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

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.

Improved vascular organization enhances functional integration of engineered skeletal muscle grafts

“…3A). In contrast, the human morphogenes, capillary morphogenesis genes (CMG-1, CMG-2, and CD39), angiogenic factors (VEGF-A, VEGF-B, and FGF2) and the hypoxia marker HIF1α, all critical factors in angiogenesis, vessel survival, and stabilization (17)(18)(19)(20)(21)(22)(23)(24)(25), were still highly expressed in three-week in vitro grafts (Fig. S2A).…”

Human genetic variation altering anthrax toxin sensitivity

“…Like the two other known anthrax toxin receptors located at the surface of mammalian cells (TEM8 and integrin β1) (26,27), CMG2 protein includes a von Willebrand domain (vWA) that binds to multiple extracellular matrix proteins, including collagen IV, laminin, and fibronectin (38). Mutations located within the CMG2 vWA domain, the CMG2 transmembrane region, or the CMG2 cytosolic tail can result in hyaline fibromatosis syndrome (HFS), a rare and lethal autosomal recessive disease characterized by the accumulation of hyaline material in the skin and other organs (40,41). Although CMG2 mutations associated with HFS have been identified in the vicinity of the polymorphic locus studied here (i.e., P357A) (40, 41) point mutations affecting the cytosolic tail do not necessarily diminish CMG2 ability to function as an anthrax toxin receptor (42,43).…”

Capillary morphogenesis protein-2 is the major receptor mediating lethality of anthrax toxin in vivo

“…CMG2 and TEM8 are anchored on the cell surface by single-pass TM domains that are essential to their biological functions (22,23). Furthermore, mutations in the TM region of CMG2 are frequently found in JHF and ISH patients (19,20). In this report, gene targeting vectors were used to delete the TM domains and thereby inactivate the receptors in mice.…”

“…TEM8 was initially identified as a tumor endothelium marker that is up-regulated in human colorectal cancer endothelium (18), suggesting it as a candidate for tumor targeting. Recently, mutations within CMG2 have been identified as causing 2 rare human autosomal recessive conditions, juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) (19,20). The wide tissue expression of TEM8 and CMG2 suggest that both receptors could play a role in anthrax pathogenesis (5, 6).…”