An intronic ABCA3 mutation responsible for respiratory disease

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 non-coding 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 an 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 on 2132 control chromosomes. CONCLUSION: These findings support that this variant is a disease-causing mutation, which may account for additional cases of ABCA3 deficiency with negative genetic studies.