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.
Highlights
Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV; MIM# 265380) is a rare developmental disorder of the lung [1]
Ethics Statement Patients with histopathologically-verified ACDMPV were recruited after signing consent for the study, Institutional Review Board (IRB) protocol # H-8712 ‘‘Molecular genetics of Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV)’’ approved by the IRB for Baylor College of Medicine (BCM) and Affiliated Hospitals
To identify transcriptional changes in the neonate ACDMPV lungs, we compared the whole genome expression in the lungs of eight patients with ACDMPV with transcriptional changes in P0.5 Foxf1+/2 mouse lungs, and appropriate control lungs. This approach enabled us to identify gene ontologies and pathways associated with ACDMPV and gain a better understanding of the disease
Summary
Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV; MIM# 265380) is a rare developmental disorder of the lung [1]. ACDMPV was first described by McMahon [2] and its genetic basis emerged as more patients [3] and familial cases were reported [4]. The primary diagnostic features of ACDMPV include misalignment (malposition) of pulmonary veins, medial thickening of smooth muscles in pulmonary arteries, hyperplasia of alveolar epithelium, and drastically decreased number of capillaries and lobular underdevelopment [5]. Treatment, including high pressure oxygen, nitric oxide, extra corporeal membrane oxygenation (ECMO) [8,9,10,11], and more recently Sildenafil [12], only provide temporary relief as the disease is uniformly lethal. The majority of the patients with ACDMPV have extra-pulmonary anomalies, including gastrointestinal, cardiovascular, and genitourinary systems [14]
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