Dataset Information

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

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.

SUBMITTER: Sen P

PROVIDER: S-EPMC3663886 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Sen Partha P Yang Yaping Y Navarro Colby C Silva Iris I Szafranski Przemyslaw P Kolodziejska Katarzyna E KE Dharmadhikari Avinash V AV Mostafa Hasnaa H Kozakewich Harry H Kearney Debra D Cahill John B JB Whitt Merrissa M Bilic Masha M Margraf Linda L Charles Adrian A Goldblatt Jack J Gibson Kathleen K Lantz Patrick E PE Garvin A Julian AJ Petty John J Kiblawi Zeina Z Zuppan Craig C McConkie-Rosell Allyn A McDonald Marie T MT Peterson-Carmichael Stacey L SL Gaede Jane T JT Shivanna Binoy B Schady Deborah D Friedlich Philippe S PS Hays Stephen R SR Palafoll Irene Valenzuela IV Siebers-Renelt Ulrike U Bohring Axel A Finn Laura S LS Siebert Joseph R JR Galambos Csaba C Nguyen Lananh L Riley Melissa M Chassaing Nicolas N Vigouroux Adeline A Rocha Gustavo G Fernandes Susana S Brumbaugh Jane J Roberts Kari K Ho-Ming Luk L Lo Ivan F M IF Lam Stephen S Gerychova Romana R Jezova Marta M Valaskova Iveta I Fellmann Florence F Afshar Katayoun K Giannoni Eric E Muhlethaler Vincent V Liang Jinlong J Beckmann Jacques S JS Lioy Janet J Deshmukh Hitesh H Srinivasan Lakshmi L Swarr Daniel T DT Sloman Melissa M Shaw-Smith Charles C van Loon Rosa Laura RL Hagman Cecilia C Sznajer Yves Y Barrea Catherine C Galant Christine C Detaille Thierry T Wambach Jennifer A JA Cole F Sessions FS Hamvas Aaron A Prince Lawrence S LS Diderich Karin E M KE Brooks Alice S AS Verdijk Robert M RM Ravindranathan Hari H Sugo Ella E Mowat David D Baker Michael L ML Langston Claire C Welty Stephen S Stankiewicz Pawel P

Human mutation 20130412 6

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 pu ...[more]

PMID: 23505205

Similar Datasets

Project description:BackgroundAlveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a fatal congenital lung disorder strongly associated with genomic alterations in the Forkhead box F1 (FOXF1) gene and its regulatory region. However, little is known about how FOXF1 genomic alterations cause ACD/MPV and what molecular mechanisms are affected by these mutations. Therefore, the effect of ACD/MPV patient-specific mutations in the FOXF1 gene on the molecular function of FOXF1 was studied.MethodsEpitope-tagged FOXF1 constructs containing one of the ACD/MPV-associated mutations were expressed in mammalian cell lines to study the effect of FOXF1 mutations on protein function. EMSA binding assays and luciferase assays were performed to study the effect on target gene binding and activation. Immunoprecipitation followed by SDS‒PAGE and western blotting were used to study protein‒protein interactions. Protein phosphorylation was studied using phos-tag western blotting.ResultsAn overview of the localization of ACD/MPV-associated FOXF1 mutations revealed that the G91-S101 region was frequently mutated. A three-dimensional model of the forkhead DNA-binding domain of FOXF1 showed that the G91-S101 region consists of an α-helix and is predicted to be important for DNA binding. We showed that FOXF1 missense mutations in this region differentially affect the DNA binding of the FOXF1 protein and influence the transcriptional regulation of target genes depending on the location of the mutation. Furthermore, we showed that some of these mutations can affect the FOXF1 protein at the posttranscriptional level, as shown by altered phosphorylation by MST1 and MST2 kinases.ConclusionMissense mutations in the coding region of the FOXF1 gene alter the molecular function of the FOXF1 protein at multiple levels, such as phosphorylation, DNA binding and target gene activation. These results indicate that FOXF1 molecular pathways may be differentially affected in ACD/MPV patients carrying missense mutations in the DNA-binding domain and may explain the phenotypic heterogeneity of ACD/MPV.

Dataset Information

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Publications

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets