title: Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3.
abstract: TheABCA3gene encodes a lipid transporter in type II pneumocytes critical for survival and normal respiratory function. The frequent ABCA3 variant R288K increases the risk for neonatal respiratory distress syndrome among term and late preterm neonates, but its role in children's interstitial lung disease has not been studied in detail. In a retrospective cohort study of 228 children with interstitial lung disease related to the alveolar surfactant system, the frequency of R288K was assessed and the phenotype of patients carrying a single R288K variant further characterized by clinical course, lung histology, computed tomography and bronchoalveolar lavage phosphatidylcholine PC 32:0. Cell lines stably transfected with ABCA3-R288K were analyzed for intracellular transcription, processing and targeting of the protein. ABCA3 function was assessed by detoxification assay of doxorubicin, and the induction and volume of lamellar bodies. We found nine children with interstitial lung disease carrying a heterozygous R288K variant, a frequency significantly higher than in the general Caucasian population. All identified patients had neonatal respiratory insufficiency, recovered and developed chronic interstitial lung disease with intermittent exacerbations during early childhood.In vitroanalysis showed normal transcription, processing, and targeting of ABCA3-R288K, but impaired detoxification function and smaller lamellar bodies. We propose that the R288K variant can underlie interstitial lung disease in childhood due to reduced function of ABCA3, demonstrated by decelerated detoxification of doxorubicin, reduced PC 32:0 content and decreased lamellar body volume.
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, German Lung Research Center (DZL), Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wittmann
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, German Lung Research Center (DZL), Munich, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Frixel
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, German Lung Research Center (DZL), Munich, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Höppner
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, German Lung Research Center (DZL), Munich, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schindlbeck
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, German Lung Research Center (DZL), Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schams
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, German Lung Research Center (DZL), Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kappler
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, German Lung Research Center (DZL), Hannover, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Hegermann
authors.affiliation: Institute of Functional and Applied Anatomy, Hannover Medical School, German Lung Research Center (DZL), Hannover, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Wrede
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Liebisch
authors.affiliation: Paediatric Intensive Care, University Children's Hospital, University of Cologne, Cologne, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Vierzig
authors.affiliation: Department of Pediatrics, Wilhelminenspital, Vienna, Austria.
authors.forename: Angela
authors.initials: A
authors.lastname: Zacharasiewicz
authors.affiliation: Department of Pediatric Allergy and Pulmonology, University Löbeck, Airway Research Center North (ARCN), Löbeck, Germany.
authors.forename: Matthias Volkmar
authors.initials: MV
authors.lastname: Kopp
authors.affiliation: Children's Hospital, University of Töbingen, Töbingen, Germany.
authors.forename: Christian F
authors.initials: CF
authors.lastname: Poets
authors.affiliation: Children's Hospital, University of Töbingen, Töbingen, Germany.
authors.forename: Winfried
authors.initials: W
authors.lastname: Baden
authors.affiliation: Children's Hospital, University of Töbingen, Töbingen, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
authors.affiliation: Department of Neonatology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Anton H
authors.initials: AH
authors.lastname: van Kaam
authors.affiliation: Hohentwielstr. 32, Tengen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.affiliation: Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany.
authors.forename: Charalampos
authors.initials: C
authors.lastname: Aslanidis
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, German Lung Research Center (DZL), Munich, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Zarbock
authors.affiliation: Dr. von Hauner Children's Hospital, Ludwig-Maximilians University, German Lung Research Center (DZL), Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese