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

Am J Hum Genet. 2018 Dec 6;103(6):976-983. doi: 10.1016/j.ajhg.2018.10.013.

Linda Xu ¹, Hanne Jensen ², Jennifer J Johnston ³, Emilio Di Maria ⁴, Katja Kloth ⁵, Ileana Cristea ¹, Julie C Sapp ³, Thomas N Darling ⁶, Laryssa A Huryn ⁷, Lisbeth Tranebjærg ⁸, Elisa Cinotti ⁹, Christian Kubisch ⁵, Eyvind Rødahl ¹⁰, Ove Bruland ¹¹, Leslie G Biesecker ³, Gunnar Houge ¹², Cecilie Bredrup ¹

Affiliations

1 Department of Ophthalmology, Haukeland University Hospital, N-5021 Bergen, Norway; Department of Medical Genetics, Haukeland University Hospital, N-5021 Bergen, Norway; Department of Clinical Medicine, University of Bergen, N-5021 Bergen, Norway.
2 Eye Department Glostrup Hospital, Rigshospitalet, the Kennedy Centre, DK 2600 Glostrup, Denmark.
3 National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, US.
4 Department of Health Sciences, Division of Medical Genetics, University of Genova, Galliera Hospital, 16128 Genova, Italy.
5 Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
6 Uniformed Services University of the Health Sciences, Bethesda, MD 20814, US.
7 National Eye Institute, National Institutes of Health, Bethesda, MD 20892, US.
8 Department of Clinical Genetics, The Kennedy Center, Copenhagen University Hospital, DK-2200 Copenhagen, Denmark; Institute of Clinical Medicine, University of Copenhagen, DK-2200 Copenhagen, Denmark.
9 Department of Medical, Surgical and Neuro-Sciences, Dermatology Unit, University of Siena, 53100 Siena, Italy.
10 Department of Ophthalmology, Haukeland University Hospital, N-5021 Bergen, Norway; Department of Clinical Medicine, University of Bergen, N-5021 Bergen, Norway.
11 Department of Medical Genetics, Haukeland University Hospital, N-5021 Bergen, Norway.
12 Department of Medical Genetics, Haukeland University Hospital, N-5021 Bergen, Norway. Electronic address: gunnar.houge@helse-bergen.no.

PMID: 30449416 DOI: 10.1016/j.ajhg.2018.10.013

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 growth-regulatory 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.

Keywords

DDR2; acro-osteolysis; chronic skin ulcers; contractures; corneal neovascularization; keloid formation; lipodystrophy.

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