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Year : 2017  |  Volume : 12  |  Issue : 3  |  Page : 213-215
The most frequent ABCA3 nonsense mutation -p.Tyr1515* (Y1515X) causing lethal neonatal respiratory failure in a term neonate

1 Department of Pediatrics, Security Forces Hospital, Alfaisal University, Riyadh, Saudi Arabia
2 Department of Pediatrics, Creteil Intercommunal Hospital, France
3 Research Center, King Fahad Medical City, Riyadh, Saudi Arabia
4 Genetic Department, Henri Mondor Hospital, France
5 Department of Pediatrics, NICU, Security Forces Hospital, Riyadh, Saudi Arabia

Date of Submission22-Nov-2016
Date of Acceptance11-Jan-2017
Date of Web Publication13-Jul-2017

Correspondence Address:
AlNashmi AlAnazi
Department of Pediatrics, Security Forces Hospital, Alfaisal University, Riyadh
Saudi Arabia
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/atm.ATM_386_16

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Defects in the surfactant biosynthesis are associated with respiratory distress syndrome, commonly occurring in premature infants due to lung immaturity. However, interstitial lung diseases have also been observed in full-term infants with mutations in the SFTPC, SFTPB, NKX2-1, or ABCA3 genes, involved in the surfactant metabolism. Herein, we report a newborn baby with neonatal respiratory distress and diffuse lung disease caused by ABCA3 mutation. The baby died at 5 weeks of age after developing pulmonary hypertension. Genomic DNA was analyzed for four genes involved in surfactant metabolism out of which the c. 4545C>G (p.Tyr1515*) homozygous mutation in exon 29 of ABCA3 was identified which is one of the most frequent mutation causing lethal neonatal respiratory failure in a term neonate. This case study emphasizes the importance of raising awareness about this diagnosis in the clinical settings for fruitful outcomes in health-care delivery.

Keywords: Interstitial lung disease, neonatal respiratory failure, pediatric pulmonology

How to cite this article:
AlAnazi A, Epaud R, Heena H, de becdelievre A, Miqdad AM, Fanen P. The most frequent ABCA3 nonsense mutation -p.Tyr1515* (Y1515X) causing lethal neonatal respiratory failure in a term neonate. Ann Thorac Med 2017;12:213-5

How to cite this URL:
AlAnazi A, Epaud R, Heena H, de becdelievre A, Miqdad AM, Fanen P. The most frequent ABCA3 nonsense mutation -p.Tyr1515* (Y1515X) causing lethal neonatal respiratory failure in a term neonate. Ann Thorac Med [serial online] 2017 [cited 2023 Jan 28];12:213-5. Available from:

Defects in the surfactant biosynthesis are associated with respiratory distress syndrome, which commonly occurs in premature infants due to lung immaturity. However, inherited surfactant metabolism disorders may cause a similar presentation in full-term newborns along with interstitial lung diseases (ILDs) in older children and adults. ILD have been observed in full-term infants with mutations in the SFTPC, SFTPB, NKX2-1, or ABCA3 genes, which are involved in the surfactant biosynthesis.[1],[2] ABCA3 is a member of the ATP-binding cassette (ABC) transporter family which encodes membrane proteins involved in the transport of compounds across biologic membranes. ABCA3 is a 1704-amino-acid protein highly expressed in alveolar epithelial cells at the limiting membrane of lamellar bodies [3] and is crucial for AT2 cells homeostasis, lipid composition (importation of phospholipids in lamellar bodies) and protein maturation of surfactant.[4] More than 150 recessive mutations of the ABCA3 gene have been reported in newborn babies with respiratory failure and in older children or adults with ILD.[5] We report here a full-term infant with severe respiratory failure after 8 days of life, in whom we identified an ABCA3 null mutation at the homozygous state, namely, p. Tyr1515* (Y1515X). This truncating mutation causes a total loss of function of the ABCA3 protein.

   Case Report Top

Our patient was from a consanguineous family (parents were first cousins) originating from Saudi Arabia. One older sister was asymptomatic, but there was a familial history since one sibling had died at 5 days of life due to meconium aspiration syndrome and bilateral pneumothorax with persistent pulmonary hypertension of the newborn [Figure 1].
Figure 1: Pedigree of the family and identification of the homozygous mutation

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The index patient was a full-term baby boy delivered normally with a weight of 3.74 kg after an uneventful pregnancy. Within the first few hours of life, he developed severe respiratory distress and required invasive ventilation. Chest radiograms at first few hours showed diffuse reticular granularity and air bronchograms [Figure 2] due to which the baby received three doses of exogenous surfactant (4 ml/kg) as standard first-line treatment but with only transient improvement. Although the blood cultures were negative, the boy remained ventilated with worsening of the chest radiogram and developed pulmonary hypertension despite receiving intravenous corticosteroids (dexamethasone) treatment (0.1 mg/kg/dose once daily for 2 weeks). As the baby's condition worsened, the respiratory failure occurred due to the hypoxemia initially and at later stages due to CO2 retention. Ultimately, he needed more respiratory support and was put on high-frequency ventilation with inhaled nitric oxide at 20 ppm.
Figure 2: The chest X-ray images of the neonate

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Due to the family history, genetic analysis of genes associated with surfactant metabolism disorders was performed. Informed consent was obtained from the parents according to the current regulations. Genomic DNA was extracted from a peripheral blood ethylenediaminetetraacetic acid sample. The four genes involved in surfactant metabolism deficiency were explored by Sanger sequencing of all coding exons and their intronic flanking regions: SFTPC (NM_003018.3), SFTPB (NM_00542.3), NKX2-1 (NM_001079668), and ABCA3 (NM_001089.2). Sequence variations' pathogenicity was evaluated in silico on Alamut Visual version 2.7 software (Interactive Biosoftwares, Rouen, France). No mutation was detected in the SFTPC, SFTPB, and NKX2-1 genes, however, we identified the c.4545C>G (p. Tyr1515*) mutation in homozygosity in exon 29 of ABCA3 [Figure 1]. This substitution of a tyrosine codon by a premature stop codon is predicted to lead to a truncated protein.

After the genetic result of ABCA3-related surfactant, metabolism disorder was obtained, another course of dexamethasone was given without any further improvement. The baby deceased at the age of 5 weeks.

   Discussion Top

Pulmonary surfactant constitutes a tensioactive film covering the alveolar lumen and is necessary to avoid alveolar collapse during dynamic compression and decompression. The hydrophobic surfactant proteins SP-B and SP-C play a role in innate host lung defense and are transported to and stored in lamellar bodies-the secretory organelles of AT2 cells where they undergo posttranslational maturation before secretion at the epithelial surface.[4] Mature SP-B and SP-C interact with phospholipids to confer tension-active properties to the pulmonary surfactant.

Four genes have mainly been implicated in genetic abnormalities of the surfactant: SFTPB, SFTPC, NKX2-1, and ABCA3, encoding respectively the specific proteins of the surfactant SP-B and SP-C, the transcription factor NKX2-1 which regulates the transcription of SFTPB, SFTPC, and ABCA3 genes. As with SP-B deficiency, ABCA3 deficiency is now recognized as the most frequent cause of genetic surfactant metabolism disorder [6] and should be suspected in full-term infants with severe neonatal respiratory distress syndrome refractory to conventional treatment [5],[7],[8] ABCA3 deficiency leads to abnormal lamellar bodies' structure and abnormal surfactant lipid composition, associated with impaired processing of SP-B and SP-C protein.[9],[10] Total loss of function leads to dramatic progress with neonatal distress syndrome and death within the 1st year of life whereas residual ABCA3 function is associated with milder disease.[5] Most mutations are unique, which can make the genetic counseling difficult in the families, especially in the case of missense mutations (amino acid substitution) where phenotype-genotype correlation is unknown. However, some are considered “frequent,” as they have been reported among multiple patients as is the case for the p. Glu292Val (E292V) mutation which is the most frequent mutation in a population of European descent.[11] Similarly, p. Tyr1515* mutation in the ABCA3 gene seemed to be more frequent in the Middle East,[5] as it was recently described in 18 consanguineous families originating from Middle East region. In our extensive study, although it was considered as a null mutation (no residual function of ABCA3) no functional study was performed. Unfortunately, no bronchoalveolar lavage was available for our patient hence neither mRNA nor SP studies could be carried out to determine if nonsense-mediated mRNA decay degraded abnormal transcribed mRNA or if it was translated into a truncated protein. However, this mutation was located at the end of the functional nucleotide binding domain 2, which binds adenosine triphosphate and allows channel gating and lipid transport. Such mutation at the homozygous state is thought to cause a complete absence of functional ABCA3 protein and thus a severe defect in surfactant biosynthesis.

Neonate respiratory distress due to impaired surfactant metabolism is a rare condition, and most clinical centers examine very few cases. Therefore, the ChILD-EU (ILD in children) collaboration recently published guidelines to diagnose the disease and to treat it when it is possible.[12] Besides oxygen therapy, usual treatment suggestions include methylprednisolone, hydroxychloroquine, and azithromycin. However, in case of neonatal presentation, where rapid intubation and ventilation is required, respiratory failure often leads to death or lung transplantation is performed where available. Our case drew similarities to all 19 p. Tyr1515* homozygous patients described recently with patients presenting with severe respiratory distress syndrome and death before 3 months of age.[5] Since ABCA3 is a large gene of 30 coding exons, so the molecular analysis is time-consuming. In such cases with a frequent mutation according to geographic origin, the mutation could be searched for as a first rapid step of the study, followed by analysis of all exons. This could help expedite the therapeutic approach or the ending of the care resulting in the reduced burden on the health-care resources of a country. This case also illustrates the need for genetic analysis in patients presenting with ILD. Indeed, in this consanguineous family, two children died of surfactant metabolism deficiency before 1 month of life. Elucidating the molecular cause of the disease in families is of tremendous importance for genetic counseling and mandatory prenatal diagnosis to prevent further pregnancies and toward achieving better health outcomes. Genetic studies of all SPs, not only ABCD3, should be studied in suspected cases because the presentations of the different SPs deficiencies may be overlapping. Moreover, ABCA3 gene mutation is important because it might ultimately obviate the need for lung biopsy with improved patient outcomes in these cases.[13]

The findings from this case report emphasize the need to perform genetic analysis in newborns with severe respiratory distress to adapt a better therapeutic approach along with timely genetic counseling.

   Conclusions Top

p. Tyr1515* (Y1515X) is one of the most frequent mutations in exon 29 of ABCA3, usually leading to death within the 1st months. Appropriate prenatal diagnosis will help to deliver specific patient care and better outcomes. Similarly, mandatory genetic counseling is of remarkable importance to prevent further pregnancies and hence achieve better health outcomes. This case study aims to act as stepping stone to raise awareness of genetic counseling among parents as well as health-care providers.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

Mukhtar GM, Al Otaibi WH, Al-Mobaireek KF, Al-Saleh S. Adenosine triphosphate-binding cassette member A3 gene mutation in children from one family from Saudi Arabia. Ann Thorac Med 2016;11:227-9.  Back to cited text no. 1
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Wambach JA, Yang P, Wegner DJ, Heins HB, Kaliberova LN, Kaliberov SA, et al. Functional characterization of ATP-binding cassette transporter A3 mutations from infants with respiratory distress syndrome. Am J Respir Cell Mol Biol 2016;55:716-21.  Back to cited text no. 2
Wittmann T, Schindlbeck U, Höppner S, Kinting S, Frixel S, Kröner C, et al. Tools to explore ABCA3 mutations causing interstitial lung disease. Pediatr Pulmonol 2016;51:1284-94.  Back to cited text no. 3
Bush A, Cunningham S, de Blic J, Barbato A, Clement A, Epaud R, et al. European protocols for the diagnosis and initial treatment of interstitial lung disease in children. Thorax 2015;70:1078-84.  Back to cited text no. 4
Wambach JA, Casey AM, Fishman MP, Wegner DJ, Wert SE, Cole FS, et al. Genotype-phenotype correlations for infants and children with ABCA3 deficiency. Am J Respir Crit Care Med 2014;189:1538-43.  Back to cited text no. 5
Flamein F, Riffault L, Muselet-Charlier C, Pernelle J, Feldmann D, Jonard L, et al. Molecular and cellular characteristics of ABCA3 mutations associated with diffuse parenchymal lung diseases in children. Hum Mol Genet 2012;21:765-75.  Back to cited text no. 6
Whitsett JA, Wert SE, Weaver TE. Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease. Annu Rev Med 2010;61:105-19.  Back to cited text no. 7
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Garmany TH, Wambach JA, Heins HB, Watkins-Torry JM, Wegner DJ, Bennet K, et al. Population and disease-based prevalence of the common mutations associated with surfactant deficiency. Pediatr Res 2008;63:645-9.  Back to cited text no. 9
Cheong N, Zhang H, Madesh M, Zhao M, Yu K, Dodia C, et al. ABCA3 is critical for lamellar body biogenesis in vivo. J Biol Chem 2007;282:23811-7.  Back to cited text no. 10
Hartl D, Griese M. Interstitial lung disease in children – Genetic background and associated phenotypes. Respir Res 2005;6:32.  Back to cited text no. 11
Shulenin S, Nogee LM, Annilo T, Wert SE, Whitsett JA, Dean M. ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 2004;350:1296-303.  Back to cited text no. 12
Yamano G, Funahashi H, Kawanami O, Zhao LX, Ban N, Uchida Y, et al. ABCA3 is a lamellar body membrane protein in human lung alveolar type II cells. FEBS Lett 2001;508:221-5.  Back to cited text no. 13


  [Figure 1], [Figure 2]

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