Forskning
Udskriv Udskriv
Switch language
Region Hovedstaden - en del af Københavns Universitetshospital
Udgivet

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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

  1. Exome-Derived Adiponectin-Associated Variants Implicate Obesity and Lipid Biology

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Complex Compound Inheritance of Lethal Lung Developmental Disorders Due to Disruption of the TBX-FGF Pathway

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Associations of Mitochondrial and Nuclear Mitochondrial Variants and Genes with Seven Metabolic Traits

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  4. Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  1. Novel HARS2 missense variants identified in individuals with sensorineural hearing impairment and Perrault syndrome

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  2. Functional Assessment of Variants Associated with Wolfram Syndrome

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  3. Association of SLC26A4 mutations, morphology, and hearing in pendred syndrome and NSEVA

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Linda Xu
  • Hanne Jensen
  • Jennifer J Johnston
  • Emilio Di Maria
  • Katja Kloth
  • Ileana Cristea
  • Julie C Sapp
  • Thomas N Darling
  • Laryssa A Huryn
  • Lisbeth Tranebjærg
  • Elisa Cinotti
  • Christian Kubisch
  • Eyvind Rødahl
  • Ove Bruland
  • Leslie G Biesecker
  • Gunnar Houge
  • Cecilie Bredrup
Vis graf over relationer

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.

OriginalsprogEngelsk
TidsskriftAmerican Journal of Human Genetics
Vol/bind103
Udgave nummer6
Sider (fra-til)976-983
Antal sider8
ISSN0002-9297
DOI
StatusUdgivet - 6 dec. 2018

ID: 56213280