Wittmann, Thomas, Frixel, Sabrina, Hoeppner, Stefanie, Schindlbeck, Ulrike, Schams, Andrea, Kappler, Matthias, Hegermann, Jan, Wrede, Christoph, Liebisch, Gerhard ORCID: 0000-0003-4886-0811, Vierzig, Anne, Zacharasiewicz, Angela, Kopp, Matthias Volkmar, Poets, Christian F., Baden, Winfried, Hartl, Dominik, van Kaam, Anton H., Lohse, Peter, Aslanidis, Charalampos, Zarbock, Ralf and Griese, Matthias (2016). Increased Risk of Interstitial Lung Disease in Children with a Single R288K Variant of ABCA3. Mol. Med., 22. MANHASSET: FEINSTEIN INST MED RES. ISSN 1528-3658

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Abstract

The ABCA3 gene 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 vitro analysis 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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wittmann, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frixel, SabrinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoeppner, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schindlbeck, UlrikeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schams, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kappler, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hegermann, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wrede, ChristophUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Liebisch, GerhardUNSPECIFIEDorcid.org/0000-0003-4886-0811UNSPECIFIED
Vierzig, AnneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zacharasiewicz, AngelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kopp, Matthias VolkmarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Poets, Christian F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baden, WinfriedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartl, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
van Kaam, Anton H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lohse, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aslanidis, CharalamposUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zarbock, RalfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Griese, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-293080
DOI: 10.2119/molmed.2015.00244
Journal or Publication Title: Mol. Med.
Volume: 22
Date: 2016
Publisher: FEINSTEIN INST MED RES
Place of Publication: MANHASSET
ISSN: 1528-3658
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
RESPIRATORY-DISTRESS-SYNDROME; CFTR GENE-MUTATIONS; SURFACTANT HOMEOSTASIS; DEFICIENCY; INFANTS; CLASSIFICATION; BRONCHIECTASIS; PANCREATITIS; EXPRESSION; GENOTYPEMultiple languages
Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & ExperimentalMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/29308

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