Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies

Hammel, M; Michel, Geert; Hoefer, Christina; Klaften, Matthias; Müller‐Höcker, Josef; Angelis, Martin Hrabé de; Holzinger, Andreas

doi:10.1016/j.bbrc.2007.05.219

Cited by 41 publications

(28 citation statements)

References 13 publications

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“…The biochemical response to deletion of ABCA3 in the adult lung is consistent with the known role of ABCA3 in surfactant homeostasis in perinatal adaptation, with respiratory failure being associated with decreased alveolar phospholipids following birth (1,9,13). ABCA3 is located in limiting membranes of the lamellar bodies, where it mediates transport of phospholipids, primarily PC and PG, into the organelle (5,(23)(24)(25). Consistent with previous findings in patients with ABCA3 deficiency (19,20), alveolar PC and PG decreased after deletion of ABCA3.…”

Section: Discussionsupporting

confidence: 88%

Alveolar injury and regeneration following deletion of ABCA3

Rindler¹,

Stockman²,

Filuta³

et al. 2017

JCI Insight

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Section: Discussionsupporting

confidence: 88%

Alveolar injury and regeneration following deletion of ABCA3

Rindler¹,

Stockman²,

Filuta³

et al. 2017

JCI Insight

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“…Previously, we reported the generation of mice lacking ABCA3, and those animals died much more rapidly after birth than did Abca12 Ϫ/Ϫ mice (16). The Abca3 Ϫ/Ϫ mice were never able to inflate their lungs, a finding subsequently confirmed by several other groups, and they failed to form lung lamellar bodies and secrete surfactant into the alveolar space (15,16,35,36). Furthermore, we found ABCA3 to be highly expressed in the lung, whereas ABCA12 is not (Ref.…”

Section: That Their Abca12supporting

confidence: 58%

ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters

Zuo

Zhuang

Han

et al. 2008

Journal of Biological Chemistry

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Harlequin ichthyosis is a congenital scaling syndrome of the skin in which affected infants have epidermal hyperkeratosis and a defective permeability barrier. Mutations in the gene encoding a member of the ABCA transporter family, ABCA12, have been linked to harlequin ichthyosis, but the molecular function of the protein is unknown. To investigate the activity of ABCA12, we generated Abca12 null mice and analyzed the impact on skin function and lipid content. Abca12 ؊/؊ mice are born with a thickened epidermis and die shortly after birth, as water rapidly evaporates from their skin. In vivo skin proliferation measurements suggest a lack of desquamation of the skin cells, rather than enhanced proliferation of basal layer keratinocytes, accounts for the 5-fold thickening of the Abca12 ؊/؊ stratum corneum. Electron microscopy revealed a loss of the lamellar permeability barrier in Abca12 ؊/؊ skin. This was associated with a profound reduction in skin linoleic esters of long-chain -hydroxyceramides and a corresponding increase in their glucosyl ceramide precursors. Because -hydroxyceramides are required for the barrier function of the skin, these results establish that ABCA12 activity is required for the generation of longchain ceramide esters that are essential for the development of normal skin structure and function. Harlequin ichthyosis (HI)2 is the most severe of the congenital, autosomal ichthyoses with affected infants developing large, hard, plate-like scales over all of their epidermal surfaces. Abnormal temperature regulation, enhanced water loss, and bacterial super-infections develop as a consequence of defects in the barrier functions of the skin, making survival through the neonatal period difficult. In recent years, several groups have linked HI, as well as less severe forms of ichthyosis, to mutations in the gene encoding a member of the ABCA family of transporters, ABCA12 (1-7). The A class of ABC transporters consists of at least eleven transporters in humans and mice, several of which are known to play critical roles in human disease. ABCA1, the best studied of the proteins, is causally linked to Tangier disease and is associated with defective phospholipid and cholesterol transport from intracellular lipid stores to the major amphipathic helical apoprotein of high density lipoprotein, apolipoprotein A-1 (8 -11). ABCA3 mutations cause a form of neonatal respiratory failure that arises from a failure to transport pulmonary phospholipids comprising surfactant from their storage site in the lamellar bodies of alveolar type II cells to the alveolar space (12)(13)(14). This transport process, like the one involving ABCA1, appears to depend on the lipidation of an acceptor amphipathic helical protein, surfactant protein B (15, 16). ABCA4 causes Stargadt macular degeneration and visual loss that is associated with a defect in the transport of phosphatidylethanolamine-retinylidene adducts out of retinal pigment epithelial cells (17)(18)(19). The role of any acceptor proteins in this process is unknown. T...

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“…The clinical and pathological features of these diseases vary, however, and no therapy is available (Whitsett et al, 2010). Mouse models generated by deletion of the genes involved recapitulate the most severe forms of the disease and do not reproduce the clinical spectrum associated with the multitude of mutations observed in human populations (Ban et al, 2007;Clark et al, 1995;Fitzgerald et al, 2007;Glasser et al, 2001;Hammel et al, 2007). iPSC-derived models will therefore allow deeper insight into pathogenesis and might allow screening for drugs that could correct the phenotypes caused by at least some specific mutations.…”

Section: Modelling Human Lung Diseasementioning

confidence: 99%

Modeling human lung development and disease using pluripotent stem cells

Snoeck

2015

Development

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Directed differentiation of human pluripotent stem cells (hPSCs) into mature cells, tissues and organs holds major promise for the development of novel approaches in regenerative medicine, and provides a unique tool for disease modeling and drug discovery. Sometimes underappreciated is the fact that directed differentiation of hPSCs also provides a unique model for human development, with a number of important advantages over model organisms. Here, I discuss the importance of using human stem cell models for understanding human lung development and disease.

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Targeted inactivation of the murine Abca3 gene leads to respiratory failure in newborns with defective lamellar bodies

Cited by 41 publications

References 13 publications

Alveolar injury and regeneration following deletion of ABCA3

Alveolar injury and regeneration following deletion of ABCA3

ABCA12 Maintains the Epidermal Lipid Permeability Barrier by Facilitating Formation of Ceramide Linoleic Esters

Modeling human lung development and disease using pluripotent stem cells

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