PARP15 Is a Susceptibility Locus for Clarkson Disease (Monoclonal Gammopathy-Associated Systemic Capillary Leak Syndrome)

Vascular leakage is a deadly complication of severe infections, ranging from bacterial sepsis to malaria. Worldwide, septicemia is among the top 10 causes of lethality because of the shock and multiorgan dysfunction that arise from the host vascular response. In the monoclonal gammopathy-associated...

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Vydané v:	Arteriosclerosis, thrombosis, and vascular biology Ročník 44; číslo 12; s. 2628
Hlavní autori:	Chan, Eunice C, Ablooglu, Ararat J, Ghosh, Chandra C, Desai, Abhishek, Schaible, Niccole, Chen, Xiuying, Zhao, Ming, Olano, M Renee, Ganesan, Sundar, Lack, Justin B, Krishnan, Ramaswamy, Parikh, Samir M, Druey, Kirk M
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States 01.12.2024
Predmet:	Animals Capillary Leak Syndrome - genetics Capillary Permeability Cells, Cultured Disease Models, Animal Endothelial Cells - enzymology Endothelial Cells - metabolism Female Genetic Predisposition to Disease Humans Loss of Function Mutation Male Mice Mice, Inbred C57BL Mice, Knockout p38 Mitogen-Activated Protein Kinases - genetics p38 Mitogen-Activated Protein Kinases - metabolism Paraproteinemias - complications Paraproteinemias - genetics Phenotype Poly(ADP-ribose) Polymerases - genetics Poly(ADP-ribose) Polymerases - metabolism diphtheria toxin influenza, human endothelial cells histamine adenosine diphosphate ribose
ISSN:	1524-4636, 1524-4636
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Shrnutí:	Vascular leakage is a deadly complication of severe infections, ranging from bacterial sepsis to malaria. Worldwide, septicemia is among the top 10 causes of lethality because of the shock and multiorgan dysfunction that arise from the host vascular response. In the monoclonal gammopathy-associated capillary leak syndrome (MG-CLS), even otherwise mundane infections induce recurrent septic-like episodes of profound microvascular hyperpermeability and shock. There are no defined genetic risk factors for MG-CLS or effective treatments for acute crises. We characterized predicted loss-of-function mutations in PARP15 (poly[ADP-ribose] polymerase 15), a protein of unknown function that is absent in mice, in patients with MG-CLS. We analyzed barrier function in PARP15-deficient vascular endothelial cells and vascular leakage in mice engineered to express wild-type or loss-of-function variant human PARP15. We discovered several loss-of-function PARP15 variants associated with MG-CLS. These mutations severely reduced PARP15 enzymatic function. The presence of the most frequently detected variant (G628R) correlated with clinical markers of severe vascular leakage. In human microvascular endothelial cells, PARP15 suppressed cytokine-induced barrier disruption by ADP-ribosylating the scaffold protein JIP3 (c-Jun N-terminal kinase-interacting protein 3) and inhibiting p38 MAP (mitogen-activated protein) kinase activation. Mice expressing enzymatically inactive human PARP15(G628R) were significantly more prone to inflammation-associated vascular leakage than mice expressing wild-type PARP15 in a p38-dependent fashion. represents a previously unrecognized genetic susceptibility factor for MG-CLS. PARP15-mediated ADP ribosylation is an essential and genetically determined mechanism of the human vascular response to inflammation.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1524-4636 1524-4636
DOI:	10.1161/ATVBAHA.124.321522