Whole Exome Sequencing to Identify a Novel Gene (Caveolin-1) Associated With Human Pulmonary Arterial Hypertension

被引:333
作者
Austin, Eric D. [1 ]
Ma, Lijiang [3 ]
LeDuc, Charles
Rosenzweig, Erika Berman [3 ]
Borczuk, Alain [4 ]
Phillips, John A., III [1 ]
Palomero, Teresa [4 ]
Sumazin, Pavel [5 ]
Kim, Hyunjae R. [6 ]
Talati, Megha H. [2 ]
West, James [2 ]
Loyd, James E. [2 ]
Chung, Wendy K. [3 ]
机构
[1] Vanderbilt Univ, Med Ctr, Dept Pediat, Nashville, TN 37232 USA
[2] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
[3] Columbia Univ, Med Ctr, Dept Pediat, New York, NY USA
[4] Columbia Univ, Med Ctr, Dept Pathol, New York, NY USA
[5] Columbia Univ, Med Ctr, Joint Ctr Syst Biol, New York, NY USA
[6] Columbia Univ, Med Ctr, Herbert Irving Comprehens Canc Ctr, New York, NY USA
关键词
genetics; BMPR2; caveolae; pulmonary hypertension; EXPRESSION; MUTATIONS; BMPR2; RECEPTOR; DEFECTS; MICE;
D O I
10.1161/CIRCGENETICS.111.961888
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
Background-Heritable and idiopathic pulmonary arterial hypertension (PAH) are phenotypically identical and associated with mutations in several genes related to transforming growth factor (TGF) beta signaling, including bone morphogenetic protein receptor type 2, activin receptor-like kinase 1, endoglin, and mothers against decapentaplegic 9. Approximately 25% of heritable cases lack identifiable mutations in any of these genes. Methods and Results-We used whole exome sequencing to study a 3-generation family with multiple affected family members with PAH, but no identifiable TGF beta mutation. We identified a frameshift mutation in caveolin-1 (CAV1), which encodes a membrane protein of caveolae abundant in the endothelium and other cells of the lung. An independent de novo frameshift mutation was identified in a child with idiopathic PAH. Western blot analysis demonstrated a reduction in caveolin-1 protein, while lung tissue immunostaining studies demonstrated a reduction in normal caveolin-1 density within the endothelial cell layer of small arteries. Conclusions-Our study represents successful elucidation of a dominant Mendelian disorder using whole exome sequencing. Mutations in CAV1 are associated in rare cases with PAH. This may have important implications for pulmonary vascular biology, as well as PAH-directed therapeutic development. (Circ Cardiovasc Genet. 2012;5:336-343.)
引用
收藏
页码:336 / 343
页数:8
相关论文
共 29 条
[1]
Loss of caveolin and heme oxygenase expression in severe pulmonary hypertension [J].
Achcar, ROD ;
Demura, Y ;
Rai, PR ;
Taraseviciene-Stewart, L ;
Kasper, M ;
Voelkel, NF ;
Cool, CD .
CHEST, 2006, 129 (03) :696-705
[2]
Genetics of Pulmonary Arterial Hypertension [J].
Austin, Eric D. ;
Loyd, James E. ;
Phillips, John A. .
SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE, 2009, 30 (04) :386-398
[3]
Pulmonary Arterial Hypertension Baseline Characteristics From the REVEAL Registry [J].
Badesch, David B. ;
Raskob, Gary E. ;
Elliott, C. Greg ;
Krichman, Abby M. ;
Farber, Harrison W. ;
Frost, Adaani E. ;
Barst, Robyn. J. ;
Benza, Raymond L. ;
Liou, Theodore G. ;
Turner, Michelle ;
Giles, Scott ;
Feldkircher, Kathy ;
Miller, Dave P. ;
McGoon, Michael D. .
CHEST, 2010, 137 (02) :376-387
[4]
SNAP predicts effect of mutations on protein function [J].
Bromberg, Yana ;
Yachdav, Guy ;
Rost, Burkhard .
BIOINFORMATICS, 2008, 24 (20) :2397-2398
[5]
High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension [J].
Cogan, Joy D. ;
Pauciulo, Michael W. ;
Batchman, Amy P. ;
Prince, Melissa A. ;
Robbins, Ivan M. ;
Hedges, Lora K. ;
Stanton, Krista C. ;
Wheeler, Lisa A. ;
Phillips, John A., III ;
Loyd, James E. ;
Nichols, William C. .
AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 2006, 174 (05) :590-598
[6]
Role of caveolae and caveolins in health and disease [J].
Cohen, AW ;
Hnasko, R ;
Schubert, W ;
Lisanti, MP .
PHYSIOLOGICAL REVIEWS, 2004, 84 (04) :1341-1379
[7]
Familial primary pulmonary hypertension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene [J].
Deng, ZM ;
Morse, JH ;
Slager, SL ;
Cuervo, N ;
Moore, KJ ;
Venetos, G ;
Kalachikov, S ;
Cayanis, E ;
Fischer, SG ;
Barst, RJ ;
Hodge, SE ;
Knowles, JA .
AMERICAN JOURNAL OF HUMAN GENETICS, 2000, 67 (03) :737-744
[8]
Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice [J].
Drab, M ;
Verkade, P ;
Elger, M ;
Kasper, M ;
Lohn, M ;
Lauterbach, B ;
Menne, J ;
Lindschau, C ;
Mende, F ;
Luft, FC ;
Schedl, A ;
Haller, H ;
Kurzchalia, TV .
SCIENCE, 2001, 293 (5539) :2449-2452
[9]
Chromosomal localization, genomic organization, and developmental expression of the murine caveolin gene family (Cav-1, -2, and -3) - Cav-1 and Cav-2 genes map to a known tumor suppressor locus (6-A2/731) [J].
Engelman, JA ;
Zhang, XL ;
Galbiati, F ;
Lisanti, MP .
FEBS LETTERS, 1998, 429 (03) :330-336
[10]
Gene expression patterns in the lungs of patients with primary pulmonary hypertension - A gene microarray analysis [J].
Geraci, MW ;
Moore, M ;
Gesell, T ;
Yeager, ME ;
Alger, L ;
Golpon, H ;
Gao, BF ;
Loyd, JE ;
Tuder, RM ;
Voelkel, NF .
CIRCULATION RESEARCH, 2001, 88 (06) :555-562