Heterozygous TGFBR2 mutations in Marfan syndrome.
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). Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-beta 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-beta 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.
Mizuguchi
Takeshi
T
Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
Collod-Beroud
Gwenaëlle
G
Akiyama
Takushi
T
Abifadel
Marianne
M
Harada
Naoki
N
Morisaki
Takayuki
T
Allard
Delphine
D
Varret
Mathilde
M
Claustres
Mireille
M
Morisaki
Hiroko
H
Ihara
Makoto
M
Kinoshita
Akira
A
Yoshiura
Koh-ichiro
K
Junien
Claudine
C
Kajii
Tadashi
T
Jondeau
Guillaume
G
Ohta
Tohru
T
Kishino
Tatsuya
T
Furukawa
Yoichi
Y
Nakamura
Yusuke
Y
Niikawa
Norio
N
Boileau
Catherine
C
Matsumoto
Naomichi
N
D000595:Amino Acid Sequence; D002893:Chromosomes, Human, Pair 3; D005260:Female; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II