Novel FOXF1 Mutations in Sporadic and Familial Cases of Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins Imply a Role for its DNA Binding Domain

Partha Sen, Yaping Yang, Colby Navarro, Iris Silva, Przemyslaw Szafranski, Katarzyna E. Kolodziejska, Avinash V. Dharmadhikari, Hasnaa Mostafa, Harry Kozakewich, Debra Kearney, John B. Cahill, Merrissa Whitt, Masha Bilic, Linda Margraf, Adrian Charles, Jack Goldblatt, Kathleen Gibson, Patrick E. Lantz, A. Julian Garvin, John PettyZeina Kiblawi, Craig Zuppan, Allyn Mcconkie-Rosell, Marie T. Mcdonald, Stacey L. Peterson-Carmichael, Jane T. Gaede, Binoy Shivanna, Deborah Schady, Philippe S. Friedlich, Stephen R. Hays, Irene Valenzuela Palafoll, Ulrike Siebers-Renelt, Axel Bohring, Laura S. Finn, Joseph R. Siebert, Csaba Galambos, Lananh Nguyen, Melissa Riley, Nicolas Chassaing, Adeline Vigouroux, Gustavo Rocha, Susana Fernandes, Jane Brumbaugh, Kari Roberts, Luk Ho-ming, Ivan F M Lo, Stephen Lam, Romana Gerychova, Marta Jezova, Iveta Valaskova, Florence Fellmann, Katayoun Afshar, Eric Giannoni, Vincent Muhlethaler, Jinlong Liang, Jacques S. Beckmann, Janet Lioy, Hitesh Deshmukh, Lakshmi Srinivasan, Daniel T. Swarr, Melissa Sloman, Charles Shaw-Smith, Rosa Laura van Loon, Cecilia Hagman, Yves Sznajer, Catherine Barrea, Christine Galant, Thierry Detaille, Jennifer A. Wambach, F. Sessions Cole, Aaron Hamvas, Lawrence S. Prince, Karin E M Diderich, Alice S. Brooks, Robert M. Verdijk, Hari Ravindranathan, Ella Sugo, David Mowat, Michael L. Baker, Claire Langston, Stephen Welty, Pawel Stankiewicz

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis. FOXF1 mutations result in Alveolar Capillary Dysplasia with Misaligned Pulmonary Veins, a deadly neonatal lung disorder that is uniformly fatal. The data in the article is the outcome of a global collaboration presenting the up to date list of causative mutations in FOXF1. The maternally inherited familial cases support the paternal imprinting of the gene in human lungs.

Original languageEnglish (US)
Pages (from-to)801-811
Number of pages11
JournalHuman mutation
Volume34
Issue number6
DOIs
StatePublished - Jun 2013

Keywords

  • ACD/MPV
  • Angiogenesis
  • Development
  • FOXF1
  • Imprinting
  • Lung

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