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Published ahead of print on October 11, 2007, doi:10.1164/rccm.200703-499OC

Am. J. Respir. Crit. Care Med., Volume 177, Number 1, January 2008, 99-107

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Submitted on March 28, 2007
Accepted on October 11, 2007

Proteomics of Transformed Lymphocytes from a Family with Familial Pulmonary Arterial Hypertension

Barbara O Meyrick1*, David B Friedman2, D. Dean Billheimer3, Joy D Cogan4, Melissa A Prince4, John A Phillips4, and James E Loyd5

1 Departmnet of Pathology, Vanderbilt University Medical Center, Nashville, TN, United States; Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA, 2 Department of Biochemistry, Vanderbilt University Medical Center, Nashville, TN, USA, 3 Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA, 4 Department of Genetics, Vanderbilt University Medical Center, Nashville, TN, USA, 5 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA

* To whom correspondence should be addressed. E-mail: Barbara.meyrick{at}vanderbilt.edu.

Rationale: Not all family members with BMPR2 mutations develop pulmonary arterial hypertension (PAH) implying that additional modifier genes or proteins are necessary for full expression of the disease. Objective: Determine whether protein expression is altered in patients with familial PAH (FPAH) compared to obligate carriers and non-diseased controls. Methods: Protein extracts from transformed blood lymphocytes from four FPAH patients, three obligate carriers and three married-in controls, from one family with a known BMPR2 mutation (exon 3 T354G) were labeled with either Cy3 or Cy5. Cy3/5 pairs were separated by standard 2D-DIGE using a Cy2-labeled internal standard of all patient samples. Log volume ratios were analyzed using a linear mixed effects model. Proteins were identified by matrix-assisted laser desorption ionization, time-of-flight mass spectrometry (MALDI-TOF MS) and tandem TOF/TOF MS/MS. Measurements and Main Results: Hierarchical clustering (HC), heat-map and principal component analysis revealed marked changes in protein expression in patients with FPAH when compared with obligate carriers. Significant changes were apparent in expression of 16 proteins (p <0.05) when affected patients were compared with obligates - nine showed a significant increase and seven showed a significant reduction. Conclusions: A series of novel proteins with altered expression were found that could distinguish affected patients from obligate carriers and married-in controls in a single family with a BMPR2 mutation. These differences provide new information highlighting proteins that may be involved in the mechanism(s) that differentiates those individuals with a BMPR2 mutation who develop FPAH from those who do not.
Key words: 2D-DIGE, obligate individuals without FPAH, catalytic activity, MALDI-TOF MS






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