Tools to explore ABCA3 mutations causing interstitial lung disease

Wittmann, Thomas; Schindlbeck, Ulrike; Höppner, Stefanie; Kinting, Susanna; Frixel, Sabrina; Kröner, Carolin; Liebisch, Gerhard; Hegermann, Jan; Aslanidis, Charalampos; Brasch, Frank; Reu, Simone; Zarbock, Ralf; Griese, Matthias

doi:10.1002/ppul.23471

Cited by 23 publications

(31 citation statements)

References 30 publications

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“…Abbreviation “n.t.” stands for nontreated control. Images of WT and p.K1388N have been published (Wittmann et al., ). B : Ratio of complex‐type oligosaccharides to high‐mannose oligosaccharides (i.e., 190 to 180 kDa) in noncleaved ABCA3‐HA protein quantified by relative densitometry using ImageJ.…”

Section: Resultsmentioning

confidence: 99%

“…Human A549 cells (German Collection of Microorganisms, DSMZ, Braunschweig, Germany) were cultured as previously described (Wittmann et al., ). ABCA3‐HA WT and the variations c.622C > T (p.R208W), c.643C > A (p.Q215K), c.863G > A (p.R288K), c.875A > T (p.E292V), c.2279T > G (p.M760R), c.2891G > A (p.G964D), and c.4164G > C (p.K1388N) were stably transfected into A549 cells using the “Sleeping Beauty” transposon system (Geurts et al., ).…”

Section: Methodsmentioning

confidence: 99%

“…Unfortunately, clinical data and in particular lung tissue or molecular investigations are not always available. In order to gain insight into the cellular phenotype, we developed a number of tools to assess cellular pathologies related to ABCA3 mutations in a previous study, where we could demonstrate close correlations between in vitro results and ex vivo data (Brasch et al., ; Campo et al., ; Wittmann et al., ; Wittmann et al., ).…”

Section: Introductionmentioning

confidence: 99%

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ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

Schindlbeck¹,

Wittmann²,

Höppner³

et al. 2018

Human Mutation

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Mutations in the ATP-binding cassette subfamily A member 3 (ABCA3) gene are the most common monogenetic cause of surfactant dysfunction disorders in newborns and interstitial lung diseases in children and young adults. Although the effect of mutations resulting in truncated or incomplete proteins can be predicted, the consequences of missense variants cannot be as easily. Our aim was to investigate the intracellular handling and disturbance of the cellular surfactant system in a stable cell model with several different clinically relevant ABCA3 missense mutations. We found that the investigated missense mutations within the ABCA3 gene affect surfactant homeostasis in different ways: first by disrupting intracellular ABCA3 protein localization (c.643C > A, p.Q215K; c.2279T > G, p.M760R), second by impairing the lipid transport of ABCA3 protein (c.875A > T, p.E292V; c.4164G > C, p.K1388N), and third by yet undetermined mechanisms predisposing for the development of interstitial lung diseases despite correct localization and normal lipid transport of the variant ABCA3 protein (c.622C > T, p.R208W; c.863G > A, p.R288K; c.2891G > A, p.G964D). In conclusion, we classified cellular consequences of missense ABCA3 sequence variations leading to pulmonary disease of variable severity. The corresponding molecular pathomechanisms of such ABCA3 variants may specifically be addressed by targeted treatments.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

Schindlbeck¹,

Wittmann²,

Höppner³

et al. 2018

Human Mutation

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“…A pT2/HB transposon vector (Addgene, Cambridge, plasmid#26557) was generated, containing hABCA3 cDNA (NM_001089) with corresponding CMV promoter elements fused to a C-terminal HAtag and puromycin resistance gene, as described before. 33 between ABCA3 and cystic fibrosis transmembrane conductance regulator (CFTR) to identify amino acids homologous to F508 and G551 in CFTR. Variations F629L and G667R were identified using the Exome Aggregation Consortium (ExAc) Browser, 27 with G667 corresponding to G550 in CFTR since no mutation was listed for position G668 in ABCA3.…”

Section: Plasmidsmentioning

confidence: 99%

Potentiation of ABCA3 lipid transport function by ivacaftor and genistein

Kinting

Li²,

Forstner

et al. 2019

J Cellular Molecular Medi

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ABCA3 is a phospholipid transporter implicated in pulmonary surfactant homoeostasis and localized at the limiting membrane of lamellar bodies, the storage compartment for surfactant in alveolar type II cells. Mutations in ABCA3 display a common genetic cause for diseases caused by surfactant deficiency like respiratory distress in neonates and interstitial lung disease in children and adults, for which currently no causal therapy exists. In this study, we investigated the effects of ivacaftor and genistein, two potentiators of the cystic fibrosis transmembrane conductance regulator (CFTR), on ABCA3‐specific lipid transport function. Wild‐type (WT) and functional ABCA3 mutations N568D, F629L, G667R, T1114M and L1580P were stably expressed in A549 cells. Three‐dimensional modelling predicted functional impairment for all five mutants that was confirmed by in vitro experiments (all <14% of WT functional activity). Treatment with potentiators rescued the mutants N568D (up to 114% of WT), F629L (up to 47% of WT), and G667R (up to 60% of WT), the latter variation needing higher concentrations of genistein, showing reduced affinity of the potentiator to the mutant protein. Our results present a first proof that functional ABCA3 mutations are rescued by CFTR potentiators, making them a potential therapeutical option for patients suffering from surfactant deficiency due to ABCA3 mutations.

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“…These authors report improvement after initiation of therapy with a prostacyclin analogue and warfarin. Finally, a paper from Germany outlined the use of in vitro molecular tools to evaluate the effects of ABCA3 variants on protein activity . Such techniques will prove to be useful in determining the pathogenicity of such variants, and may provide insight to potential therapeutic targets.…”

Section: Rare Lung Diseasementioning

confidence: 99%

Pediatric Pulmonologyyear in review 2016: Part 1

et al. 2017

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Our journal covers a broad range of research and scholarly topics related to children's respiratory disorders. For updated perspectives on the rapidly expanding knowledge in our field, we will summarize the past year's publications in our major topic areas, as well as selected publications in these areas from the core clinical journal literature outside our own pages. The current review covers articles on neonatal lung disease, pulmonary physiology, and respiratory infection.Word count: 71 3

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Tools to explore ABCA3 mutations causing interstitial lung disease

Cited by 23 publications

References 30 publications

ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

Potentiation of ABCA3 lipid transport function by ivacaftor and genistein

Pediatric Pulmonologyyear in review 2016: Part 1

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