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

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 quite 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, as well as the mechanisms of alveolar epithelial cell dysregulation caused by the expression of its mutant forms, are beginning to emerge. These insights, as well as 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.

Aberrant lung remodeling in a mouse model of surfactant dysregulation induced by modulation of the Abca3 gene

“…2), mAbca3 +/− mice appear to have a reverse effect exhibiting decreased number of LBs (Cheong et al, 2007) while no changes in LB sizes have been reported. Thus, the variation between the two models supports the concept that mutations in the mAbca3 gene modify the severity of lung phenotype in the mAbca3 E 292 V –rNeo + mice, similar to those human ABCA3 mutations that have been considered to play a role as modifier genes by either co-expression with other surfactant component gene mutations such as SFTPC mutations (Bullard and Nogee, 2007; Crossno et al, 2010) or expressed in compound heterozygous state (Bullard et al, 2005; Shulenin et al, 2004; Garmany et al, 2006; Doan et al, 2008; Flamein et al, 2012; Beers and Mulugeta, 2016). …”

“…It has become increasingly evident that there are additional cis - and trans -allelic mutations within ABCA3 gene that can act as disease modifiers (Bullard and Nogee, 2007; Kitazawa et al, 2013; Flamein et al, 2012; Goncalves et al, 2014; Beers and Mulugeta, 2016). Several reports have identified patients suffering from chronic lung disorders (with diagnoses of various types of DPLD including pulmonary fibrosis) that carry compound heterozygous mutations (Bullard et al, 2005; Bullard and Nogee, 2007; Kitazawa et al, 2013; Flamein et al, 2012) or an accompanying SFTPC mutation mutations (Bullard and Nogee, 2007; Crossno et al, 2010).…”

Multiplexed single-cell transcriptomic analysis of normal and impaired lung development in the mouse

“…3h, Supplementary Figure 3e). Meg3 is a known regulator of epithelial cell differentiation, while Abca3 is a crucial factor in surfactant and lamellar bodies' metabolism 11,12 . Mutations of Abca3 have been associated with interstitial lung disease and progressive respiratory distress syndrome and further, knock-down of Abca3 resulted in abnormal lamellar bodies 13 .…”

Development, remodeling and regeneration of the lung: coping with the structural and functional challenges of breathing

“…Interestingly, one and the same type of mutation may cause different courses of disease. In this issue, Beers and Mulugeta (2017) provide a comprehensive and detailed review of ABCA3 biology and the consequences of its dysfunction.…”