ABCA3 mutations led to pulmonary fibrosis and emphysema with pulmonary hypertension in an 8‐year‐old girl

Abstract

ABCA3 is highly expressed in alveolar epithelial type 2 cells and is associated with surfactant homeostasis. Patients with ABCA3 mutations develop various respiratory complications, such as fatal respiratory distress syndrome or interstitial lung disease. We describe a patient with pulmonary fibrosis and emphysema with pulmonary hypertension, associated with compound heterozygous mutations of the ABCA3 gene. This is the first report showing that mutations in the ABCA3 gene lead to pulmonary fibrosis and emphysema, including combined pulmonary fibrosis and emphysema, in childhood. Treatment with prostacyclin analogue, warfarin, and inhaled oxygen was effective to improve patient's hemodynamic condition as well as pulmonary fibrosis and emphysema. Pediatr Pulmonol. 2016;51:E21-E23. © 2016 Wiley Periodicals, Inc.

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

“…Similarly, as Figure 3 schematically illustrates, over 200 distinct ABCA3 mutations have been identified and are recognized as the most prevalent group of mutations among genes associated with surfactant related lung disorders (Shulenin et al, 2004; Ota et al, 2016; Peca et al, 2015; Bullard et al, 2005; Garmany et al, 2006; Doan et al, 2008; Flamein et al, 2012; Wambach et al, 2014; Goncalves et al, 2014). Various types of coding and non-coding variants in the ABCA3 gene have been described including missense, nonsense, frameshift, insertion, deletion, and splice site mutations.…”

“…Less frequent are ABCA3 mutations that are associated with a more chronic phenotype that affect older children and adults often resulting in chILD, IPF, or DPLD (Bullard et al, 2005; Bullard and Nogee, 2007; Doan et al, 2008; Wert et al, 2009; Crossno et al, 2010; Epaud et al, 2014; Crossno et al, 2010; Ota et al, 2016). These disease causing ABCA3 mutations have been shown to result in either partial loss-of-function caused by aberrant ABCA3 protein trafficking or impaired ABCA3 lipid-pump function, or alternatively promote a toxic gain-of-function phenotype through induction of cell stress pathways (Matsumura et al, 2006; Cheong et al, 2006; Matsumura et al, 2008).…”

“…As illustrated in Figure 3, compound heterozygous variants account for approximately three quarters of all report lung disease-associated ABCA3 mutations to date (Shulenin et al, 2004; Matsumura et al, 2008; Ota et al, 2016; Peca et al, 2015; Bullard et al, 2005; Garmany et al, 2006; Doan et al, 2008; Flamein et al, 2012; Wambach et al, 2014; Goncalves et al, 2014). Many of these mutations are clustered within the first and forth luminal loops as well as in the cytosolic domains, particularly within or adjacent to the second nucleotide-binding domain (NBD2).…”

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

“…The patient was a compound heterozygous for ABCA3 mutation with E292V variant in one allele and a nonsense mutation producing a null allele in the other. Likewise, a second 8 year old child, also with compound heterozygous mutation with an L34P and a p. F1203_L1204del mutations has been described with a diagnosis of pulmonary fibrosis and emphysema along with pulmonary hypertension (Ota et al, 2016). Taken together, these reports further support the proposal that disruption of the ABCA3 gene can promote an aberrant lung phenotype characterized by both fibrotic and emphysema-like lung remodeling.…”

Pediatric Pulmonologyyear in review 2016: Part 1

“…They report clinical improvement upon treatment with hydroxychloroquine, azithromycin, and pulse steroids. Another report from Japan highlighted a phenotype of emphysema, interstitial fibrosis, and pulmonary hypertension in a compound heterozygote for two different ABCA3 variants . These authors report improvement after initiation of therapy with a prostacyclin analogue and warfarin.…”