Original Article
Fatal Familial Lung Disease Caused by ABCA3 Deficiency without Identified ABCA3 Mutations

This work was presented at the 2009 International Meeting of the American Thoracic Society in San Diego, California (May 15-20, 2009).
https://doi.org/10.1016/j.jpeds.2010.01.010Get rights and content

Objective

To test the hypothesis that some functionally significant variants in the gene encoding member A3 of the ATP Binding Cassette family (ABCA3) are not detected using exon-based sequencing approaches.

Study design

The first of 2 female siblings who died from neonatal respiratory failure was examined for mutations with sequence analysis of all ABCA3 exons and known regulatory elements within the 5' untranslated region. Lung tissue from both siblings was immunostained for ABCA3 and examined with electron microscopy. Segregation of ABCA3 alleles was determined with analysis of polymorphisms in the parents and all children.

Results

No mutations were identified with ABCA3 sequence analysis in the first affected infant. Affected siblings were concordant for their ABCA3 alleles, but discordant from those of their unaffected siblings. ABCA3 protein was not detectable with immunostaining in lung tissue samples from both affected infants. Electron microscopy demonstrated small, dense lamellar bodies, characteristically seen with ABCA3 mutations.

Conclusions

The segregation of ABCA3 alleles, absence of ABCA3 immunostaining, lung pathology, and ultrastructural findings support genetic ABCA3 deficiency as the cause of lung disease in these 2 infants, despite the lack of an identified genetic variant.

Section snippets

Case Histories

Two female siblings died >10 years apart from severe neonatal respiratory failure with similar presentations and courses. Both parents are of Asian descent, and no history of consanguinity was reported. Figure 1 illustrates the 2-generation pedigree for this family. The first affected child (II.1) was born at term via vaginal delivery with a birth weight of 2850 g to a healthy mother. No meconium was noted at birth. Respiratory distress and hypoxemia were noted later, on day-of-life (DOL) 1.

Methods

All members of the family described here were enrolled in an institutional review board-approved protocol focused on identifying genetic causes of lung disease in children. The parents provided informed, written consent for their own participation and that of their children.

Results

With H&E staining and light microscopy of lung tissue samples from both affected infants, proteinaceous material filling the alveolar airspaces was shown. Absent staining for ABCA3 protein was demonstrated with immunohistochemical staining. ABCA3 was easily detected in a non-diseased, human, pediatric, control lung at 1:500 without the use of antigen retrieval (data not shown). Normal staining was seen for proSP-B (not shown), proSP-C, and mature SP-B (Figure 3). Examination with EM of alveolar

Discussion

The clinical picture with the lung histopathology, immunohistochemistry, and EM findings suggest that surfactant dysfunction was the cause of fatal lung disease in these 2 infants from the same family. However, no mutations in the 3 genes known to cause surfactant dysfunction (ABCA3, SFTPB, or SFTPC) were identified. The immunostaining patterns and finding that the affected infants were discordant for their SFTPB alleles further exclude SP-B deficiency as the basis for their lung disease. The

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    Supported by The Hartwell Foundation and Arricale Family Foundation (W.G.), The Eudowood Foundation and National Institutes of Health HL54703 (L.N.), and National Institutes of Health HL085610 (J.W., S.W.). None of the funding entities were involved in the study design or the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit for publication. The authors declare no conflicts of interest.

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