Article

An intronic ABCA3 mutation responsible for respiratory disease

Department of Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Pediatric Research (Impact Factor: 2.31). 02/2012; 71(6):633-7. DOI: 10.1038/pr.2012.21
Source: PubMed

ABSTRACT

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.
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.
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.
These findings support that this variant is a disease-causing mutation that may account for additional cases of ABCA3 deficiency with negative genetic studies.

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Available from: Daniel J Wegner, Aug 11, 2015
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    • "In particular, current analytical methods cannot detect all mutations that cause surfactant disorders (i.e., large rearrangements identified by conventional Sanger sequencing). Moreover, functionally significant variants may be present in untranslated regions that are not examined through routine clinical sequencing or in other genes not yet associated to the disease[6]. In our case, standard sequencing methodologies did not detect mutations in SFTPB, ABCA3, and NKX2 genes, but only identified the SFTPC IVS4 + 39C > T rare variant located 21 nucleotides downstream to the termination codon, in the 3′UTR. "
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    • "In the APC gene, abnormal splicing by a 3' splice site mutation in intron 3 causes exon 4 skipping due to a frameshift in hepatoblastoma [19]. A mutation in intron 25 of the ABCA3 gene creates novel 5' splice sites [20]. The spliceosome is known to recognize cryptic splice sites instead of typical splice sites. "
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