title: ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system.
abstract: Genetic disorders of the surfactant system are rare diseases with a broad range of clinical manifestations, from fatal respiratory distress syndrome (RDS) in neonates to chronic interstitial lung disease (ILD) in children and adults. ABCA3 [ATP-binding cassette (ABC), subfamily A, member 3] is a lung-specific phospholipid transporter critical for intracellular surfactant synthesis and storage in lamellar bodies (LBs). Its expression is developmentally regulated, peaking prior to birth under the influence of steroids and transcription factors. Bi-allelic mutations of the ABCA3 gene represent the most frequent cause of congenital surfactant deficiency, indicating its critical role in lung function. Mutations affect surfactant lipid and protein processing and LBs' morphology, leading to partial or total surfactant deficiency. Approximately 200 mutations have been reported, most of which are unique to individuals and families, which makes diagnosis and prognosis challenging. Various types of mutations, affecting different domains of the protein, account in part for phenotype diversity. Disease-causing mutations have been reported in most coding and some non-coding regions of the gene, but tend to cluster in the first extracellular loop and the second nucleotide-binding domain (NBD), leading to defective glycosylation and trafficking defects and interfering with ATP binding and hydrolysis respectively. Mono-allelic damaging and benign variants are often subclinical but may act as disease modifiers in lung diseases such as RDS of prematurity or associate with mutations in other surfactant-related genes. Diagnosis is complex but essential and should combine pathology and ultrastructure studies on lung biopsy with broad-spectrum genetic testing of surfactant-related genes, made possible by recent technology advances in the massive parallel sequencing technology.
authors.affiliation: Department of Medical and Surgical Neonatology, Bambino Gesù Children's Hospital, 4 Piazza S. Onofrio, Rome 00165, Italy Division of Pulmonology, Bambino Gesù Children's Hospital, 4 Piazza S. Onofrio, Rome 00165, Italy.
authors.forename: Donatella
authors.initials: D
authors.lastname: Peca
authors.affiliation: Division of Pulmonology, Bambino Gesù Children's Hospital, 4 Piazza S. Onofrio, Rome 00165, Italy.
authors.forename: Renato
authors.initials: R
authors.lastname: Cutrera
authors.affiliation: Gene Expression and Microarrays Laboratory, Bambino Gesù Children's Hospital, Viale di San Paolo 15, Rome 00146, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Masotti
authors.affiliation: Clinical Pathology Unit, Bambino Gesù Children's Hospital, 4 Piazza S. Onofrio, Rome 00165, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Boldrini
authors.affiliation: Department of Medical and Surgical Neonatology, Bambino Gesù Children's Hospital, 4 Piazza S. Onofrio, Rome 00165, Italy Division of Neonatology, University of California San Francisco, 1001 Potrero Avenue, San Francisco, CA 194116, U.S.A. olivier.danhaive@ucsf.edu.
authors.forename: Olivier
authors.initials: O
authors.lastname: Danhaive
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009154:Mutation; D011663:Pulmonary Surfactants / Q000378:metabolism*; D012127:Respiratory Distress Syndrome, Newborn / Q000235:genetics* / Q000378:metabolism
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D011663:Pulmonary Surfactants
keywords: genetics; interstitial lung disease; neonate; respiratory distress syndrome; surfactant; ultrastructure