Journal ArticleDOI
Dysregulation of TGF-β activation contributes to pathogenesis in Marfan syndrome
Enid Neptune,Pamela A. Frischmeyer,Dan E. Arking,Loretha Myers,Tracie E. Bunton,Barbara Gayraud,Francesco Ramirez,Lynn Y. Sakai,Harry C. Dietz +8 more
TLDR
It is shown that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-β (TGF-β) activation and signaling, resulting in apoptosis in the developing lung, and that perturbation of this function can contribute to the pathogenesis of disease.Abstract:
Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1‐3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome 4 . Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-β (TGF-β) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-β attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.read more
Citations
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Hundreds of variants clustered in genomic loci and biological pathways affect human height
Hana Lango Allen,Karol Estrada,Guillaume Lettre,Sonja I. Berndt,Michael N. Weedon,Fernando Rivadeneira,Cristen J. Willer,Anne U. Jackson,Sailaja Vedantam,Sailaja Vedantam,Soumya Raychaudhuri,Soumya Raychaudhuri,Teresa Ferreira,Andrew R. Wood,Robert J. Weyant,Ayellet V. Segrè,Ayellet V. Segrè,Elizabeth K. Speliotes,Elizabeth K. Speliotes,Eleanor Wheeler,Nicole Soranzo,Nicole Soranzo,Ju-Hyun Park,Jian Yang,Daniel F. Gudbjartsson,Nancy L. Heard-Costa,Joshua C. Randall,Lu Qi,Albert V. Smith,Reedik Mägi,Tomi Pastinen,Liming Liang,Iris M. Heid,Jian'an Luan,Gudmar Thorleifsson,Thomas W. Winkler,Michael E. Goddard,Michael E. Goddard,Ken Sin Lo,Cameron D. Palmer,Cameron D. Palmer,Tsegaselassie Workalemahu,Yurii S. Aulchenko,Åsa Johansson,Åsa Johansson,M. Carola Zillikens,Mary F. Feitosa,Tõnu Esko,Tõnu Esko,Toby Johnson,Toby Johnson,Toby Johnson,Shamika Ketkar,Peter Kraft,Massimo Mangino,Inga Prokopenko,Devin Absher,Eva Albrecht,Florian Ernst,Nicole L. Glazer,Caroline Hayward,Jouke-Jan Hottenga,Kevin B. Jacobs,Joshua W. Knowles,Zoltán Kutalik,Zoltán Kutalik,Keri L. Monda,Ozren Polasek,Michael Preuss,Nigel W. Rayner,Neil R. Robertson,Valgerdur Steinthorsdottir,Jonathan Tyrer,Benjamin F. Voight,Benjamin F. Voight,Fredrik Wiklund,Jianfeng Xu,Jing Hua Zhao,Dale R. Nyholt,Niina Pellikka,Niina Pellikka,Markus Perola,Markus Perola,John Perry,Ida Surakka,Ida Surakka,Mari Liis Tammesoo,Elizabeth L. Altmaier,Elizabeth L. Altmaier,Najaf Amin,Thor Aspelund,Tushar Bhangale,Gabrielle Boucher,Daniel I. Chasman,Constance Chen,Lachlan J. M. Coin,Mark E. Cooper,Anna L. Dixon,Quince Gibson,Elin Grundberg,Elin Grundberg,Ke Hao,M. Juhani Junttila,Lee M. Kaplan,Johannes Kettunen,Johannes Kettunen,Inke R. König,Tony Kwan,Robert W. Lawrence,Douglas F. Levinson,Mattias Lorentzon,Barbara McKnight,Andrew P. Morris,Martina Müller,Julius S. Ngwa,Shaun Purcell,Shaun Purcell,Suzanne Rafelt,Rany M. Salem,Rany M. Salem,Erika Salvi,Serena Sanna,Jianxin Shi,Ulla Sovio,John R. Thompson,John R. Thompson,Michael C. Turchin,Michael C. Turchin,Liesbeth Vandenput,Dominique J. Verlaan,Veronique Vitart,Charles C. White,Andreas Ziegler,Peter Almgren,Anthony J. Balmforth,Harry Campbell,Lorena Citterio,Alessandro De Grandi,Anna F. Dominiczak,Jubao Duan,Paul Elliott,Roberto Elosua,Johan G. Eriksson,Nelson B. Freimer,Eco J. C. de Geus,Nicola Glorioso,Shen Haiqing,Anna-Liisa Hartikainen,Aki S. Havulinna,Andrew A. Hicks,Jennie Hui,Jennie Hui,Wilmar Igl,Thomas Illig,Antti Jula,Eero Kajantie,Tuomas O. Kilpeläinen,Markku Koiranen,Ivana Kolcic,Seppo Koskinen,Peter Kovacs,Jaana Laitinen,Jianjun Liu,Marja-Liisa Lokki,Ana Marušić,Andrea Maschio,Thomas Meitinger,Antonella Mulas,Guillaume Paré,Alex N. Parker,John F. Peden,Astrid Petersmann,Irene Pichler,Kirsi H. Pietiläinen,Anneli Pouta,Anneli Pouta,Martin Ridderstråle,Jerome I. Rotter,Jennifer G. Sambrook,Jennifer G. Sambrook,Alan R. Sanders,Carsten Oliver Schmidt,Juha Sinisalo,Jan Smit,Heather M. Stringham,G. Bragi Walters,Elisabeth Widen,Sarah H. Wild,Gonneke Willemsen,Laura Zagato,Lina Zgaga,Paavo Zitting,Helene Alavere,Martin Farrall,Wendy L. McArdle,Mari Nelis,Mari Nelis,Marjolein J. Peters,Samuli Ripatti,Samuli Ripatti,Joyce B. J. van Meurs,Katja K.H. Aben,Kristin G. Ardlie,Jacques S. Beckmann,John Beilby,John Beilby,Richard N. Bergman,Sven Bergmann,Sven Bergmann,Francis S. Collins,Daniele Cusi,Martin den Heijer,Gudny Eiriksdottir,Pablo V. Gejman,Alistair S. Hall,Anders Hamsten,Heikki V. Huikuri,Carlos Iribarren,Carlos Iribarren,Mika Kähönen,Jaakko Kaprio,Jaakko Kaprio,Sekar Kathiresan,Sekar Kathiresan,Sekar Kathiresan,Lambertus A. Kiemeney,Thomas D. Kocher,Lenore J. Launer,Terho Lehtimäki,Olle Melander,Thomas H. Mosley,Arthur W. Musk,Arthur W. Musk,Markku S. Nieminen,Christopher J. O'Donnell,Christopher J. O'Donnell,Claes Ohlsson,Ben A. Oostra,Lyle J. Palmer,Lyle J. Palmer,Olli T. Raitakari,Paul M. Ridker,John D. Rioux,Aila Rissanen,Carlo Rivolta,Heribert Schunkert,Alan R. Shuldiner,Alan R. Shuldiner,David S. Siscovick,Michael Stumvoll,Anke Tönjes,Jaakko Tuomilehto,Jaakko Tuomilehto,Gert-Jan B. van Ommen,Jorma Viikari,Andrew C. Heath,Nicholas G. Martin,Grant W. Montgomery,Michael A. Province,Manfred Kayser,Alice M. Arnold,Larry D. Atwood,Eric Boerwinkle,Stephen J. Chanock,Panos Deloukas,Christian Gieger,Henrik Grönberg,Per Hall,Andrew T. Hattersley,Christian Hengstenberg,Wolfgang Hoffman,G. Mark Lathrop,Veikko Salomaa,Stefan Schreiber,Manuela Uda,Dawn M. Waterworth,Alan F. Wright,Themistocles L. Assimes,Inês Barroso,Inês Barroso,Albert Hofman,Karen L. Mohlke,Dorret I. Boomsma,Mark J. Caulfield,L. Adrienne Cupples,Jeanette Erdmann,Caroline S. Fox,Vilmundur Gudnason,Ulf Gyllensten,Tamara B. Harris,Richard B. Hayes,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Marjo-Riitta Järvelin,Vincent Mooser,Patricia B. Munroe,Willem H. Ouwehand,Willem H. Ouwehand,Willem H. Ouwehand,Brenda W.J.H. Penninx,Brenda W.J.H. Penninx,Peter P. Pramstaller,Thomas Quertermous,Igor Rudan,Igor Rudan,Nilesh J. Samani,Nilesh J. Samani,Tim D. Spector,Henry Völzke,Hugh Watkins,James F. Wilson,Leif Groop,Talin Haritunians,Frank B. Hu,Robert C. Kaplan,Andres Metspalu,Andres Metspalu,Kari E. North,David Schlessinger,Nicholas J. Wareham,David J. Hunter,Jeffrey R. O'Connell,David P. Strachan,H.-Erich Wichmann,Ingrid B. Borecki,Cornelia M. van Duijn,Eric E. Schadt,Eric E. Schadt,Unnur Thorsteinsdottir,Unnur Thorsteinsdottir,Leena Peltonen,André G. Uitterlinden,Peter M. Visscher,Nilanjan Chatterjee,Ruth J. F. Loos,Michael Boehnke,Mark I. McCarthy,Erik Ingelsson,Cecilia M. Lindgren,Gonçalo R. Abecasis,Kari Stefansson,Kari Stefansson,Timothy M. Frayling,Joel N. Hirschhorn,Joel N. Hirschhorn +344 more
TL;DR: It is shown that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait, and indicates that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
Hundreds of variants clustered in genomic loci and biological pathways affect human height
Hana Lango Allen,Karol Estrada,Guillaume Lettre,Sonja I. Berndt,Michael N. Weedon,Fernando Rivadeneira,Cristen J. Willer,Anne U. Jackson,Sailaja Vedantam,Soumya Raychaudhuri,Teresa Ferreira,Andrew R. Wood,Robert J. Weyant,Ayellet V. Segrè,Elizabeth K. Speliotes,Eleanor Wheeler,Nicole Soranzo,Ju-Hyun Park,Jian Yang,Daniel F. Gudbjartsson,Nancy L. Heard-Costa,Joshua C. Randall,Lu Qi,Albert V. Smith,Reedik Maegi,Tomi Pastinen,Liming Liang,Iris M. Heid,Jian'an Luan,Gudmar Thorleifsson,Thomas W. Winkler,Michael E. Goddard,Ken Sin Lo,Cameron D. Palmer,Tsegaselassie Workalemahu,Yurii S. Aulchenko,Åsa Johansson,M. Carola Zillikens,Mary F. Feitosa,Tõnu Esko,Toby Johnson,Shamika Ketkar,Peter Kraft,Massimo Mangino,Inga Prokopenko,Devin Absher,Eva Albrecht,Florian Ernst,Nicole L. Glazer,Caroline Hayward,Jouke-Jan Hottenga,Kevin B. Jacobs,Joshua W. Knowles,Zoltán Kutalik,Keri L. Monda,Ozren Polasek,Michael Preuss,Nigel W. Rayner,Neil R. Robertson,Valgerdur Steinthorsdottir,Jonathan Tyrer,Benjamin F. Voight,Fredrik Wiklund,Jianfeng Xu,Jing Hua Zhao,Dale R. Nyholt,Niina Pellikka,Markus Perola,John R. B. Perry,Ida Surakka,Mari-Liis Tammesoo,Elizabeth L. Altmaier,Najaf Amin,Thor Aspelund,Tushar Bhangale,Gabrielle Boucher,Daniel I. Chasman,Constance Chen,Lachlan J. M. Coin,Mark E. Cooper,Anna L. Dixon,Quince Gibson,Elin Grundberg,Ke Hao,M. Juhani Junttila,Lee M. Kaplan,Johannes Kettunen,Inke R. Koenig,Tony Kwan,Robert Lawrence,Douglas F. Levinson,Mattias Lorentzon,Barbara McKnight,Andrew P. Morris,Martina Mueller,Julius S. Ngwa,Shaun Purcell,Suzanne Rafelt,Rany M. Salem,Erika Salvi,Serena Sanna,Jianxin Shi,Ulla Sovio,John R. Thompson,Michael C. Turchin,Liesbeth Vandenput,Dominique J. Verlaan,Veronique Vitart,Charles C. White,Andreas Ziegler,Peter Almgren,Anthony J. Balmforth,Harry Campbell,Lorena Citterio,Alessandro De Grandi,Anna F. Dominiczak,Jubao Duan,Paul Elliott,Roberto Elosua,Johan G. Eriksson,Nelson B. Freimer,Eco J. C. de Geus,Nicola Glorioso,Shen Haiqing,Anna-Liisa Hartikainen,Aki S. Havulinna,Andrew A. Hicks,Jennie Hui,Wilmar Igl,Thomas Illig,Antti Jula,Eero Kajantie,Tuomas O. Kilpelaeinen,Markku Koiranen,Ivana Kolcic,Seppo Koskinen,Peter Kovacs,Jaana Laitinen,Jianjun Liu,Marja-Liisa Lokki,Ana Marušić,Andrea Maschio,Thomas Meitinger,Antonella Mulas,Guillaume Paré,Alex N. Parker,John F. Peden,Astrid Petersmann,Irene Pichler,Kirsi H. Pietiläinen,Anneli Pouta,Martin Riddertrale,Jerome I. Rotter,Jennifer G. Sambrook,Alan R. Sanders,Carsten Oliver Schmidt,Juha Sinisalo,Jan Smit,Heather M. Stringham,G. Bragi Walters,Elisabeth Widen,Sarah H. Wild,Gonneke Willemsen,Laura Zagato,Lina Zgaga,Paavo Zitting,Helene Alavere,Martin Farrall,Wendy L. McArdle,Mari Nelis,Marjolein Peters,Samuli Ripatti,Joyce B. J. vVan Meurs,Katja K.H. Aben,Kristin G. Ardlie,Jacques S. Beckmann,John Beilby,Richard N. Bergman,Sven Bergmann,Francis S. Collins,Daniele Cusi,Martin den Heijer,Gudny Eiriksdottir,Pablo V. Gejman,Alistair S. Hall,Anders Hamsten,Heikki V. Huikuri,Carlos Iribarren,Mika Kähönen,Jaakko Kaprio,Sekar Kathiresan,Lambertus A. Kiemeney,Thomas D. Kocher,Lenore J. Launer,Terho Lehtimäki,Olle Melander,Thomas H. Mosley,Arthur W. Musk,Markku S. Nieminen,Christopher J. O'Donnell,Claes Ohlsson,Ben A. Oostra,Lyle J. Palmer,Olli T. Raitakari,Paul M. Ridker,John D. Rioux,Aila Rissanen,Carlo Rivolta,Heribert Schunkert,Alan R. Shuldiner,David S. Siscovick,Michael Stumvoll,Anke Toenjes,Jaakko Tuomilehto,Gert-Jan B. van Ommen,Jorma Viikari,Andrew C. Heath,Nicholas G. Martin,Grant W. Montgomery,Michael A. Province,Manfred Kayser,Alice M. Arnold,Larry D. Atwood,Eric Boerwinkle,Stephen J. Chanock,Panos Deloukas,Christian Gieger,Henrik Grönberg,Per Hall,Andrew T. Hattersley,Christian Hengstenberg,Wolfgang Hoffman,G. Mark Lathrop,Veikko Salomaa,Stefan Schreiber,Manuela Uda,Dawn M. Waterworth,Alan F. Wright,Themistocles L. Assimes,Inês Barroso,Albert Hofman,Karen L. Mohlke,Dorret I. Boomsma,Mark J. Caulfield,L. Adrienne Cupples,Jeanette Erdmann,Caroline S. Fox,Vilmundur Gudnason,Ulf Gyllensten,Tamara B. Harris,Richard B. Hayes,Marjo-Ritta Jarvelin,Vincent Mooser,Patricia B. Munroe,Willem H. Ouwehand,Brenda W.J.H. Penninx,Peter P. Pramstaller,Thomas Quertermous,Igor Rudan,Nilesh J. Samani,Tim D. Spector,Henry Voelzke,Hugh Watkins,James F. Wilson,Leif Groop,Talin Haritunians,Frank B. Hu,Robert C. Kaplan,Andres Metspalu,Kari E. North,David Schlessinger,Nicholas J. Wareham,David J. Hunter,Jeffrey R. O'Connell,David P. Strachan,H. Erich Schadt,Unnur Thorsteinsdottir,Leena Peltonen,André G. Uitterlinden,Peter M. Visscher,Nilanjan Chatterjee,Ruth J. F. Loos,Michael Boehnke,Mark I. McCarthy,Erik Ingelsson,Cecilia M. Lindgren,Gonçalo R. Abecasis,Kari Stefansson,Timothy M. Frayling,Joel N. Hirschhorn +289 more
TL;DR: In this paper, the authors show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait, revealing patterns with important implications for genetic studies of common human diseases and traits.
Journal ArticleDOI
Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome.
Jennifer P Habashi,Daniel P. Judge,Tammy M. Holm,Ronald D. Cohn,Bart Loeys,Timothy K. Cooper,Loretha Myers,Erin C Klein,Guosheng Liu,Carla L. Calvi,Megan Podowski,Enid Neptune,Marc K. Halushka,Djahida Bedja,Kathleen L. Gabrielson,Daniel B. Rifkin,Luca Carta,Francesco Ramirez,David L. Huso,Harry C. Dietz +19 more
TL;DR: Losartan, a drug already in clinical use for hypertension, merits investigation as a therapeutic strategy for patients with Marfan syndrome and has the potential to prevent the major life-threatening manifestation of this disorder.
Journal ArticleDOI
A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2
Bart Loeys,Junji Chen,Enid Neptune,Daniel P. Judge,Megan Podowski,Tammy M. Holm,Jennifer Meyers,Carmen C. Leitch,Nicholas Katsanis,Neda A. Sharifi,F Lauren Xu,Loretha Myers,Philip J. Spevak,Duke E. Cameron,Julie De Backer,Jan Hellemans,Yan Chen,Elaine C. Davis,Catherine L. Webb,Wolfram Kress,Paul Coucke,Daniel B. Rifkin,Anne De Paepe,Harry C. Dietz +23 more
TL;DR: These data definitively implicate perturbation of TGFβ signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.
Journal ArticleDOI
Targeting the TGFβ signalling pathway in disease.
Rosemary J. Akhurst,Akiko Hata +1 more
TL;DR: Why the TGFβ signalling pathway is a drug target, the potential clinical applications of TGF β inhibition, the issues arising with anti-TGFβ therapy and how these might be tackled using personalized approaches to dosing, monitoring of biomarkers as well as brief and/or localized drug-dosing regimens are considered.
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Direct binding of Smad3 and Smad4 to critical TGF beta-inducible elements in the promoter of human plasminogen activator inhibitor-type 1 gene.
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Fibulin-5/DANCE is essential for elastogenesis in vivo
Tomoyuki Nakamura,Pilar Ruiz Lozano,Yasuhiro Ikeda,Yoshitaka Iwanaga,Aleksander Hinek,Susumu Minamisawa,Ching-Feng Cheng,Kazuhiro Kobuke,Nancy D. Dalton,Yoshikazu Takada,Kei Tashiro,John Ross,Tasuku Honjo,Kenneth R. Chien +13 more
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Journal ArticleDOI
Latent Transforming Growth Factor β-binding Protein 1 Interacts with Fibrillin and Is a Microfibril-associated Protein
Zenzo Isogai,Robert N. Ono,Shin Ushiro,Douglas R. Keene,Yan Chen,Roberta Mazzieri,Noe L. Charbonneau,Dieter P. Reinhardt,Daniel B. Rifkin,Lynn Y. Sakai +9 more
TL;DR: Immunolocalization data were consistent with the hypothesis that LTBP-1 is a fibrillin-associated protein present in certain tissues but not in others, and a model depicting the relationship between LT BP-1 and fibrillins microfibrils is proposed.
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Mechanisms of TGF-beta signaling in regulation of cell growth and differentiation.
TL;DR: The molecular pathways that describe the anti-proliferative and transdifferentiating effects of TGF-beta in epithelial cells have been uncovered to great molecular detail and a future challenge will be to test their generality in other systems, including the immune system.
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