CMG2/ANTXR2 regulates extracellular collagen VI which accumulates in hyaline fibromatosis syndrome

Abstract

Loss-of-function mutations in capillary morphogenesis gene 2 (CMG2/ANTXR2), a transmembrane surface protein, cause hyaline fibromatosis syndrome (HFS), a severe genetic disorder that is characterized by large subcutaneous nodules, gingival hypertrophy and severe painful joint contracture. Here we show that CMG2 is an important regulator of collagen VI homoeostasis. CMG2 loss of function promotes accumulation of collagen VI in patients, leading in particular to nodule formation. Similarly, collagen VI accumulates massively in uteri of Antxr2−/− mice, which do not display changes in collagen gene expression, and leads to progressive fibrosis and sterility. Crossing Antxr2−/− with Col6a1−/− mice leads to restoration of uterine structure and reversion of female infertility. We also demonstrate that CMG2 may act as a signalling receptor for collagen VI and mediates its intracellular degradation.

Anthrax Toxin as a Molecular Platform to Target Nociceptive Neurons and Modulate Pain

“…Given that ANTXR2 is enriched in nociceptive neurons, we first determined whether deleting the receptor would affect pain behavior in the absence of toxin administration. The endogenous function of ANTXR2 is not fully understood, with reported roles in binding to extracellular matrix proteins and mediating their internalization and degradation (41). Compared between littermates, the absence of ANTXR2 did not affect most pain modalities at baseline, including mechanical pain thresholds assayed with von Frey filaments; thermal pain thresholds assayed with the Hargreaves apparatus and hot plate; and cold plate responses ( Fig.…”

“…The physiological role of ANTXR2 is not fully understood but may involve maintaining homeostasis of the extracellular matrix (ECM). ANTXR2 has been reported to bind to collagen type IV and laminin (56) and mediate the internalization and degradation of collagen type IV (41). Global ANTXR2 knock-out mice develop normally but show parturition defects due to abnormal deposition of ECM proteins in the uterus (57,58).…”

Síndrome de fibromatosis hialina: reporte de un caso y revisión bibliográfica

“…El gen ANTXR2/CMG2 codifica para una proteína que contiene un péptido de señal, un dominio tipo A extracelular del factor de von Willebrand (vWA), un dominio similar a la inmunoglubulina, un dominio transmembrana y una porción final citosólica. 6,7 Las mutaciones en el gen ANTXR2 alteran la síntesis de glucosaminoglicanos por los fibroblastos, lo que provoca deficiencia del metabolismo del colágeno. Se han propuesto tres posibles vías por las que se altera la permeabilidad de la membrana basal de los tejidos, provocando las lesiones papulares y nodulares típicas de la enfermedad: 1) aumento en la síntesis y degradación del colágeno tipo I, 2) reducción significativa del metabolismo del colágeno tipo III y IV y 3) depósitos de colágeno tipo VI.…”

“…1,2,4,[8][9][10][11] La pérdida de la función de CGM2 provoca la acumulación de colágeno VI en la matriz extracelular, con subsiguiente ruptura del tejido a largo plazo. 6 Las manifestaciones iniciales aparecen en los primeros meses de vida, 6,7 con contracturas articulares y lesiones pápulo-nodulares aperladas en el cuello y la región periorificial (oral, nasal y anal), acompañadas de hipertrofia gingival progresiva. 12,13 El diagnóstico de síndrome de fibromatosis hialina se establece mediante hallazgos clínicos, con apoyo del examen histopatológico de tejido cutáneo o intestinal, en el que se identifica la acumulación de material hialino 14,15 y se confirma con el análisis molecular del gen ANTXR2 (único gen identificado, hasta hoy, asociado con la enfermedad).…”

Anthrax toxin receptor 1/tumor endothelial marker 8 promotes gastric cancer progression through activation of the PI3K/AKT/mTOR signaling pathway

“…Seneca Valley virus has shown encouraging results and a favorable safety profile as an oncolytic virus in clinical trials, and this finding offers a promising biomarker for selecting patient response to treatment . The extracellular domains of ANTXR1 share homology with integrins, and interactions with collagen IV, collagen VI, and laminin suggest a possible function in basement membrane assembly and angiogenesis . In comparison with the wide distribution in normal tissue of ANTXR2, ANTXR1 is overexpressed in tumor cells and the vasculature of developing carcinoma .…”