Comparative analyses of lung transcriptomes in patients with alveolar capillary dysplasia with misalignment of pulmonary veins and in foxf1 heterozygous knockout mice.
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.
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Partha
P
Sen
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
Avinash V
AV
Dharmadhikari
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Tadeusz
T
Majewski
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Mahmoud A
MA
Mohammad
Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America.
Tanya V
TV
Kalin
Institute of Informatics, University of Warsaw, Warsaw, Poland.
Joanna
J
Zabielska
Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America.
Xiaomeng
X
Ren
Department of Epidemiology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Molly
M
Bray
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Robinson Research Institute, School of Pediatrics and Reproductive Health, University of Adelaide, Adelaide, Australia.
Hannah M
HM
Brown
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America.
Stephen
S
Welty
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
Sundararajah
S
Thevananther
Department of Pathology, Baylor College of Medicine, Houston, Texas, United States of America.
Claire
C
Langston
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
Przemyslaw
P
Szafranski
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
Monica J
MJ
Justice
Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, Ohio, United States of America.
Vladimir V
VV
Kalinichenko
Institute of Informatics, University of Warsaw, Warsaw, Poland; Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, Poland.
Anna
A
Gambin
Department of Pediatrics, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
John
J
Belmont
Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America; Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, United States of America.
Pawel
P
Stankiewicz
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005804:Genes, Lethal; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000002:abnormalities / Q000098:blood supply / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D018345:Mice, Knockout; D010547:Persistent Fetal Circulation Syndrome / Q000235:genetics* / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000002:abnormalities* / Q000098:blood supply / Q000378:metabolism; D011667:Pulmonary Veins / Q000002:abnormalities / Q000378:metabolism*; D059467:Transcriptome
C098521:FOXF1 protein, human; D051858:Forkhead Transcription Factors; C486293:Foxf1 protein, mouse