Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a lethal neonatal diffuse developmental disorder of the lungs, which is commonly associated with multiple congenital anomalies involving the cardiac, gastrointestinal, and genitourinary systems. Infants affected with ACD/MPV develop severe respiratory distress with pulmonary hypertension within the first few days of life and despite intensive care they usually die soon thereafter. Recently, we have found that haploinsufficiency due to point mutations or genomic deletions of the transcription factor Forkhead Box F1 (FOXF1) on 16q24.1 results in ACD/MPV and a broad spectrum of congenital malformations. In addition, we have identified two distinct microdeletions upstream of FOXF1, implicating a position effect in the pathogenesis of the disease. Pleiotropic effects encountered in FOXF1 microdeletions, such as hypoplastic left heart syndrome and gastrointestinal atresias, may be due to haploinsufficiency for the neighboring genes, FOXC2 and FOXL1, both part of the FOX cluster at 16q24.1. Heterozygous Foxf1 mice die from pulmonary hemorrhage with severe defects in lung alveolarization and vasculogenesis along with other organ anomalies, although they do not completely recapitulate ACD/MPV in humans. The expression of the Foxf1 gene during development suggests an intriguing pattern of gene regulation. We hypothesize that this complex regulation of Foxf1 may be due to both position effects and genomic imprinting in a tissue- and time-specific manner;ACD/MPV can also be caused by disruption of other gene(s) or FOXF1 regulatory elements;and the lung defect in Foxf1 mice can be prevented perinatally by increasing the dosage of the Foxf1 protein in the capillary endothelium and surrounding mesenchyme. We have designed three aims to test these hypotheses.
In aim 1, we will dissect gene regulation of FOXF1 in two ways. First, regulatory elements that may be important to the expression of the FOX gene cluster or to FOXF1 specific expression will be identified and tested using reporter assays, ChIP-on-chip, and chromatin conformation capture (3C) techniques. Second, we will analyze the segregation and allele-specific expression of Foxf1 in mice.
In aim 2, we will use the knowledge gained from our studies in aim 1 to screen for point mutations and copy-number variations in the regulatory elements identified upstream or downstream to FOXF1 and in the ACD/MPV candidate genes. Finally, in aim 3, we will explore therapeutic options by use of adenoviral vector-based Foxf1 gene transfer in peripheral murine lungs. ACD/MPV is a lethal disorder and there is no available treatment at the present time. We believe that a gene therapy approach using viral vectors may have the potential to correct the lethal phenotype of ACD/MPV patients by reversing the abnormal formation of the lethal capillary defect. Moreover, the risks related to this experimental therapy may be justified from a risk: benefit standpoint and have potential to be translated in the hospital setting.

Public Health Relevance

We will unravel the pathogenesis and identify other causative gene(s) responsible for a neonatal diffuse developmental disorder of the lungs, Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), commonly associated with multiple congenital malformations involving the cardiac, gastrointestinal, and genitourinary systems. This lethal disease has no available treatment at the present time. We believe that a gene therapy approach using viral vectors in mice may have the potential to correct the lethal phenotype of ACD/MPV patients by reversing the abnormal formation of the lethal capillary defect.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL101975-03
Application #
8259439
Study Section
Therapeutic Approaches to Genetic Diseases (TAG)
Program Officer
Blaisdell, Carol J
Project Start
2010-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
3
Fiscal Year
2012
Total Cost
$446,430
Indirect Cost
$155,596
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Dharmadhikari, Avinash V; Sun, Jenny J; Gogolewski, Krzysztof et al. (2016) Lethal lung hypoplasia and vascular defects in mice with conditional Foxf1 overexpression. Biol Open 5:1595-1606
Szafranski, Przemyslaw; Herrera, Carmen; Proe, Lori A et al. (2016) Narrowing the FOXF1 distant enhancer region on 16q24.1 critical for ACDMPV. Clin Epigenetics 8:112
Szafranski, Przemyslaw; Gambin, Tomasz; Dharmadhikari, Avinash V et al. (2016) Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins. Hum Genet 135:569-86
Reiter, Joel; Szafranski, Przemyslaw; Breuer, Oded et al. (2016) Variable phenotypic presentation of a novel FOXF1 missense mutation in a single family. Pediatr Pulmonol 51:921-7
Prothro, Stephanie L; Plosa, Erin; Markham, Melinda et al. (2016) Prenatal Diagnosis of Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins. J Pediatr 170:317-8
Campbell, Ian M; Shaw, Chad A; Stankiewicz, Pawel et al. (2015) Somatic mosaicism: implications for disease and transmission genetics. Trends Genet 31:382-92
Campbell, Ian M; Yuan, Bo; Robberecht, Caroline et al. (2014) Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am J Hum Genet 95:173-82
Dharmadhikari, Avinash V; Gambin, Tomasz; Szafranski, Przemyslaw et al. (2014) Molecular and clinical analyses of 16q24.1 duplications involving FOXF1 identify an evolutionarily unstable large minisatellite. BMC Med Genet 15:128
Sen, Partha; Dharmadhikari, Avinash V; Majewski, Tadeusz et al. (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:e94390
Campbell, Ian M; Stewart, Jonathan R; James, Regis A et al. (2014) Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am J Hum Genet 95:345-59

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