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Title: Comparative analyses of lung transcriptomes in patients with alveolar capillary dysplasia with misalignment of pulmonary veins and in foxf1 heterozygous knockout mice

Author
item SEN, PARTHA - Baylor College Of Medicine
item DHARMADHIKARI, AVINASH - Baylor College Of Medicine
item MAJEWSKI, TADEUSZ - Md Anderson Cancer Center
item MOHAMMAD, MAHMOUD - Baylor College Of Medicine
item KALIN, TANYA - Cincinnati Children'S Research Hospital
item ZABIELSKA, JOANNA - University Of Warsaw
item REN, XIAOMENG - Cincinnati Children'S Research Hospital
item BRAY, MOLLY - University Of Alabama
item BROWN, HANNAH - Baylor College Of Medicine
item WELTY, STEPHEN - Baylor College Of Medicine
item THEVANANTHER, SUNDARARAJAH - Baylor College Of Medicine
item LANGSTON, CLAIRE - Baylor College Of Medicine
item SZAFRANSKI, PRZEMYSLAW - Baylor College Of Medicine
item JUSTICE, MONICA - Baylor College Of Medicine
item KALINICHENKO, VLADIMIR - Cincinnati Children'S Research Hospital
item GAMBIN, ANNA - University Of Warsaw
item BELMONT, JOHN - Children'S Nutrition Research Center (CNRC)
item STANKIEWICZ, PAWEL - Baylor College Of Medicine

Submitted to: PLOS ONE
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/14/2014
Publication Date: 4/10/2014
Citation: Sen, P., Dharmadhikari, A.V., Majewski, T., Mohammad, M.A., Kalin, T.V., Zabielska, J., Ren, X., Bray, M., Brown, H.M., Welty, S., Thevananther, S., Langston, C., Szafranski, P., Justice, M.J., Kalinichenko, V.V., Gambin, A., Belmont, J., Stankiewicz, P. 2014. Comparative analyses of lung transcriptomes in patients with alveolar capillary dysplasia with misalignment of pulmonary veins and in foxf1 heterozygous knockout mice. PLoS One. 9(4):e94390

Interpretive Summary: Rare genetic conditions can teach us important lessons about much more common health problems. We studied Alveolar Capillary Dysplasia (ACD) which causes a severe problem with a newborn baby's lungs. Babies with ACD die very soon after birth because of the inability to breathe. We used a method survey to look at the activity of more than 15,000 genes in lung tissue samples. We found that the ACD gene, called FOXF1, is a master gene that controls hundreds of other genes required for lung function. The ACD gene probably plays a role in common lung diseases like asthma and COPD. Understanding how it controls lung development and function is an important step in reducing side effects from current treatments for lung disease. It is now known that maternal nutritional abnormalities (like malnutrition and obesity) can alter the regulation of genes that control normal development. Future research will determine whether FOXF1 is altered by maternal obesity and diabetes.

Technical Abstract: Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a developmental disorder of the lungs, primarily affecting their vasculature. FOXF1 haploinsufficiency due to heterozygous genomic deletions and point mutations have been reported in most patients with ACDMPV. The majority of mice with heterozygous loss-of-function of Foxf1 exhibit neonatal lethality with evidence of pulmonary hemorrhage in some of them. By comparing transcriptomes of human ACDMPV lungs with control lungs using expression arrays, we found that several genes and pathways involved in lung development, angiogenesis, and in pulmonary hypertension development, were deregulated. Similar transcriptional changes were found in lungs of the postnatal day 0.5 Foxf1 +/- mice when compared to their wildtype littermate controls; 14 genes, COL15A1, COL18A1, COL6A2, ESM1, FSCN1, GRINA, IGFBP3, IL1B, MALL, NOS3, RASL11B, MATN2, PRKCDBP, and SIRPA, were found common to both ACDMPV and Foxf1 heterozygous lungs. Our results advance knowledge toward understanding of the molecular mechanism of ACDMPV, lung development, and its vasculature pathology. These data may also be useful for understanding etiologies of other lung disorders, e.g. pulmonary hypertension, bronchopulmonary dysplasia, or cancer.