Mutations in the Gene Encoding Capillary Morphogenesis Protein 2 Cause Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis

Hanks, Sandra; Adams, Sarah; Douglas, Jenny; Arbour, Laura; Atherton, D.J.; Balcí, Sevim; Bode, Harald; Campbell, Mary Ellen; Feingold, Murray; Keser, Gökhan; Kleijer, Wim J.; Mancini, Grazia M.S.; McGrath, John A.; Muntoni, F.; Nanda, Arti; Teare, M. Dawn; Warman, Matthew L.; Pope, F. Michael; Superti‐Furga, Andrea; Futreal, P. Andrew; Rahman, Nazneen

doi:10.1086/378418

Cited by 202 publications

(251 citation statements)

References 21 publications

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“…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).…”

Section: Discussionmentioning

confidence: 99%

Human genetic variation altering anthrax toxin sensitivity

Martchenko¹,

Candille²,

Tang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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The outcome of exposure to infectious microbes or their toxins is influenced by both microbial and host genes. Some host genes encode defense mechanisms, whereas others assist pathogen functions. Genomic analyses have associated host gene mutations with altered infectious disease susceptibility, but evidence for causality is limited. Here we demonstrate that human genetic variation affecting capillary morphogenesis gene 2 ( CMG2 ), which encodes a host membrane protein exploited by anthrax toxin as a principal receptor, dramatically alters toxin sensitivity. Lymphoblastoid cells derived from a HapMap Project cohort of 234 persons of African, European, or Asian ancestry differed in sensitivity mediated by the protective antigen (PA) moiety of anthrax toxin by more than four orders of magnitude, with 99% of the cohort showing a 250-fold range of sensitivity. We find that relative sensitivity is an inherited trait that correlates strongly with CMG2 mRNA abundance in cells of each ethnic/geographical group and in the combined population pool ( P = 4 × 10 −11 ). The extent of CMG2 expression in transfected murine macrophages and human lymphoblastoid cells affected anthrax toxin binding, internalization, and sensitivity. A CMG2 single-nucleotide polymorphism (SNP) occurring frequently in African and European populations independently altered toxin uptake, but was not statistically associated with altered sensitivity in HapMap cell populations. Our results reveal extensive human diversity in cell lethality dependent on PA-mediated toxin binding and uptake, and identify individual differences in CMG2 expression level as a determinant of this diversity. Testing of genomically characterized human cell populations may offer a broadly useful strategy for elucidating effects of genetic variation on infectious disease susceptibility.

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Section: Discussionmentioning

confidence: 99%

Human genetic variation altering anthrax toxin sensitivity

Martchenko¹,

Candille²,

Tang³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…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.…”

Section: Generation Of Transmembrane Domain Deleted-tem8 and -Cmg2mentioning

confidence: 99%

“…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).…”

mentioning

confidence: 99%

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

Liu

Crown²,

Miller-Randolph³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

145

221

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Anthrax toxin, a major virulence factor of Bacillus anthracis, gains entry into target cells by binding to either of 2 von Willebrand factor A domain-containing proteins, tumor endothelium marker-8 (TEM8) and capillary morphogenesis protein-2 (CMG2). The wide tissue expression of TEM8 and CMG2 suggest that both receptors could play a role in anthrax pathogenesis. To explore the roles of TEM8 and CMG2 in normal physiology, as well as in anthrax pathogenesis, we generated TEM8-and CMG2-null mice and TEM8/ CMG2 double-null mice by deleting TEM8 and CMG2 transmembrane domains. TEM8 and CMG2 were found to be dispensable for mouse development and life, but both are essential in female reproduction in mice. We found that the lethality of anthrax toxin for mice is mostly mediated by CMG2 and that TEM8 plays only a minor role. This is likely because anthrax toxin has approximately 11-fold higher affinity for CMG2 than for TEM8. Finally, the CMG2-null mice are also shown to be highly resistant to B. anthracis spore infection, attesting to the importance of both anthrax toxin and CMG2 in anthrax infections.edema toxin ͉ lethal toxin ͉ tumor endothelium marker-8 B acillus anthracis is a Gram-positive, rod-shaped, sporeforming bacterium, and the causative agent of anthrax. Anthrax toxin is the major virulence factor for this organism and responsible for its lethal effects in the host. Although treatment with antibiotics to eliminate the bacteria can be life-saving at the earlier stages of anthrax disease, once enough toxin has been produced, the disease is often lethal despite treatment. Thus, countermeasures that block toxin or limit its effects are essential at later stages of disease (1). Therefore, a detailed understanding of the interaction between anthrax toxin and the host is needed as a basis for developing improved interventions.Anthrax toxin is a 3-part toxin consisting of protective antigen (PA, 83 kDa), edema factor (EF, 90 kDa), and lethal factor (LF, 89 kDa) (2-4). These 3 proteins are individually nontoxic, but can assemble on the cell surface to form toxic complexes. To intoxicate host mammalian cells, PA binds to its cellular receptors, tumor endothelium marker-8 [TEM8, also named anthrax toxin receptor 1 (ANTXR1)] and capillary morphogenesis protein-2 [CMG2, also named anthrax toxin receptor 2 (ANTXR2)] (5, 6) with the involvement of a coreceptor LRP6 (7,8) and is then proteolytically processed to the active form, cell-surface bound PA63. PA63 spontaneously oligomerizes to form a heptamer that binds and delivers LF and EF into the cytosol. EF, which combines with PA to form edema toxin (ET), is a calmodulin-dependent adenylate cyclase that elevates intracellular cAMP levels, thereby causing diverse effects including impairment of phagocytosis and death of experimental animals (9, 10). LF, which combines with PA to form lethal toxin (LT), is a zinc-dependent metalloproteinase that cleaves and inactivates the mitogen-activated protein kinase kinases (MEKs) 1-4, 6, and 7 (11-13), blocking the ERK, p38, and Jun...

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“…More recently, Denadai proposed to merge juvenile hyaline fibromatosis (OMIM 228600) and infantile systemic hyalinosis (OMIM 236490) into a single name, hyaline fibromatosis syndrome (HFS), because of the identification of genetic alterations in the same gene (CMG2 or ANTXR2) on chromosome 4q21 and because of the overlapping features of the two conditions [1, 6,7]. The pathogenesis is not yet fully understood, but many theories propose a key role for aberrant synthesis of GAG's by fibroblasts and for abnormal collagen metabolism [8].…”

Section: Discussionmentioning

confidence: 99%

Hyaline fibromatosis syndrome (juvenile hyaline fibromatosis): whole-body MR findings in two siblings with different subcutaneous nodules distribution

et al. 2017

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Hyaline fibromatosis syndrome (juvenile hyaline fibromatosis) is a rare, progressive, autosomal recessive disorder whose main hallmark is the deposition of amorphous hyaline material in soft tissues, with an evolutionary course and health impairment. It may present involvement of subcutaneous or periskeletal soft tissue, or may develop as a visceral infiltration entity with poor prognosis. Very few radiological data about this inherited condition have been reported, due to the extreme rarity of disease. We herein present a case of two siblings, affected by different severity of the disease, with different clinical features. They were examined by wholebody MR (WBMR) in order to assess different lesions localization, to rule out any visceral involvement and any other associated anomalies and to define patients' management.

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Mutations in the Gene Encoding Capillary Morphogenesis Protein 2 Cause Juvenile Hyaline Fibromatosis and Infantile Systemic Hyalinosis

Cited by 202 publications

References 21 publications

Human genetic variation altering anthrax toxin sensitivity

Human genetic variation altering anthrax toxin sensitivity

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

Hyaline fibromatosis syndrome (juvenile hyaline fibromatosis): whole-body MR findings in two siblings with different subcutaneous nodules distribution

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