Common and specific effects of TIE2 mutations causing venous malformations

Human Molecular Genetics
Marjut NatynkiLauri Eklund

Abstract

Venous malformations (VMs) are localized defects in vascular morphogenesis frequently caused by mutations in the gene for the endothelial tyrosine kinase receptor TIE2. Here, we report the analysis of a comprehensive collection of 22 TIE2 mutations identified in patients with VM, either as single amino acid substitutions or as double-mutations on the same allele. Using endothelial cell (EC) cultures, mouse models and ultrastructural analysis of tissue biopsies from patients, we demonstrate common as well as mutation-specific cellular and molecular features, on the basis of which mutations cluster into categories that correlate with data from genetic studies. Comparisons of double-mutants with their constituent single-mutant forms identified the pathogenic contributions of individual changes, and their compound effects. We find that defective receptor trafficking and subcellular localization of different TIE2 mutant forms occur via a variety of mechanisms, resulting in attenuated response to ligand. We also demonstrate, for the first time, that TIE2 mutations cause chronic activation of the MAPK pathway resulting in loss of normal EC monolayer due to extracellular matrix (ECM) fibronectin deficiency and leading to upregulation o...Continue Reading

References

Jul 1, 1978·Proceedings of the National Academy of Sciences of the United States of America·C R BirdwellG L Nicolson
Oct 1, 1976·Proceedings of the National Academy of Sciences of the United States of America·L B ChenJ K McDougall
Oct 15, 1996·Proceedings of the National Academy of Sciences of the United States of America·D S OryR C Mulligan
Mar 21, 2003·Journal of Cellular Biochemistry·Xavier HouardMaurice Pagano
Oct 31, 2003·Experimental Hematology·Toshio KitamuraHidetoshi Kumagai
Nov 5, 2004·Journal of Molecular Medicine : Official Organ of the Gesellschaft Deutscher Naturforscher Und Ärzte·Paul N MorrisNicholas P J Brindle
Apr 16, 2005·Molecular and Cellular Biology·Dirk-E Schmidt-ArrasFrank-D Böhmer
Dec 13, 2006·Arteriosclerosis, Thrombosis, and Vascular Biology·James A S MuldowneyDouglas E Vaughan
Jul 28, 2007·American Journal of Respiratory Cell and Molecular Biology·Jeffrey C HorowitzVictor J Thannickal
Sep 29, 2007·Arteriosclerosis, Thrombosis, and Vascular Biology·Clarence M FindleyChristopher D Kontos
Apr 17, 2008·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Séverine Tabone-EglingerJean-François Emile
May 17, 2008·Cancer Research·Joseph N ContessaTheodore S Lawrence
Jul 23, 2008·Archives of Dermatology·Anne DompmartinLaurence M Boon
Aug 1, 2009·Nature Protocols·Anna M LaibHellmut G Augustin
Nov 6, 2009·European Journal of Human Genetics : EJHG·Vinciane WoutersMiikka Vikkula
Nov 18, 2009·Archives of Dermatology·Anne DompmartinLaurence M Boon
May 25, 2011·The Journal of Clinical Investigation·Marie JeanssonSusan E Quaggin
Jul 18, 2012·Seminars in Pediatric Surgery·Florent GuérinSophie Branchereau
Jan 29, 2013·Methods in Enzymology·Carl M HurtTimothy Angelotti
Mar 19, 2013·The Journal of Biological Chemistry·Daishi YamakawaNobuyuki Takakura
May 2, 2013·Human Molecular Genetics·Melanie UebelhoerMiikka Vikkula
Jun 27, 2013·Molecular Syndromology·J SobletM Vikkula
Mar 1, 2014·Biochimica Et Biophysica Acta·Vassiliki Kostourou, Vassilis Papalazarou
Aug 11, 2015·The Journal of Clinical Investigation·Elisa BoscoloLaurence M Boon

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Citations

Dec 8, 2015·American Journal of Human Genetics·Nisha LimayeMiikka Vikkula
Apr 1, 2016·Science Translational Medicine·Pau CastelJosé Baselga
Apr 1, 2016·Science Translational Medicine·Sandra D CastilloBart Vanhaesebroeck
Aug 23, 2016·The Journal of Clinical Investigation·Emilia A KorhonenPipsa Saharinen
Oct 22, 2016·The Journal of Pathology·Sandra D CastilloNeil J Sebire
Aug 16, 2016·The Journal of Investigative Dermatology·Julie SobletMiikka Vikkula
May 23, 2017·Nature Reviews. Drug Discovery·Pipsa SaharinenKari Alitalo
Jan 20, 2018·Journal of Neurosurgery. Pediatrics·Daniel DuranKristopher T Kahle
Apr 19, 2018·Basic & Clinical Pharmacology & Toxicology·Jaakko KangasLauri Eklund
Feb 7, 2018·Ophthalmic Plastic and Reconstructive Surgery·Guosheng LiCharles G Eberhart
Jan 11, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Xian LiElisa Boscolo
Mar 12, 2019·Current Opinion in Hematology·Emmanuel SerontMiikka Vikkula
Apr 3, 2019·International Angiology : a Journal of the International Union of Angiology·Stefano PaolacciMatteo Bertelli
Dec 13, 2016·Clinical Science·Lauri EklundPipsa Saharinen
Jun 20, 2020·American Journal of Clinical Dermatology·An Van DammeMiikka Vikkula
Sep 2, 2020·Cell Communication and Signaling : CCS·Yameng SiHongbing Jiang
May 23, 2018·Angiogenesis·Jillian GoinesElisa Boscolo
Dec 8, 2020·Phlebology·Eleanor J BudgeChung Sim Lim
Oct 28, 2020·Journal of Clinical Medicine·Stefano PaolacciMatteo Bertelli
Oct 5, 2019·American Journal of Human Genetics·Samantha N McNultyJonathan W Heusel
Apr 13, 2021·Angiogenesis·Corina MarzianoKaren K Hirschi
May 1, 2021·Children·Johanna AronniemiRiitta Lassila
Nov 29, 2020·Journal of Vascular Surgery. Venous and Lymphatic Disorders·Zhong DuYan-An Wang
Jun 25, 2021·Circulation Research·Angela QueisserMiikka Vikkula
Jul 10, 2021·Orphanet Journal of Rare Diseases·Guillaume CanaudKim M Keppler-Noreuil
Jun 10, 2021·The Journal of Cardiovascular Surgery·Jovan N Markovic, Cynthia K Shortell
Dec 9, 2017·Otolaryngologic Clinics of North America·Angela QueisserMiikka Vikkula
Oct 16, 2021·Cold Spring Harbor Molecular Case Studies·Christopher L SudduthArin K Greene

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