Nature Genetics
36, 855 - 860 (2004)
Published online: 4 July 2004; | doi:10.1038/ng1392
Heterozygous TGFBR2 mutations in Marfan syndromeTakeshi Mizuguchi1, 2, 16, Gwenaëlle Collod-Beroud3, 4, 16, 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, 16
& Naomichi Matsumoto1, 2, 15, 161
Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki Japan. 2
CREST, Japan Science and Technology Agency, Kawaguchi, Japan. 3
Laboratoire de Génétique Moléculaire, Institut Universitaire de Recherche Clinique, Montpellier, France. 4
INSERM U383, Université Paris V, Hôpital Necker-Enfants Malades, Paris, France. 5
Division of Pediatric Surgery, National Okayama Medical Center, Okayama, Japan. 6
Kyushu Medical Science Nagasaki Laboratory, Nagasaki, Japan. 7
Department of Bioscience, National Cardiovascular Center Research Institute, Suita, Japan. 8
Department of Radiation Biophysics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. 9
Laboratoire de Biochimie, d'Hormonologie et de Génétique Moléculaire, Hôpital Ambroise Paré, Boulogne, France. 10
Hachioji, Japan. 11
Service de Cardiologie, Hôpital Ambroise Paré, Boulogne, France. 12
Division of Functional Genomics, Center for Frontier Life Sciences, Nagasaki University, Nagasaki, Japan. 13
The Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Ishikari-tobetsu, Japan. 14
Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. 15
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. 16
These authors equally contributed to this work.
Correspondence should be addressed to Catherine Boileau boileau@necker.fr or Naomichi Matsumoto naomat@yokohama-cu.ac.jpMarfan 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- 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- 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.
MORE ARTICLES LIKE THIS These links to content published by NPG are automatically generated.
|
