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  • In this study we were able derive new insights into


    In this study, we were able derive new insights into the biology of DDR2 including the demonstration that cellular tyrosine phosphorylated proteins co-localise with DDR2 and exogenously added collagen I (Fig. 1G). This finding suggests that similar to the focal adhesion complexes associated with integrin activation by collagen [21], DDR2 signalling is a spatially localised event occurring at discrete locations at the cell-surface interface where it is in close proximity with the collagen ligand. Taken together, our imaging data on DDR2 and the body of work on DDR1 trafficking supports the view that the DDRs are localised to the cell surface where these receptors bind to collagen and induce tyrosine DASA-58 [6,7,22,23]. By utilising immunofluorescence microscopy, this study reveals the spatial heterogeneity associated with DDR2 phosphorylation-mediated signalling and the functional components required for receptor localisation, ultimately uncovering new insights into DDR2 signalling in both space and time.
    Conflicts of interest
    Acknowledgments This work was supported by grants from the Institute of Cancer Research (ICR) and Biotechnology and Biological Sciences Research Council (BB/I014276/1 and BB/M013782/1).
    Main Text In 2006, Warburg et al. described an apparently distinct connective-tissue disorder characterized by blepharophimosis, progressive corneal vascularization, retinal dystrophy, conductive hearing loss, acro-osteolysis, and wasting of subcutaneous tissue in the face, hands, and feet. For updated pictures of the described individual, see Figure 1. Cinotti et al. later reported an individual with similar features. In this report we extend the clinical description by identifying four additional individuals, three of whom are from a single family, and identify the molecular cause of this syndrome. The clinical findings are illustrated in Figures 1 and 2 and are summarized in Tables 1 and S1. Pedigrees are provided in Supplemental Figures S1–S4. Individuals 1 and 2 have been described in detail.1, 2 The proband of the third pedigree (individual 3) is a 31-year-old female with two affected children (Figures 2 and S3). She was born with a clubfoot, which was successfully treated. When she was 5 years old, the first red, linear, and firm keloid-like plaque appeared spontaneously on her left forearm. This was slowly progressive. Over the years, several additional red papules and linear or annular plaques developed on her arms and feet, without preceding trauma or inflammation. In contrast, no keloid formations have occurred after surgical and traumatic wounds, with the exception of one instance after an ear helix piercing. At age 14, finger flexion contractures, preceded by painless, non-erythematous swelling of the involved joints, developed. This progressed to ankylosis of proximal interphalangeal (PIP) joints and cutaneous fusion between the digits and the palm (Figures 2E and 2F). Surgical correction and collagenase injections allowed the fixated digit to extend, but rapid recurrence and progression occurred. Gradual cutaneous fusion of the toes led to little or no separation of the toes (Figures 2I and 2J). She has had numerous sterile abscesses of the hands and feet, and these abscesses were often followed by scarring, cutaneous fusions, and contractures. From the age of 25, she developed corneal neovascularization and subsequent pannus and symblepharon formation on the right eye; eventually, there was complete conjunctivalization of the cornea and a reduction of her visual acuity to hand motion only. Her left eye has normal vision, but examination showed limbal stem-cell deficiency (LSCD), a superior corneal vascular pannus, reduction of the central corneal thickness to 419 μm, and endothelial-cell dysfunction with disruption of healthy hexagonal morphology (Figures 2A–2C). Fundoscopy showed normal retinal findings. Her facial features include a mild narrowing of the nasal bridge, mild lower-midface retrusion, and mild epicanthal folds. The lengths of her palpebral fissures are normal. She was diagnosed with hypothyroidism in her 20s. She has generalized thin skin and erythema.The hyperkeratosis of follicular orifices of her arms, neck, and chest resembles DASA-58 keratosis pilaris. Radiographs of the hands showed relatively normal phalanges with contractures. Radiographs of the feet showed small, hypodense distal phalanges and deformed middle phalanges, and in the 3-5th toe severe lateral angulation of the DIP joints could be seen (Figure 2H). She had enlarged frontal sinuses on skull films and no apparent osteolysis.