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Yang, X.* ; Forstner, M.* ; Rapp, C.K.* ; Rothenaigner, I. ; Li, Y.* ; Hadian, K. ; Griese, M.*

ABCA3 deficiency-variant-specific response to hydroxychloroquine.

Int. J. Mol. Sci. 24:13 (2023)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Biallelic variants in ABCA3, the gene encoding the lipid transporter ATP-binding cassette subfamily A member 3 (ABCA3) that is predominantly expressed in alveolar type II cells, may cause interstitial lung diseases in children (chILD) and adults. Currently, there is no proven therapy, but, frequently, hydroxychloroquine (HCQ) is used empirically. We hypothesized that the in vitro responsiveness to HCQ might correlate to patients' clinical outcomes from receiving HCQ therapy. The clinical data of the subjects with chILD due to ABCA3 deficiency and treated with HCQ were retrieved from the literature and the Kids Lung Register data base. The in vitro experiments were conducted on wild type (WT) and 16 mutant ABCA3-HA-transfected A549 cells. The responses of the functional read out were assessed as the extent of deviation from the untreated WT. With HCQ treatment, 19 patients had improved or unchanged respiratory conditions, and 20 had respiratory deteriorations, 5 of whom transiently improved then deteriorated. The in vitro ABCA3 functional assays identified two variants with complete response, five with partial response, and nine with no response to HCQ. The variant-specific HCQ effects in vivo closely correlated to the in vitro data. An ABCA3+ vesicle volume above 60% of the WT volume was linked to responsiveness to HCQ; the HCQ treatment response was concentration dependent and differed for variants in vitro. We generated evidence for an ABCA3 variant-dependent impact of the HCQ in vitro. This may also apply for HCQ treatment in vivo, as supported by the retrospective and uncontrolled data from the treatment of chILD due to ABCA3 deficiency.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Abca3 ; Atp-binding Cassette Subfamily A Member 3 ; Hcq ; Ild ; Child ; Childhood Interstitial Lung Disease ; Diffuse Parenchymal Lung Disease ; Hydroxychloroquine ; Interstitial Lung Disease; Lung-disease; Pulmonary Surfactant; Respiratory-distress; Lipid Transporter; Mutations; Children; Health
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 1661-6596
e-ISSN 1422-0067
Zeitschrift International Journal of Molecular Sciences
Quellenangaben Band: 24, Heft: 9, Seiten: , Artikelnummer: 13 Supplement: ,
Verlag MDPI
Verlagsort Basel
Begutachtungsstatus Peer reviewed
Institut(e) Research Unit Signaling and Translation (SAT)
POF Topic(s) 30203 - Molecular Targets and Therapies
Forschungsfeld(er) Enabling and Novel Technologies
PSP-Element(e) G-509800-003
Förderungen German Center for Lung Research DZL, Munich
Deutsche Forschungsgemeinschaft DFG
DOI 10.3390/ijms24098179
WOS ID 000986778900001
Scopus ID 85159350226
PubMed ID 37175887
Erfassungsdatum 2023-10-06
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