Novel mutations in the gene encoding ATP binding cassette protein member A3 (ABCA3) resulting in fatal neonatal lung disease

Aim: To investigate whether intractable respiratory distress syndrome in three Norwegian term infants was due to mutations in the ABCA3 gene. Methods: The genes encoding SP-B (SFTPB), SP-C (SFTPC), and ABCA3 (ABCA3) were sequenced from the parents of one infant and two unrelated infants with fatal neonatal lung disease. Lung tissue was examined by histology, immunohistochemistry and electron microscopy. Results: Novel ABCA3 mutations were identified in each family. One patient had a phenotype differing from previous descriptions of this disease with an initial uneventful period. The diagnosis was established 19 years after death by analysing DNA material from the parents, with an ABCA3 mutation identified on one allele in each parent. The other two infants had more typical clinical courses with the onset of respiratory symptoms immediately after birth. ABCA3 mutations were identified on both alleles from these two infants, and electron microscopy of alveolar type 2 cells demonstrated abnormal lamellar body formation characteristic of this disorder. Conclusion: ABCA3 mutations were the basis for lung disease in all three patients. Children with lung disease due to ABCA3 deficiency may not have symptoms at birth. The finding of five novel mutations indicates allelic heterogeneity for ABCA3 mutations within the Norwegian population.