Several of the keloid like
Several of the keloid-like lesions seen in these individuals were pigmented. It is of potential relevance that genetic variants in DDR1 [MIM: 600408] have been associated with vitiligo, and DDR1 activation is involved when DRB are attached to collagen-IV fibers. Because DDR1 and DDR2 are paralogous receptors, we hypothesize that activated DDR2 has a role in the migration or function of melanocytes.
In conclusion, we have identified the cause of a fibrotic syndrome that is inherited in an autosomal-dominant pattern. This syndrome is characterized by corneal vascularization, acro-osteolysis, contractures, thin skin, keloid-like plaques, and ulcerations, particularly of the toes and feet. We suggest it should be designated Warburg-Cinotti syndrome, after the authors of the first two clinical reports. In addition, we have identified a family and another singleton individual with the same condition. All affected individuals had activating variants in DDR2, either p.Leu610Pro or p.Tyr740Cys. We show that dasatinib inhibited the ligand-independent DDR2 autophosphorylation induced by both variants in vitro, suggesting an approach for treatment.
Declaration of Interests
Acknowledgments We thank Unni Larsen for technical assistance and Raoul C.M. Hennekam and Karen Brøndum-Nielsen for professional assistance. The work was supported by grants from the Western Norway Regional Health Authority (911977 and 912161 to C.B.), the Dr. Jon S. Larsens Foundation (to C.B.), and the Olav Raagholt and Gerd Meidel Raagholt Foundation for Research (to C.B.). L.G.B., J.J.J., and J.C.S. were supported by the Intramural Research Program of the National Human Genome Research Institute, grants HG200328 12 and HG200388 04. The NIH Intramural Sequencing Center performed exome sequencing on the family identified at the NIH (individuals 3–5).
Introduction Discoidin domain receptor 2 (DDR2) is a receptor tyrosine kinase that is activated by fibrillar collagens, which act as its endogenous ligand , , , , . DDR2 binds to and is activated by collagen I, II, III, V, and X, with the notable exception of basement membrane collagen IV , , , , , , . DDR2 is expressed in connective tissues arising from embryonic mesoderm , , , . DDR2 regulates cell proliferation, cell adhesion, and migration as well as extracellular matrix remodeling , , , , . We previously identified a recessive, loss-of-function allele for Ddr2 (designated ) that causes dwarfism and infertility . DDR2 null allele mice exhibit dwarfing with a shortening of the long bones and a reduction in body weight, which caused by a reduced proliferation rate of chondrocytes . A decrease in endogenous DDR2 by shRNA represses osteoblastic marker gene expression and osteogenic differentiation in murine preosteoblastic cells . The clonal cell line ATDC5 was isolated from the feeder-independent teratocarcinoma stem cell line AT805 on the basis of chondrogenic potentials in the presence of insulin , . ATDC5 cells can keep track of the multistep proliferation and differentiation process encompassing all endochondral ossification stages, from mesenchymal condensation to calcification in vitro, , , , . To better understand the role of DDR2 signaling in cellular proliferation in endochondral ossification, we produced ATDC5 cell lines with stably lower Ddr2 expression by using miRNA’s inhibitory effect on Ddr2 mRNA. We then analyzed cell proliferation and searched for differentiation in the stable miDdr2-expressed ATDC5 cell lines. The formation of mammalian endochondral bone is controlled spatially and environmentally by many signaling molecules , , . To investigate the molecular role of DDR2 in endochondral cellular proliferation in vivo, we also produced transgenic mice in which the expression of dominant-negative DDR2 protein is induced, and we evaluated the DDR2 function in cellular proliferation by analyzing the phenotypes. Dominant-negative DDR2 was made of kinase-dead DDR2 mutant (KD-DDR2), which is a truncated form lacking the kinase domain but retaining the extracellular and transmembrane domains , .