However, whether variations in ABCA3 have a role in the development of adult ILD, including idiopathic pulmonary fibrosis (IPF), remains to be addressed.
Mutations in the gene for adenosine triphosphate-binding cassette transporter A3 (ABCA3) have been reported in infants and children with fatal surfactant deficiency and interstitial lung disease.
Moreover, ABCA3 mutations found in patients with DPLD interfere with this protective effect of ABCA3, resulting in free cholesterol induced cell death.
Mutations in ABCA3 display a common genetic cause for diseases caused by surfactant deficiency like respiratory distress in neonates and interstitial lung disease in children and adults, for which currently no causal therapy exists.
Importantly, these findings support the notion that electron microscopy is useful in distinguishing between surfactant protein-B and ABCA3 deficiency, and has an important role in evaluating biopsies or autopsies of term infants with unexplained severe respiratory failure and interstitial lung disease.
In children with ABCA3-deficiency from two ILD causing mutations saturated and monounsaturated phosphatidylcholine species with 30 and 32 carbons and almost all phosphatidylglycerol species were severely reduced.
Mutations in the gene encoding ABCA3 have been found in children with severe neonatal respiratory disease and older children with some forms of interstitial lung disease.
Mutations in the gene for adenosine triphosphate-binding cassette transporter subfamily A member 3 (ABCA3) have been reported in infants and children with surfactant deficiency and interstitial lung disease.
To test the hypothesis that ABCA3 mutations are not always associated with fatal neonatal lung disease but are a cause of pediatric interstitial lung disease.
Mutations in the ABCA3 gene are an important genetic cause for respiratory distress syndrome in neonates and interstitial lung disease in children and adults, for which there is currently no cure.
Mutations in the genes encoding surfactant protein C, SFTPC, and a member of the adenosine triphosphate-binding cassette family of proteins, ABCA3, have been shown to result in pediatric interstitial lung diseases inherited in autosomal-dominant and autosomal-recessive patterns, respectively.
Term infants carrying the E292V missense mutation of the gene encoding ABCA3 are likely to develop respiratory distress syndrome, and the mutation has also been linked to interstitial lung disease in paediatric patients.
Nonsense, missense, frameshift, and splice-site mutations in the ABCA3 gene (ABCA3) have been reported as causes of neonatal respiratory failure (NRF) and interstitial lung disease.
Mutations in the ATP-binding cassette transporter A3 gene (ABCA3) result in severe neonatal respiratory distress syndrome and childhood interstitial lung disease.
Mutations in the genes encoding the surfactant proteins B and C (SP-B and SP-C) and the phospholipid transporter, ABCA3, are associated with respiratory distress and interstitial lung disease in the pediatric population.
Genetic variations considered responsible were detected in six (67%) of the nine infants with ILD: three with hPAP (SFTPC p.Leu45Arg and p.Gln145fs, and ABCA3p.Arg1583Trp/p.Val1495CysfsX21), two with interstitial pneumonitis (SFTPC p.Lys63Glu and p.Ser72Asn/p.Gly100Ala), and one with ACD/MPV (FOXF1 p.Leu300ArgfsX79).
Translational research has linked heterozygous mutations in the ABCA3 transporter to an increased risk of interstitial lung diseases, not only in neonates, but also in older children and adults.
These findings demonstrate that subclinical fibrotic changes may be present in family members of patients with SFTPC mutation-associated interstitial lung disease and suggest that ABCA3 variants could affect disease pathogenesis.
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).
Pulmonary surfactant deficiency caused by mutations in ABCA3 (ATP-binding cassette transporter of the A subfamily, member 3) gene results in diffuse parenchymal lung disease (DPLD) in children.