ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes

Abstract

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.

Bi-allelic missenseABCA3mutations in a patient with childhood ILD who reached adulthood

“…In the absence of functional studies, it is difficult to comprehend the exact mechanism of each disease-causing mutation. In general, it is known that ABCA3 mutations dysregulate the normal processing and trafficking of ABCA3 protein and impair its ATPase activity and lipid transport function resulting in disordered lamellar body organisation and increased interleukin-8 production in AEC-2 cells [13, 16]. Based on these observations, therapeutic interventions such as corticosteroids, hydroxychloroquine and macrolides have been widely applied to patients with ABCA3 mutations, with moderate-to-very poor efficacy to date [7].…”

A Newly Observed Mutation of the ABCA3 Gene Causing Lethal Respiratory Failure of a Full-Term Newborn: A Case Report

“…ABCA3 missense mutations might lead to impaired trafficking or dysfunction of ABCA3 protein. Matsumura et al distinguished type 1 mutations with an abnormal intracellular localization and type 2 mutations with decreased ATP hydrolysis despite correct intracellular localization of ABCA3 protein ( Schindlbeck et al, 2018 ). The compound heterozygous combination of types 1 and 2 mutations is currently discussed as a type 3 mutation and often presents with a more severe phenotype ( Beers and Mulugeta, 2017 ).…”

A New ABCA3 Gene Mutation c.3445G>A (p.Asp1149Asn) as a Causative Agent of Newborn Lethal Respiratory Distress Syndrome

“…The opportunities presented by an enhanced understanding of ABCA3 biology for targeted therapeutic strategies have recently been addressed [14]. With a special focus on correlating ABCA3 gene missense mutations to clinical phenotypes, investigators developed new tools which demonstrate the association between in vitro observations and clinical data [17].…”

“…The in silico analysis showed no other genetic impairment of the ABCA3 gene or of another relevant surfactant gene. Recent studies by Schindlbeck et al [17] in terms of depicting correlations between missense mutations in ABCA3 gene and the clinical severity of the disease by investigation of molecular pathomechanisms added new data in the bibliography. For instance, a full-term newborn with the homozygous combination of p.Q215K and p.R288K missense ABCA3 gene mutations was presented with severe respiratory distress syndrome and early neonatal death due to ABCA3 malfunction [19,20].…”