Genetic regulation of neonatal pulmonary surfactant deficiency has been suggested by studies of gender, genetic linkage, recurrent familial cases, targeted gene ablation in murine lineages, and by racial disparity in risk of neonatal respiratory distress syndrome. Successful fetal-neonatal pulmonary transition requires production of the pulmonary surfactant, a phospholipid-protein film that lines alveoli and maintains alveolar patency at end expiration. Our goal is to understand the genetic mechanisms that disrupt pulmonary surfactant metabolism and cause neonatal respiratory distress syndrome. Studies in human newborn infants have demonstrated that 3 genes are critical for surfactant metabolism: surfactant protein B (SFTPB), surfactant protein C (SFTPC), and an ATP-binding cassette transporter, ABCA3 (ABCA3). To understand genetic regulatory mechanisms, we will investigate the association of variation in each of these genes with neonatal respiratory distress syndrome by testing the hypothesis that genetic variants in SFTPB, SFTPC, and ABCA3 disrupt pulmonary surfactant metabolism. Using high throughput automated sequencing to genotype, multidimensional protein identification technology to assess quantitative and qualitative differences in surfactant protein B and C expression, in vivo metabolic labeling with stable isotopically labeled precursors to estimate surfactant protein B and C and phospholipid metabolic rates, and cohort sizes that provide statistical power (0.8), we will use race-specific, severity-stratified case-control (N=480) and case comparison (N=250) designs to understand genetically regulated, metabolic mechanisms that cause surfactant deficiency by disrupting expression or altering processing of surfactant proteins B or C or by disrupting surfactant phospholipid composition in human newborn infants. Improved understanding of genetic regulation of surfactant deficiency will suggest novel diagnostic strategies to identify and categorize high risk infants and therapeutic strategies that target discrete steps in pulmonary surfactant metabolism to improve outcomes of infants with neonatal respiratory distress syndrome. Inherited deficiencies in any one of 3 genes (surfactant protein B, surfactant protein C, and ATP-binding cassette transporter A3) cause neonatal respiratory distress syndrome by disrupting metabolism of the pulmonary surfactant. We will use state of the art methods to link specific changes in the genetic code of each of these genes with disruption of discrete steps in the metabolism of the pulmonary surfactant in human newborn infants. These studies will lead to improved diagnostic capabilities and suggest novel strategies to correct surfactant deficiency in newborn infants.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Blaisdell, Carol J
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Eldridge, Whitney B; Zhang, Qunyuan; Faro, Albert et al. (2017) Outcomes of Lung Transplantation for Infants and Children with Genetic Disorders of Surfactant Metabolism. J Pediatr 184:157-164.e2
Chen, Yu-Jun; Wambach, Jennifer Anne; DePass, Kelcey et al. (2016) Population-based frequency of surfactant dysfunction mutations in a native Chinese cohort. World J Pediatr 12:190-5
Wambach, Jennifer A; Yang, Ping; Wegner, Daniel J et al. (2016) Functional Characterization of ATP-Binding Cassette Transporter A3 Mutations from Infants with Respiratory Distress Syndrome. Am J Respir Cell Mol Biol 55:716-721
Shen, Carol L; Zhang, Qunyuan; Meyer Hudson, Julia et al. (2016) Genetic Factors Contribute to Risk for Neonatal Respiratory Distress Syndrome among Moderately Preterm, Late Preterm, and Term Infants. J Pediatr 172:69-74.e2
Jackson, T; Wegner, D J; White, F V et al. (2015) Respiratory failure in a term infant with cis and trans mutations in ABCA3. J Perinatol 35:231-2
Szafranski, Przemyslaw; Dharmadhikari, Avinash V; Wambach, Jennifer A et al. (2014) Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins. Am J Med Genet A 164A:2013-9
Coghlan, Meghan A; Shifren, Adrian; Huang, Howard J et al. (2014) Sequencing of idiopathic pulmonary fibrosis-related genes reveals independent single gene associations. BMJ Open Respir Res 1:e000057
Ramos, E I; Bien-Willner, G A; Li, J et al. (2014) Genetic variation in MKL2 and decreased downstream PCTAIRE1 expression in extreme, fatal primary human microcephaly. Clin Genet 85:423-32
Wambach, Jennifer A; Wegner, Daniel J; Heins, Hillary B et al. (2014) Synonymous ABCA3 variants do not increase risk for neonatal respiratory distress syndrome. J Pediatr 164:1316-21.e3
Wambach, Jennifer A; Casey, Alicia M; Fishman, Martha P et al. (2014) Genotype-phenotype correlations for infants and children with ABCA3 deficiency. Am J Respir Crit Care Med 189:1538-43

Showing the most recent 10 out of 30 publications