Mutations in NOTCH1 cause aortic valve disease

被引:1140
作者
Garg, V
Muth, AN
Ransom, JF
Schluterman, MK
Barnes, R
King, IN
Grossfeld, PD
Srivastava, D
机构
[1] Univ Texas, SW Med Ctr, Dept Pediat, Dallas, TX 75390 USA
[2] Univ Texas, SW Med Ctr, Dept Mol Biol, Dallas, TX 75390 USA
[3] Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75390 USA
[4] Univ Texas, SW Med Ctr, McDermott Ctr Human Growth & Dev, Dallas, TX 75390 USA
[5] Childrens Med Ctr, Dallas, TX 75235 USA
[6] Univ Calif San Diego, Dept Pediat, Div Cardiol, San Diego, CA 92123 USA
关键词
D O I
10.1038/nature03940
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 [理学]; 0710 [生物学]; 09 [农学];
摘要
Calcification of the aortic valve is the third leading cause of heart disease in adults(1). The incidence increases with age, and it is often associated with a bicuspid aortic valve present in 1 - 2% of the population(2). Despite the frequency, neither the mechanisms of valve calcification nor the developmental origin of a two, rather than three, leaflet aortic valve is known. Here, we show that mutations in the signalling and transcriptional regulator NOTCH1 cause a spectrum of developmental aortic valve anomalies and severe valve calcification in non-syndromic autosomal-dominant human pedigrees. Consistent with the valve calcification phenotype, Notch1 transcripts were most abundant in the developing aortic valve of mice, and Notch1 repressed the activity of Runx2, a central transcriptional regulator of osteoblast cell fate. The hairy-related family of transcriptional repressors (Hrt), which are activated by Notch1 signalling, physically interacted with Runx2 and repressed Runx2 transcriptional activity independent of histone deacetylase activity. These results suggest that NOTCH1 mutations cause an early developmental defect in the aortic valve and a later de-repression of calcium deposition that causes progressive aortic valve disease.
引用
收藏
页码:270 / 274
页数:5
相关论文
共 30 条
[1]
[Anonymous], 2004, HEART DIS STROK STAT
[2]
Notch signaling: Cell fate control and signal integration in development [J].
Artavanis-Tsakonas, S ;
Rand, MD ;
Lake, RJ .
SCIENCE, 1999, 284 (5415) :770-776
[3]
The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor [J].
Brown, MS ;
Goldstein, JL .
CELL, 1997, 89 (03) :331-340
[4]
Low LDL cholesterol in African Americans resulting from frequent nonsense mutations in PCSK9 [J].
Cohen, J ;
Pertsemlidis, A ;
Kotowski, IK ;
Graham, R ;
Garcia, CK ;
Hobbs, HH .
NATURE GENETICS, 2005, 37 (03) :328-328
[5]
Bicuspid aortic valve is heritable [J].
Cripe, L ;
Andelfinger, G ;
Martin, LJ ;
Shooner, K ;
Benson, DW .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2004, 44 (01) :138-143
[6]
Osf2/Cbfa1: A transcriptional activator of osteoblast differentiation [J].
Ducy, P ;
Zhang, R ;
Geoffroy, V ;
Ridall, AL ;
Karsenty, G .
CELL, 1997, 89 (05) :747-754
[7]
An mRNA surveillance mechanism that eliminates transcripts lacking termination codons [J].
Frischmeyer, PA ;
van Hoof, A ;
O'Donnell, K ;
Guerrerio, AL ;
Parker, R ;
Dietz, HC .
SCIENCE, 2002, 295 (5563) :2258-2261
[8]
GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 [J].
Garg, V ;
Kathiriyra, IS ;
Barnes, R ;
Schluterman, MK ;
King, IN ;
Butler, CA ;
Rothrock, CR ;
Eapen, RS ;
Hirayama-Yamada, K ;
Joo, K ;
Matsuoka, R ;
Cohen, JC ;
Srivastava, D .
NATURE, 2003, 424 (6947) :443-447
[9]
Glycosylation regulates notch signalling [J].
Haines, N ;
Irvine, KD .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2003, 4 (10) :786-797
[10]
The incidence of congenital heart disease [J].
Hoffman, JIE ;
Kaplan, S .
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 2002, 39 (12) :1890-1900