ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

Hum Mutat. 2018 Jun;39(6):841-850. doi: 10.1002/humu.23416. Epub 2018 Mar 25.


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.

Keywords: ATP-binding cassette transporters; human ABCA3 protein; interstitial lung diseases; respiratory distress syndrome of the newborn; surfactant dysfunction.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • A549 Cells
  • ATP-Binding Cassette Transporters / genetics*
  • Genetic Predisposition to Disease*
  • Humans
  • Lung Diseases, Interstitial / genetics*
  • Lung Diseases, Interstitial / physiopathology
  • Mutation, Missense / genetics
  • Phenotype


  • ABCA3 protein, human
  • ATP-Binding Cassette Transporters

Supplementary concepts

  • Surfactant Dysfunction