Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg-Cinotti Syndrome

Abstract

We have investigated a distinct disorder with progressive corneal neovascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acro-osteolysis. In six affected individuals from four families, we found one of two recurrent variants in discoidin domain receptor tyrosine kinase 2 (DDR2): c.1829T>C (p.Leu610Pro) or c.2219A>G (p.Tyr740Cys). DDR2 encodes a collagen-responsive receptor tyrosine kinase that regulates connective-tissue formation. In three of the families, affected individuals comprise singleton adult individuals, and parental samples were not available for verification of the de novo occurrence of the DDR2 variants. In the fourth family, a mother and two of her children were affected, and the c.2219A>G missense variant was proven to be de novo in the mother. Phosphorylation of DDR2 was increased in fibroblasts from affected individuals, suggesting reduced receptor autoinhibition and ligand-independent kinase activation. Evidence for activation of other growthregulatory signaling pathways was not found. Finally, we found that the protein kinase inhibitor dasatinib prevented DDR2 autophosphorylation in fibroblasts, suggesting an approach to treatment. We propose this progressive, fibrotic condition should be designated as Warburg-Cinotti syndrome. Web ResourcesClinVar, https://www.ncbi.nlm.nih.gov/clinvar/ Exac Browser, http://exac.broadinstitute.org/ GnomAD Browser, http://gnomad.broadinstitute.org/ Online Mendelian Inheritance in Man, http://www.omim.org/

DDR1 promotes breast tumor growth by suppressing antitumor immunity

“…net/) (29) and off-targets were excluded using GT-Scan tools (30). Oligonucleotides with BsmB1 restriction sites for guide RNAs were synthesized by SBS Genetech Co., Ltd., then phosphorylated using T4 kinase (31). The phosphorylated oligonucleotides were cloned into LentiCRISPR v2 (Plasmid no.…”

Meeting report – first discoidin domain receptors meeting

“…Moreover, DDR2 expression is stimulated by the angiogenic growth factor VEGF. The role of DDR2 in angiogenesis was further demonstrated in the presentation by Cecilie Bredrup (Haukeland University Hospital, Bergen, Norway), who found that the L610P and Y740C mutations constitutively activate DDR2 and induce the angiogenic defect seen in Warburg-Cinotti syndrome (Xu et al, 2018). Finally, Yi-Chun Yeh (National Cheng Kung University, Tainan, Taiwan) showed that in kidney, DDR1 promotes epithelial cell differentiation by stabilizing E-cadherin at cell-cell junctions (Chen et al, 2016).…”

Lost bones: differential diagnosis of acro-osteolysis seen by the pediatric rheumatologist

“…Autosomal dominant variants in the parathyroid hormone-like hormone (PTHLH) gene, which is important in mediating bone homeostasis, can result in a syndrome characterized by acro-osteolysis, cortical irregularity of long bones and metadiaphyseal enchondromata [ 10 ]. Autosomal dominant Warburg-Cinotti syndrome due to variants in discoidin domain receptor tyrosine kinase 2 (DDR2) is associated with progressive corneal vascularization, keloid formation, chronic skin ulcers, wasting of subcutaneous tissue, flexion contractures of the fingers, and acro-osteolysis [ 11 ]. Autosomal dominant Singleton-Merten syndrome is an interferonopathy characterized by variable expression of aortic calcification, dental anomalies, osteopenia and acro-osteolysis, and to a lesser degree glaucoma, psoriasis, muscle weakness and joint laxity [ 12 ].…”