title: An intronic ABCA3 mutation that is responsible for respiratory disease.
abstract: BACKGROUND
  Member A3 of the ATP-binding cassette family of transporters (ABCA3) is essential for surfactant metabolism. Nonsense, missense, frameshift, and splice-site mutations in the ABCA3 gene (ABCA3) have been reported as causes of neonatal respiratory failure (NRF) and interstitial lung disease. We tested the hypothesis that mutations in noncoding regions of ABCA3 may cause lung disease.
  
  
  METHODS
  ABCA3-specific cDNA was generated and sequenced from frozen lung tissue from a child with fatal lung disease with only one identified ABCA3 mutation. ABCA3 was sequenced from genomic DNA prepared from blood samples obtained from the proband, parents, and other children with NRF.
  
  
  RESULTS
  ABCA3 cDNA from the proband contained sequences derived from intron 25 that would be predicted to alter the structure and function of the ABCA3 protein. Genomic DNA sequencing revealed a heterozygous C>T transition in intron 25 trans to the known mutation, creating a new donor splice site. Seven additional infants with an ABCA3-deficient phenotype and inconclusive genetic findings had this same variant, which was not found in 2,132 control chromosomes.
  
  
  CONCLUSIONS
  These findings support that this variant is a disease-causing mutation that may account for additional cases of ABCA3 deficiency with negative genetic studies.
authors.affiliation: Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Agrawal
authors.forename: Aaron
authors.initials: A
authors.lastname: Hamvas
authors.forename: F Sessions
authors.initials: FS
authors.lastname: Cole
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Wambach
authors.forename: Daniel
authors.initials: D
authors.lastname: Wegner
authors.forename: Carl
authors.initials: C
authors.lastname: Coghill
authors.forename: Keith
authors.initials: K
authors.lastname: Harrison
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Nogee
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000483:Alleles; D004247:DNA / Q000235:genetics; D017809:Fatal Outcome; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D012131:Respiratory Insufficiency / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: C441524:ABCA3 protein, human; D018528:ATP-Binding Cassette Transporters; D004247:DNA