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

Jérôme Bürgi,Andrea Superti-Furga,Ekkehart Lausch,Alessandra Piersigilli,Paolo Bonaldo,Laurence Abrami,Sabine Scholl-Bürgi,Julie Deuquet,Sheila Unger,F Gisou Van Der Goot,Béatrice Kunz

doi:10.1038/ncomms15861

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.

Highlights

Loss-of-function mutations in capillary morphogenesis gene 2 (CMG2/anthrax toxin receptor 2 (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
Since CMG2 loss of function does not lead to an increase in collagen VI gene expression either in HFS patient fibroblasts or Antxr[2] À / À mice uteri, we investigated whether CMG2 can physically interact with this extracellular matrix (ECM) protein
Analyses of HFS patient nodules and of Antxr[2] À / À mouse uteri pointed towards a non-genetic interaction of CMG2 with collagen VI

Summary

Introduction

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. HFS is caused by loss-of-function mutations in capillary morphogenesis gene 2 (refs 3,4) (CMG2), known as anthrax toxin receptor 2 (ANTXR2). We discovered an uncharacterized function of CMG2 that can account for both the presence of nodules in HFS patients and the uterine phenotype in mice. We show that both the nodules of HFS patient and the uteri of Antxr[2] À / À female mouse are highly enriched in collagen VI. The identification of CMG2 as collagen VI regulator opens new avenues towards understanding other processes involving this ECM protein such as obesityinduced insulin resistance[12,13] and muscle homoeostasis[14]

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Conclusion