title: Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans.
abstract: Outcome of TGFβ1 signaling is context dependent and differs between individuals due to germ-line genetic variation. To explore innate genetic variants that determine differential outcome of reduced TGFβ1 signaling, we dissected the modifier locus Tgfbm3, on mouse chromosome 12. On a NIH/OlaHsd genetic background, the Tgfbm3b(C57) haplotype suppresses prenatal lethality of Tgfb1(-/-) embryos and enhances nuclear accumulation of mothers against decapentaplegic homolog 2 (Smad2) in embryonic cells. Amino acid polymorphisms within a disintegrin and metalloprotease 17 (Adam17) can account, at least in part, for this Tgfbm3b effect. ADAM17 is known to down-regulate Smad2 signaling by shedding the extracellular domain of TGFβRI, and we show that the C57 variant is hypomorphic for down-regulation of Smad2/3-driven transcription. Genetic variation at Tgfbm3 or pharmacological inhibition of ADAM17, modulates postnatal circulating endothelial progenitor cell (CEPC) numbers via effects on TGFβRI activity. Because CEPC numbers correlate with angiogenic potential, this suggests that variant Adam17 is an innate modifier of adult angiogenesis, acting through TGFβR1. To determine whether human ADAM17 is also polymorphic and interacts with TGFβ signaling in human vascular disease, we investigated hereditary hemorrhagic telangiectasia (HHT), which is caused by mutations in TGFβ/bone morphogenetic protein receptor genes, ENG, encoding endoglin (HHT1), or ACVRL1 encoding ALK1 (HHT2), and considered a disease of excessive abnormal angiogenesis. HHT manifests highly variable incidence and severity of clinical features, ranging from small mucocutaneous telangiectases to life-threatening visceral and cerebral arteriovenous malformations (AVMs). We show that ADAM17 SNPs associate with the presence of pulmonary AVM in HHT1 but not HHT2, indicating genetic variation in ADAM17 can potentiate a TGFβ-regulated vascular disease.
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kawasaki
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;
authors.forename: Julia
authors.initials: J
authors.lastname: Freimuth
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;
authors.forename: Dominique S
authors.initials: DS
authors.lastname: Meyer
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;
authors.forename: Marie M
authors.initials: MM
authors.lastname: Lee
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;
authors.forename: Akiko
authors.initials: A
authors.lastname: Tochimoto-Okamoto
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;
authors.forename: Michael
authors.initials: M
authors.lastname: Benzinou
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;
authors.forename: Frederic F
authors.initials: FF
authors.lastname: Clermont
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;
authors.forename: Gloria
authors.initials: G
authors.lastname: Wu
authors.affiliation: HDFCCC Biostatistical Core Facility, University of California, San Francisco, CA 94143;
authors.forename: Ritu
authors.initials: R
authors.lastname: Roy
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;Department of Medical Genetics, University Medical Centre, KC04.084.2, Utrecht, The Netherlands;
authors.forename: Tom G W
authors.initials: TG
authors.lastname: Letteboer
authors.affiliation: Department of Medical Genetics, University Medical Centre, KC04.084.2, Utrecht, The Netherlands;
authors.forename: Johannes Kristian
authors.initials: JK
authors.lastname: Ploos van Amstel
authors.affiliation: French Hereditary Hemorrhagic Telangiectasia Reference Center, Department of Medical Genetics, Lyon University Hospital, 69622 Villeurbanne, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Giraud
authors.affiliation: French Hereditary Hemorrhagic Telangiectasia Reference Center, Department of Medical Genetics, Lyon University Hospital, 69622 Villeurbanne, France;
authors.forename: Sophie
authors.initials: S
authors.lastname: Dupuis-Girod
authors.affiliation: French Hereditary Hemorrhagic Telangiectasia Reference Center, Department of Medical Genetics, Lyon University Hospital, 69622 Villeurbanne, France;
authors.forename: Gaeten
authors.initials: G
authors.lastname: Lesca
authors.affiliation: St. Antonius Hospital, 3430 EM, Nieuwegein, The Netherlands;
authors.forename: Cornelius J J
authors.initials: CJ
authors.lastname: Westermann
authors.affiliation: Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232; and.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
authors.affiliation: Helen Diller Family Comprehensive Cancer Center (HDFCCC) and Department of Anatomy, University of California, San Francisco, CA 94158-9001;Department of Anatomy, andInstitute of Human Genetics, University of California, San Francisco, CA 94143 rakhurst@cc.ucsf.edu.
authors.forename: Rosemary J
authors.initials: RJ
authors.lastname: Akhurst
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D001808:Blood Vessels / Q000473:pathology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology*; D014644:Genetic Variation; D006801:Humans; D007150:Immunohistochemistry; D008156:Luciferases; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics
chemical_list: D051899:Smad2 Protein; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D008156:Luciferases; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse