Fatal familial lung disease caused by ABCA3 deficiency without identified ABCA3 mutations

J Pediatr. 2010 Jul;157(1):62-8. doi: 10.1016/j.jpeds.2010.01.010. Epub 2010 Mar 20.


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.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism*
  • Autopsy
  • Child
  • Chromosome Segregation
  • Exons
  • Family
  • Fatal Outcome
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Lung / metabolism*
  • Lung / ultrastructure
  • Lung Diseases / complications
  • Lung Diseases / genetics*
  • Lung Diseases / metabolism
  • Lung Diseases / pathology
  • Male
  • Microscopy, Electron
  • Mutation
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Respiratory Insufficiency / etiology
  • Siblings


  • ABCA3 protein, human
  • ATP-Binding Cassette Transporters