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The biology of the ABCA3 lipid transporter in lung health and disease

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Abstract

The lipid transporter, ATP-binding cassette class A3 (ABCA3), is a highly conserved multi-membrane-spanning protein that plays a critical role in the regulation of pulmonary surfactant homeostasis. Mutations in ABCA3 have been increasingly recognized as one of the causes of inherited pulmonary diseases. These monogenic disorders produce familial lung abnormalities with pathological presentations ranging from neonatal surfactant-deficiency-induced respiratory failure to childhood or adult diffuse parenchymal lung diseases for which specific treatment modalities remain limited. More than 200 ABCA3 mutations have been reported to date with approximately three quarters of patients presenting as compound heterozygotes. Recent advances in our understanding of the molecular basis underlying normal ABCA3 biosynthesis and processing and of the mechanisms of alveolar epithelial cell dysregulation caused by the expression of its mutant forms are beginning to emerge. These insights and the role of environmental factors and modifier genes are discussed in the context of the considerable variability in disease presentation observed in patients with identical ABCA3 gene mutations. Moreover, the opportunities afforded by an enhanced understanding of ABCA3 biology for targeted therapeutic strategies are addressed.

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Abbreviations

AT2:

Alveolar type 2

LB:

Lamellar body

ABCA3:

ATP-binding cassette class A3

SP-C:

Surfactant Protein C

SFTP(A, B, C, or D):

Gene encoding surfactant protein A, B, C, or D

DPLD:

Diffuse parenchymal lung disease

IPF:

Idiopathic pulmonary fibrosis

NBD:

Nucleotide-binding domain

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Acknowledgements

This work is supported by the National Institutes of Health (HL129150 to S. Mulugeta; HL119436 to M.F. Beers), the Department of Veterans Affairs (VA Merit Award BX001176-05A1 to M.F. Beers) and The National Institute of Environmental Health Sciences of the National Institutes of Health (P30ES013508). M.F. Beers is an Albert M. Rose Established Investigator of the Pulmonary Fibrosis Foundation.

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Authors and Affiliations

  1. Pulmonary, Allergy, and Critical Care Division, Department of Medicine, Surfactant Biology Laboratories, University of Pennsylvania Perelman School of Medicine, Edward J. Stemmler Hall, Suite 218, 3450 Hamilton Walk, Philadelphia, PA 19104, USA

    Michael F. Beers & Surafel Mulugeta

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  1. Michael F. Beers
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  2. Surafel Mulugeta
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Correspondence to Surafel Mulugeta.

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We have tried to cover as many of the published compound heterozygous mutations in the ABCA3 gene as possible and apologize for any additional reported mutations that we may have missed.

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Beers, M.F., Mulugeta, S. The biology of the ABCA3 lipid transporter in lung health and disease. Cell Tissue Res 367, 481–493 (2017). https://doi.org/10.1007/s00441-016-2554-z

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