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Am J Respir Crit Care Med. 2006 Sep 1;174(5):590-8. Epub 2006 May 25.

High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension.

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1
Division of Medical Genetics, Vanderbilt University Medical University Medical Center, Nashville, Tennessee, USA.

Abstract

RATIONALE:

Previous studies have shown that approximately 55% of patients with familial pulmonary arterial hypertension (FPAH) 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 families with PAH and 14 patients with idiopathic PAH (IPAH) was subjected to reverse transcriptase-polymerase chain reaction (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%) patients with FPAH had abnormally sized RT-PCR products. Four of the 11 patients were found to have splice-site mutations resulting in aberrant splicing, and exonic deletions/duplications were detected in the remaining seven patients. MLPA identified three deletions/duplications that were not detectable by RT-PCR. Coding sequence point mutations were identified in 11 of 30 (37%) patients. Mutations were identified in 21 of 30 (70%) patients with FPAH, with 10 of 21 mutations (48%) being exonic deletions/duplications. Two of 14 (14%) patients with IPAH exhibited BMPR2 point mutations, whereas none showed exonic deletions/duplications.

CONCLUSIONS:

Our study indicates that BMPR2 exonic deletions/duplications in patients with FPAH account for a significant proportion of mutations (48%) that until now have not been screened for. Because the complementary approach used in this study is rapid and cost effective, screening for BMPR2 deletions/duplications by MLPA and real-time PCR should accompany direct sequencing in all PAH testing.

PMID:
16728714
PMCID:
PMC2648061
DOI:
10.1164/rccm.200602-165OC
[Indexed for MEDLINE]
Free PMC Article
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