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

TY - JOUR

T1 - Recurrent, Activating Variants in the Receptor Tyrosine Kinase DDR2 Cause Warburg-Cinotti Syndrome

AU - Xu, Linda

AU - Jensen, Hanne

AU - Johnston, Jennifer J

AU - Di Maria, Emilio

AU - Kloth, Katja

AU - Cristea, Ileana

AU - Sapp, Julie C

AU - Darling, Thomas N

AU - Huryn, Laryssa A

AU - Tranebjærg, Lisbeth

AU - Cinotti, Elisa

AU - Kubisch, Christian

AU - Rødahl, Eyvind

AU - Bruland, Ove

AU - Biesecker, Leslie G

AU - Houge, Gunnar

AU - Bredrup, Cecilie

N1 - Copyright © 2018 American Society of Human Genetics. All rights reserved.

PY - 2018/12/6

Y1 - 2018/12/6

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.ajhg.2018.10.013

DO - 10.1016/j.ajhg.2018.10.013

M3 - SCORING: Journal article

C2 - 30449416

VL - 103

SP - 976

EP - 983

JO - AM J HUM GENET

JF - AM J HUM GENET

SN - 0002-9297

IS - 6

ER -