Several of the keloid like lesions
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 Sorbitol 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 The Discoidin domain receptor was discovered by homology cloning based on catalytic kinase domain and considered as orphan receptor until 1997 when two independent groups discovered that several different collagens were ligand for DDR receptors [1,2]. A cell surface receptor tyrosine kinase, discoidin domain receptor 2 (DDR2) plays a key role in communication around the circumventing environments of extracellular matrix (ECM). The signaling role of DDR2 in the developments of bone and cartilage degradation due to deposition of ECM components has suggested the paramount contribution in patho-physiological scenario in cartilage . The mechanical injuries, degradation of cartilage, inflammatory disorders and age-related changes cause accumulation of collagen at the injured site of joints. At the early stage of osteoarthritis, the expression level of DDR2 is elevated in chondrocytes because of collagen type II protein accumulation and proximity upon the degradation of cartilage. This leads to release of matrix metalloproteases (MMP). The level of MMP-1 in human fibrosarcoma cell line HT1080 has found to be overexpressed through DDR2 activation, suggesting of regulatory role in cartilage degeneration . The incremented expression of DDR2 enhances the binding of receptor to collagen type II, which in turn switch on the expression of MMP-13, causing a severe damage to extracellular matrix of cartilage, as well [4,5]. Therefore, DDR2 receptor in chondrocyte is sensed by the microenvironments created due to mechanical stress or biochemical insults. Collagen type II in cartilage could trigger more DDR2-dependent collagen signaling towards the pathological condition. The DDR2 knockout mouse has been investigated to reduce expression of MMP-13 and MMP-1 activity and found to be declined the degradation of articular cartilage significantly in some studies [6,69]. Further, these facts were fortified by the deletion of DDR2 receptor in mice model of OA and found to be reduced the extent of degradation of articular cartilage in knee joints . The articular cartilage shows the mechanical integrity due to extracellular matrix. The ECM is composed of collagen type II protein in major amount, which forms 3D network and provides cartilage to resistant against tensile forces along and external injury .