{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T21:04:45Z","timestamp":1773263085071,"version":"3.50.1"},"reference-count":28,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,7,19]],"date-time":"2019-07-19T00:00:00Z","timestamp":1563494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Mutations in adenosine triphosphate-binding cassette transporter A3 (ABCA3) (OMIM: 601615) gene constitute the most frequent genetic cause of severe neonatal respiratory distress syndrome (RDS) and interstitial lung disease (ILD) in children. Interstitial lung disease in children and especially in infants, in contrast to adults, is more likely to appear as a result of developmental deficits or is characterized by genetic aberrations of pulmonary surfactant homeostasis not responding to exogenous surfactant administration. The underlying ABCA3 gene mutations are commonly thought, regarding null mutations, to determine the clinical course of the disease while there exist mutation types, especially missense variants, whose effects on surfactant proteins are difficult to predict. In addition, clinical and radiological signs overlap with those of surfactant proteins B and C mutations making diagnosis challenging. We demonstrate a case of a one-term newborn male with lethal respiratory failure caused by homozygous missense ABCA3 gene mutation c.3445G&gt;A (p.Asp1149Asn), which, to our knowledge, was not previously reported as a causative agent of newborn lethal RDS. Therapeutic strategies for patients with ABCA3 gene mutations are not sufficiently evidence-based. Therefore, the description of the clinical course and treatment of the disease in terms of a likely correlation between genotype and phenotype is crucial for the development of the optimal clinical approach for affected individuals.<\/jats:p>","DOI":"10.3390\/medicina55070389","type":"journal-article","created":{"date-parts":[[2019,7,22]],"date-time":"2019-07-22T02:55:37Z","timestamp":1563764137000},"page":"389","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["A New ABCA3 Gene Mutation c.3445G&gt;A (p.Asp1149Asn) as a Causative Agent of Newborn Lethal Respiratory Distress Syndrome"],"prefix":"10.3390","volume":"55","author":[{"given":"Georgios","family":"Mitsiakos","sequence":"first","affiliation":[{"name":"2nd Neonatology Department and Neonatal Intensive Care Unit, Aristotle University of Thessaloniki, \u201cPapageorgiou\u201d Hospital, Thessaloniki, PC 56403, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christos","family":"Tsakalidis","sequence":"additional","affiliation":[{"name":"2nd Neonatology Department and Neonatal Intensive Care Unit, Aristotle University of Thessaloniki, \u201cPapageorgiou\u201d Hospital, Thessaloniki, PC 56403, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paraskevi","family":"Karagianni","sequence":"additional","affiliation":[{"name":"2nd Neonatology Department and Neonatal Intensive Care Unit, Aristotle University of Thessaloniki, \u201cPapageorgiou\u201d Hospital, Thessaloniki, PC 56403, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dimitra","family":"Gialamprinou","sequence":"additional","affiliation":[{"name":"2nd Neonatology Department and Neonatal Intensive Care Unit, Aristotle University of Thessaloniki, \u201cPapageorgiou\u201d Hospital, Thessaloniki, PC 56403, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ilias","family":"Chatziioannidis","sequence":"additional","affiliation":[{"name":"2nd Neonatology Department and Neonatal Intensive Care Unit, Aristotle University of Thessaloniki, \u201cPapageorgiou\u201d Hospital, Thessaloniki, PC 56403, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Papoulidis","sequence":"additional","affiliation":[{"name":"2nd Neonatology Department and Neonatal Intensive Care Unit, Aristotle University of Thessaloniki, \u201cPapageorgiou\u201d Hospital, Thessaloniki, PC 56403, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ioannis","family":"Tsanakas","sequence":"additional","affiliation":[{"name":"3rd Department of Pediatrics, Aristotle University of Thessaloniki, \u201cHippokratio\u201d Hospital, Thessaloniki, PC 54642, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vasiliki","family":"Soubasi","sequence":"additional","affiliation":[{"name":"2nd Neonatology Department and Neonatal Intensive Care Unit, Aristotle University of Thessaloniki, \u201cPapageorgiou\u201d Hospital, Thessaloniki, PC 56403, Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1750-1172-4-26","article-title":"Incidence and classification of pediatric diffuse parenchymal lung diseases in Germany","volume":"4","author":"Griese","year":"2009","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1038\/jp.2014.132","article-title":"Respiratory failure in a term newborn due to compound heterozygous ABCA3 mutation: The case report of another lethal variant","volume":"34","author":"Looman","year":"2014","journal-title":"J. Perinatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4097","DOI":"10.1038\/s41598-017-04486-y","article-title":"Variants of the ABCA3 gene might contribute to susceptibility to interstitial lung diseases in the Chinese population","volume":"7","author":"Zhou","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.1056\/NEJMoa032178","article-title":"ABCA3 gene mutations in newborns with fatal surfactant deficiency","volume":"350","author":"Shulenin","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/1465-9921-15-43","article-title":"A large kindred of pulmonary fibrosis associated with a novel ABCA3 gene variant","volume":"15","author":"Campo","year":"2014","journal-title":"Respir. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1042\/BST20150100","article-title":"ABCA3, a key player in neonatal respiratory transition and genetic disorders of the surfactant system","volume":"43","author":"Peca","year":"2015","journal-title":"Biochem. Soc. Trans."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1164\/rccm.201402-0342OC","article-title":"Genotype-phenotype correlations for infants and children with ABCA3 deficiency","volume":"189","author":"Wambach","year":"2014","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e1575","DOI":"10.1542\/peds.2012-0918","article-title":"Single ABCA3 mutations increase risk for neonatal respiratory distress syndrome","volume":"130","author":"Wambach","year":"2012","journal-title":"Pediatrics"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"183","DOI":"10.2119\/molmed.2015.00244","article-title":"Increased risk of interstitial lung disease in children with a single R288K variant of ABCA3","volume":"22","author":"Wittmann","year":"2016","journal-title":"Mol. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2676","DOI":"10.1002\/ajmg.a.36660","article-title":"Single mutations in ABCA3 increase the risk for neonatal respiratory distress syndrome in late preterm infants (gestational age 34\u201336 weeks)","volume":"164","author":"Naderi","year":"2014","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1164\/rccm.200503-504OC","article-title":"ABCA3 mutations associated with pediatric interstitial lung disease","volume":"172","author":"Bullard","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"227","DOI":"10.4103\/1817-1737.182900","article-title":"Adenosine triphosphate-binding cassette member A3 gene mutation in children from one family from Saudi Arabia","volume":"11","author":"Mukhtar","year":"2016","journal-title":"Ann. Thorac. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1016\/j.jpeds.2017.01.017","article-title":"Outcomes of lung transplantation for infants and children with genetic disorders of surfactant metabolism","volume":"184","author":"Eldridge","year":"2017","journal-title":"J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s00441-016-2554-z","article-title":"The biology of the ABCA3 lipid transporter in lung health and disease","volume":"367","author":"Beers","year":"2017","journal-title":"Cell Tissue Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"9791","DOI":"10.1074\/jbc.M507515200","article-title":"Functional and trafficking defects in ATP binding cassette A3 mutants associated with respiratory distress syndrome","volume":"281","author":"Cheong","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1152\/ajplung.90352.2008","article-title":"Aberrant catalytic cycle and impaired lipid transport into intracellular vesicles in ABCA3 mutants associated with nonfatal pediatric interstitial lung disease","volume":"295","author":"Matsumura","year":"2008","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1002\/humu.23416","article-title":"ABCA3 missense mutations causing surfactant dysfunction disorders have distinct cellular phenotypes","volume":"39","author":"Schindlbeck","year":"2018","journal-title":"Hum. Mutat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1164\/rccm.200509-1535OC","article-title":"Alteration of the pulmonary surfactant system in full-term infants with hereditary ABCA3 deficiency","volume":"174","author":"Brasch","year":"2006","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1136\/thoraxjnl-2016-208649","article-title":"Lung disease caused by ABCA3 mutations","volume":"72","author":"Wittmann","year":"2017","journal-title":"Thorax"},{"key":"ref_21","first-page":"2943","article-title":"Evaluation and management of inherited disorders of surfactant metabolism","volume":"123","author":"Hamvas","year":"2010","journal-title":"Chin. Med. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1136\/thoraxjnl-2015-207349","article-title":"chILD-EU Collaboration. European protocols for the diagnosis and initial treatment of interstitial lung disease in children","volume":"70","author":"Bush","year":"2015","journal-title":"Thorax"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1136\/adc.2009.171553","article-title":"Characteristics of disorders associated with genetic mutations of surfactant protein C","volume":"95","author":"Thouvenin","year":"2010","journal-title":"Arch. Dis. Child."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1136\/thx.2007.083766","article-title":"Clinical, radiological and pathological features of ABCA3 mutations in children","volume":"63","author":"Doan","year":"2008","journal-title":"Thorax"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1002\/ppul.22811","article-title":"Ten-year follow up of hydroxychloroquine treatment for ABCA3 deficiency","volume":"49","author":"Williamson","year":"2014","journal-title":"Pediatr. Pulmonol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/jp.2010.122","article-title":"Fatal respiratory failure in a full-term newborn with two ABCA3 gene mutations: A case report","volume":"31","author":"Ciantelli","year":"2011","journal-title":"J. Perinatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"E1","DOI":"10.1002\/ppul.23260","article-title":"ABCA3 lung disease in an ex 27 week preterm infant responsive to systemic glucocorticosteroids","volume":"51","author":"Tan","year":"2016","journal-title":"Pediatr. Pulmonol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1055\/s-0033-1363687","article-title":"Neonatal respiratory insufficiency caused by an (homozygous) ABCA3-stop mutation: A systematic evaluation of therapeutic options","volume":"226","author":"Winter","year":"2014","journal-title":"Klin. Padiatr."}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/55\/7\/389\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:07:40Z","timestamp":1760188060000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/55\/7\/389"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,7,19]]},"references-count":28,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,7]]}},"alternative-id":["medicina55070389"],"URL":"https:\/\/doi.org\/10.3390\/medicina55070389","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,7,19]]}}}