help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Published ahead of print on May 25, 2006, doi:10.1164/rccm.200602-165OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 5, September 2006, 590-598

A more recent version of this article appeared on September 1, 2006
This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200602-165OCv1
174/5/590    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cogan, J. D
Right arrow Articles by Nichols, W. C
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cogan, J. D
Right arrow Articles by Nichols, W. C

Submitted on February 3, 2006
Accepted on May 19, 2006

High Frequency of BMPR2 Exonic Deletions/Duplications in Familial Pulmonary Arterial Hypertension

Joy D Cogan1, Michael W Pauciulo2, Amy P Batchman2, Melissa A Prince1, Ivan M Robbins3, Lora K Hedges1, Krista C Stanton1, Lisa A Wheeler3, John A Phillips, III1, James E Loyd3, and William C Nichols4*

1 Division of Medical Genetics, Vanderbilt University Medical Center, Nashville, TN, USA, 2 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA, 3 Division of Pulmonary Biology, Vanderbilt University Medical Center, Nashville, TN, USA, 4 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

* To whom correspondence should be addressed. E-mail: bill.nichols{at}cchmc.org.

Rationale: Previous studies have shown that ~55% of familial pulmonary arterial hypertension (PAH) patients have BMPR2 coding sequence mutations. However, direct sequencing does not detect other types of heterozygous mutations such as exonic deletions/duplications. Objective: To estimate the frequency of BMPR2 exonic deletions/duplications in FPAH. Methods: BMPR2 mRNA from lymphoblastoid cell lines of 30 PAH families and 14 idiopathic PAH patients was subjected to RT-PCR and sequencing. Sequencing of genomic DNA was used to identify point mutations in splice donor/acceptor sites. Multiplex Ligation-dependent Probe Amplification (MLPA) was used to detect exonic deletions/duplications with verification by real-time PCR. Measurements and Main Results: Eleven (37%) FPAH patients had abnormally-sized RT-PCR products. Four of the 11 were found to have splice site mutations resulting in aberrant splicing, and exonic deletions/duplications were detected in the remaining seven. Additionally, MLPA identified 3 deletions/duplications which were not detectable by RT-PCR. Coding sequence point mutations were identified in 11 of 30 (37%). Overall, mutations were identified in 21 of 30 (70%) FPAH patients with 10 of 21 mutations(48%) being exonic deletions/duplications. Additionally, 2 of 14 (14%) IPAH patients exhibited BMPR2 point mutations while none showed exonic deletions/duplications. Conclusions: Our study indicates that BMPR2 exonic deletions/duplications in FPAH patients account for a significant proportion of mutations (48%) which to now have not been screened for. Since the complementary approach used in this study is both rapid and cost effective, screening for BMPR2 deletions/duplications by MLPA and real-time PCR should accompany direct sequencing in all PAH testing.
Key words: genetics, MLPA, dosage




This article has been cited by other articles:


Home page
 Eur Respir JHome page
E. D. Austin, J. D. Cogan, J. D. West, L. K. Hedges, R. Hamid, E. P. Dawson, L. A. Wheeler, F. F. Parl, J. E. Loyd, and J. A. Phillips III
Alterations in oestrogen metabolism: implications for higher penetrance of familial pulmonary arterial hypertension in females
Eur. Respir. J., November 1, 2009; 34(5): 1093 - 1099.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
R. D. Machado, O. Eickelberg, C. G. Elliott, M. W. Geraci, M. Hanaoka, J. E. Loyd, J. H. Newman, J. A. Phillips III, F. Soubrier, R. C. Trembath, et al.
Genetics and genomics of pulmonary arterial hypertension.
J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S32 - S42.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
G. Simonneau, I. M. Robbins, M. Beghetti, R. N. Channick, M. Delcroix, C. P. Denton, C. G. Elliott, S. P. Gaine, M. T. Gladwin, Z.-C. Jing, et al.
Updated clinical classification of pulmonary hypertension.
J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S43 - S54.
[Abstract] [Full Text] [PDF]

Home page
 J Am Coll CardiolHome page
H. A. Ghofrani, R. J. Barst, R. L. Benza, H. C. Champion, K. A. Fagan, F. Grimminger, M. Humbert, G. Simonneau, D. J. Stewart, C. Ventura, et al.
Future perspectives for the treatment of pulmonary arterial hypertension.
J. Am. Coll. Cardiol., June 30, 2009; 54(1 Suppl): S108 - S117.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
M Shintani, H Yagi, T Nakayama, T Saji, and R Matsuoka
A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension
J. Med. Genet., May 1, 2009; 46(5): 331 - 337.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. Humbert
Update in Pulmonary Hypertension 2008
Am. J. Respir. Crit. Care Med., April 15, 2009; 179(8): 650 - 656.
[Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
A. Yndestad, K.-O. Larsen, E. Oie, T. Ueland, C. Smith, B. Halvorsen, I. Sjaastad, O. H. Skjonsberg, T. M. Pedersen, O.-G. Anfinsen, et al.
Elevated levels of activin A in clinical and experimental pulmonary hypertension
J Appl Physiol, April 1, 2009; 106(4): 1356 - 1364.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
B. Sztrymf, F. Coulet, B. Girerd, A. Yaici, X. Jais, O. Sitbon, D. Montani, R. Souza, G. Simonneau, F. Soubrier, et al.
Clinical Outcomes of Pulmonary Arterial Hypertension in Carriers of BMPR2 Mutation
Am. J. Respir. Crit. Care Med., June 15, 2008; 177(12): 1377 - 1383.
[Abstract] [Full Text] [PDF]

Home page
 Physiol. GenomicsHome page
L. Moreno-Vinasco, M. Gomberg-Maitland, M. L. Maitland, A. A. Desai, P. A. Singleton, S. Sammani, L. Sam, Y. Liu, A. N. Husain, R. M. Lang, et al.
Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension
Physiol Genomics, April 1, 2008; 33(2): 278 - 291.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
K. Asosingh, M. A. Aldred, A. Vasanji, J. Drazba, J. Sharp, C. Farver, S. A.A. Comhair, W. Xu, L. Licina, L. Huang, et al.
Circulating Angiogenic Precursors in Idiopathic Pulmonary Arterial Hypertension
Am. J. Pathol., March 1, 2008; 172(3): 615 - 627.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
F. Kamezaki, H. Tasaki, K. Yamashita, M. Tsutsui, S. Koide, S. Nakata, A. Tanimoto, M. Okazaki, Y. Sasaguri, T. Adachi, et al.
Gene Transfer of Extracellular Superoxide Dismutase Ameliorates Pulmonary Hypertension in Rats
Am. J. Respir. Crit. Care Med., January 15, 2008; 177(2): 219 - 226.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
D. R. Stewart, J. D. Cogan, M. R. Kramer, W. T. Miller Jr, L. E. Christiansen, M. W. Pauciulo, L. M. Messiaen, G. S. Tu, W. H. Thompson, R. E. Pyeritz, et al.
Is Pulmonary Arterial Hypertension in Neurofibromatosis Type 1 Secondary to a Plexogenic Arteriopathy?
Chest, September 1, 2007; 132(3): 798 - 808.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2006 American Thoracic Society 		  New Orleans Int'l Conf