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Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans

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 gene...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2014-05, Vol.111 (21), p.7723-7728
Main Authors: Kawasaki, Kyoko, Freimuth, Julia, Meyer, Dominique S., Lee, Marie M., Tochimoto-Okamoto, Akiko, Benzinou, Michael, Clermont, Frederic F., Wu, Gloria, Roy, Ritu, Letteboer, Tom G. W., van Amstel, Johannes Kristian Ploos, Giraud, Sophie, Dupuis-Girod, Sophie, Lesca, Gaeten, Westermann, Cornelius J. J., Coffey, Robert J., Akhurst, Rosemary J.
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cited_by cdi_FETCH-LOGICAL-c496t-91553dbc601e828a9df61d48cead307856dfe9eb13c0964d8b49aea1711f9b653
cites cdi_FETCH-LOGICAL-c496t-91553dbc601e828a9df61d48cead307856dfe9eb13c0964d8b49aea1711f9b653
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container_issue 21
container_start_page 7723
container_title Proceedings of the National Academy of Sciences - PNAS
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creator Kawasaki, Kyoko
Freimuth, Julia
Meyer, Dominique S.
Lee, Marie M.
Tochimoto-Okamoto, Akiko
Benzinou, Michael
Clermont, Frederic F.
Wu, Gloria
Roy, Ritu
Letteboer, Tom G. W.
van Amstel, Johannes Kristian Ploos
Giraud, Sophie
Dupuis-Girod, Sophie
Lesca, Gaeten
Westermann, Cornelius J. J.
Coffey, Robert J.
Akhurst, Rosemary J.
description 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.
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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). 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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). 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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). 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subjects ADAM Proteins - genetics
ADAM Proteins - metabolism
ADAM17 Protein
Alleles
Angiogenesis
Animals
Biological Sciences
Blood Vessels - pathology
Gene expression regulation
Gene Expression Regulation - genetics
Gene Expression Regulation - physiology
Genetic loci
Genetic mutation
Genetic Variation
Hereditary hemorrhagic telangiectasia
Human genetics
Humans
Immunohistochemistry
Luciferases
Medical genetics
Mice
Mice, Inbred C57BL
NIH 3T3 Cells
Signal Transduction - genetics
Signal Transduction - physiology
Smad2 Protein - metabolism
Transforming Growth Factor beta - metabolism
Transforming Growth Factor beta1 - genetics
title Genetic variants of Adam17 differentially regulate TGFβ signaling to modify vascular pathology in mice and humans
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