ABCA3 Gene Mutations in Newborns with Fatal Surfactant Deficiency

Sergey Shulenin, Lawrence Nogee, Tarmo Annilo, Susan E. Wert, Jeffrey A. Whitsett, Michael Dean

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Pulmonary surfactant forms a lipid-rich monolayer that coats the airways of the lung and is essential for proper inflation and function of the lung. Surfactant is produced by alveolar type II cells, stored intracellularly in organelles known as lamellar bodies, and secreted by exocytosis. The gene for ATP-binding cassette transporter A3 (ABCA3) is expressed in alveolar type II cells, and the protein is localized to lamellar bodies, suggesting that it has an important role in surfactant metabolism. METHODS: We sequenced each of the coding exons of the ABCA3 gene in blood DNA from 21 racially and ethnically diverse infants with severe neonatal surfactant deficiency for which the etiologic process was unknown. Lung tissue from four patients was examined by high-resolution light and electron microscopy. RESULTS: Nonsense and frameshift mutations, as well as mutations in highly conserved residues and in splice sites of the ABCA3 gene were identified in 16 of the 21 patients (76 percent). In five consanguineous families with mutations, each pair of siblings was homozygous for the same mutation and each mutation was found in only one family. Markedly abnormal lamellar bodies were observed by ultrastructural examination of lung tissue from four-patients with different ABCA3 mutations, including nonsense, splice-site, and missense mutations. CONCLUSIONS: Mutation of the ABCA3 gene causes fatal surfactant deficiency in newborns. ABCA3 is critical for the proper formation of lamellar bodies and surfactant function and may also be important for lung function in other pulmonary diseases. Since it is closely related to ABCA1 and ABCA4, proteins that transport phospholipids in macrophages and photoreceptor cells, it may have a role in surfactant phospholipid metabolism.

Original languageEnglish (US)
Pages (from-to)1296-1303
Number of pages8
JournalNew England Journal of Medicine
Volume350
Issue number13
DOIs
StatePublished - Mar 25 2004

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ATP-Binding Cassette Transporters
Surface-Active Agents
Newborn Infant
Mutation
Lung
Genes
Alveolar Epithelial Cells
Nonsense Codon
Phospholipids
ATP Binding Cassette Transporter 1
Pulmonary Surfactants
Photoreceptor Cells
Frameshift Mutation
Economic Inflation
Exocytosis
Protein Transport
Missense Mutation
Organelles
Lung Diseases
Siblings

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Shulenin, S., Nogee, L., Annilo, T., Wert, S. E., Whitsett, J. A., & Dean, M. (2004). ABCA3 Gene Mutations in Newborns with Fatal Surfactant Deficiency. New England Journal of Medicine, 350(13), 1296-1303. https://doi.org/10.1056/NEJMoa032178

ABCA3 Gene Mutations in Newborns with Fatal Surfactant Deficiency. / Shulenin, Sergey; Nogee, Lawrence; Annilo, Tarmo; Wert, Susan E.; Whitsett, Jeffrey A.; Dean, Michael.

In: New England Journal of Medicine, Vol. 350, No. 13, 25.03.2004, p. 1296-1303.

Research output: Contribution to journalArticle

Shulenin, S, Nogee, L, Annilo, T, Wert, SE, Whitsett, JA & Dean, M 2004, 'ABCA3 Gene Mutations in Newborns with Fatal Surfactant Deficiency', New England Journal of Medicine, vol. 350, no. 13, pp. 1296-1303. https://doi.org/10.1056/NEJMoa032178
Shulenin, Sergey ; Nogee, Lawrence ; Annilo, Tarmo ; Wert, Susan E. ; Whitsett, Jeffrey A. ; Dean, Michael. / ABCA3 Gene Mutations in Newborns with Fatal Surfactant Deficiency. In: New England Journal of Medicine. 2004 ; Vol. 350, No. 13. pp. 1296-1303.
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