Heterozygous TGFBR2 mutations in Marfan syndrome (original) (raw)

• Letter
• Published: 04 July 2004
• Gwenaëlle Collod-Beroud3,4 na1,
• Takushi Akiyama5,
• Marianne Abifadel4,
• Naoki Harada1,2,6,
• Takayuki Morisaki7,
• Delphine Allard4,
• Mathilde Varret4,
• Mireille Claustres3,
• Hiroko Morisaki7,
• Makoto Ihara8,
• Akira Kinoshita1,2,
• Koh-ichiro Yoshiura1,2,
• Claudine Junien4,9,
• Tadashi Kajii10,
• Guillaume Jondeau4,11,
• Tohru Ohta2,12,13,
• Tatsuya Kishino2,12,
• Yoichi Furukawa14,
• Yusuke Nakamura14,
• Norio Niikawa1,2,
• Catherine Boileau4,9 na1 &
• …
• Naomichi Matsumoto1,2,15 na1

Nature Genetics volume 36, pages 855–860 (2004)Cite this article

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Abstract

Marfan syndrome is an extracellular matrix disorder with cardinal manifestations in the eye, skeleton and cardiovascular systems associated with defects in the gene encoding fibrillin (FBN1) at 15q21.1 (ref. 1). A second type of the disorder (Marfan syndrome type 2; OMIM 154705) is associated with a second locus, MFS2, at 3p25–p24.2 in a large French family (family MS1)2. Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-β receptor 2 (TGFBR2) in a Japanese individual with Marfan syndrome led us to consider TGFBR2 as the gene underlying association with Marfan syndrome at the MSF2 locus. The mutation 1524G→A in TGFBR2 (causing the synonymous amino acid substitution Q508Q) resulted in abnormal splicing and segregated with MFS2 in family MS1. We identified three other missense mutations in four unrelated probands, which led to loss of function of TGF-β signaling activity on extracellular matrix formation. These results show that heterozygous mutations in TGFBR2, a putative tumor-suppressor gene implicated in several malignancies, are also associated with inherited connective-tissue disorders.

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Acknowledgements

We thank the affected individuals and their families for their participation; Y. Noguchi, K. Miyazaki and N. Yanai for technical assistance; T. Imamura and K. Miyazono for cell lines Mv1Lu and DR-26 and reporter constructs p3TP-Lux and p15P751-Luc (with permission from J. Massague); and S. Tuffery-Giraud and C. Béroud for technical and scientific discussions. This study was supported in part by CREST, Japan Science and Technology Agency, and by Université René Descartes-Paris V, Ministère de l'Education Nationale, de l'Enseignement Supérieur, de la Recherche et de l'Insertion Professionnelle, Fondation de France, and Faculté de Médecine Necker.

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Author notes

1. Takeshi Mizuguchi, Gwenaëlle Collod-Beroud, Catherine Boileau and Naomichi Matsumoto: These authors equally contributed to this work.

Authors and Affiliations

1. Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
   Takeshi Mizuguchi, Naoki Harada, Akira Kinoshita, Koh-ichiro Yoshiura, Norio Niikawa & Naomichi Matsumoto
2. CREST, Japan Science and Technology Agency, Kawaguchi, Japan
   Takeshi Mizuguchi, Naoki Harada, Akira Kinoshita, Koh-ichiro Yoshiura, Tohru Ohta, Tatsuya Kishino, Norio Niikawa & Naomichi Matsumoto
3. Laboratoire de Génétique Moléculaire, Institut Universitaire de Recherche Clinique, Montpellier, France
   Gwenaëlle Collod-Beroud & Mireille Claustres
4. INSERM U383, Université Paris V, Hôpital Necker-Enfants Malades, Paris, France
   Gwenaëlle Collod-Beroud, Marianne Abifadel, Delphine Allard, Mathilde Varret, Claudine Junien, Guillaume Jondeau & Catherine Boileau
5. Division of Pediatric Surgery, National Okayama Medical Center, Okayama, Japan
   Takushi Akiyama
6. Kyushu Medical Science Nagasaki Laboratory, Nagasaki, Japan
   Naoki Harada
7. Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Japan
   Takayuki Morisaki & Hiroko Morisaki
8. Department of Radiation Biophysics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
   Makoto Ihara
9. Laboratoire de Biochimie, d'Hormonologie et de Génétique Moléculaire, Hôpital Ambroise Paré, Boulogne, France
   Claudine Junien & Catherine Boileau
10. Hachioji, Japan
    Tadashi Kajii
11. Service de Cardiologie, Hôpital Ambroise Paré, Boulogne, France
    Guillaume Jondeau
12. Division of Functional Genomics, Center for Frontier Life Sciences, Nagasaki University, Nagasaki, Japan
    Tohru Ohta & Tatsuya Kishino
13. The Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Ishikari-tobetsu, Japan
    Tohru Ohta
14. Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
    Yoichi Furukawa & Yusuke Nakamura
15. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
    Naomichi Matsumoto

Authors

1. Takeshi Mizuguchi
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2. Gwenaëlle Collod-Beroud
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3. Takushi Akiyama
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4. Marianne Abifadel
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5. Naoki Harada
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6. Takayuki Morisaki
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7. Delphine Allard
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8. Mathilde Varret
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9. Mireille Claustres
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10. Hiroko Morisaki
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11. Makoto Ihara
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12. Akira Kinoshita
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13. Koh-ichiro Yoshiura
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14. Claudine Junien
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15. Tadashi Kajii
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16. Guillaume Jondeau
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17. Tohru Ohta
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18. Tatsuya Kishino
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19. Yoichi Furukawa
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20. Yusuke Nakamura
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21. Norio Niikawa
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22. Catherine Boileau
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23. Naomichi Matsumoto
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Corresponding authors

Correspondence toCatherine Boileau or Naomichi Matsumoto.

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Mizuguchi, T., Collod-Beroud, G., Akiyama, T. et al. Heterozygous TGFBR2 mutations in Marfan syndrome.Nat Genet 36, 855–860 (2004). https://doi.org/10.1038/ng1392

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• Received: 05 February 2004
• Accepted: 02 June 2004
• Published: 04 July 2004
• Issue Date: 01 August 2004
• DOI: https://doi.org/10.1038/ng1392

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