2, a gene involved in extracellular matrix homeostasis. Sixty percent of patients carry frameshift mutations at a mutational hotspot in exon 13. We show in patient cells that these mutations lead to low ANTXR2 mRNA and undetectable protein levels. Ectopic expression of the proteins encoded by the mutated genes reveals that a 2 base insertion leads to the synthesis of a protein that is rapidly targeted to the ER associated degradation pathway due to the modified structure of the cytosolic tail, which instead of being hydrophilic and highly disordered as in wild type ANTXR2, is folded and exposes hydrophobic patches. In contrast, one base insertion leads to a truncated protein that properly localizes to the plasma membrane and retains partial function. We next show that targeting the non-sense mediated mRNA decay pathway in patient cells leads to a rescue of ANTXR2 protein in patients carrying 1 base insertion but not in those carrying 2 base insertions. This study highlights the importance of in depth analysis of the molecular consequences of specific patient mutations, which even when they occur at the same site can have drastically different consequences.
    Full-text · Article · Jul 2013 · Human Mutation
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    • "Indeed, the receptor is highly expressed in both normal and cancerous vasculature, and its pattern of expression colocalizes with collagen type IV [31]. Genetic mutations in CMG2 result in the related disorders juvenile hyaline fibromatosis and infantile systemic hyalinosis [32] that are characterized by multiple recurring tumors and inappropriate deposition of hyalin, an extracellular matrix material. Like TEM8 knockout mice, female mice which lack the CMG2 receptor do not give birth, an effect apparently mediated by defects in uterine extracellular matrix remodeling [33]–[35]. "
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    ABSTRACT: Anti-angiogenic therapies are effective for the treatment of cancer, a variety of ocular diseases, and have potential benefits in cardiovascular disease, arthritis, and psoriasis. We have previously shown that anthrax protective antigen (PA), a non-pathogenic component of anthrax toxin, is an inhibitor of angiogenesis, apparently as a result of interaction with the cell surface receptors capillary morphogenesis gene 2 (CMG2) protein and tumor endothelial marker 8 (TEM8). Hence, molecules that bind the anthrax toxin receptors may be effective to slow or halt pathological vascular growth. Here we describe development and testing of an effective homogeneous steady-state fluorescence resonance energy transfer (FRET) high throughput screening assay designed to identify molecules that inhibit binding of PA to CMG2. Molecules identified in the screen can serve as potential lead compounds for the development of anti-angiogenic and anti-anthrax therapies. The assay to screen for inhibitors of this protein-protein interaction is sensitive and robust, with observed Z' values as high as 0.92. Preliminary screens conducted with a library of known bioactive compounds identified tannic acid and cisplatin as inhibitors of the PA-CMG2 interaction. We have confirmed that tannic acid both binds CMG2 and has anti-endothelial properties. In contrast, cisplatin appears to inhibit PA-CMG2 interaction by binding both PA and CMG2, and observed cisplatin anti-angiogenic effects are not mediated by interaction with CMG2. This work represents the first reported high throughput screening assay targeting CMG2 to identify possible inhibitors of both angiogenesis and anthrax intoxication.
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