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


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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    ABSTRACT: Background: Surfactant metabolism disorders may result in diffuse lung disease in children. Case presentation: We report a 3-years-old boy with dry cough, progressive hypoxemia, dyspnea and bilateral ground glass opacities at chest high-resolution computed tomography (HRCT) who had no variants in genes encoding surfactant proteins or transcription factors. Lung histology strongly suggested an abnormality of surfactant protein. A 7-month course of pulse intravenous high-dose methylprednisolone plus oral hydroxychloroquine and azithromycin led to gradual weaning from oxygen and oral steroids, and to improvement of cough and dyspnea. Over the follow-up period, hydroxychloroquine and azithromycin were not withdrawn as cough and dyspnea re-appeared at each attempt and disappeared at re-start. At 6 years of age chest HRCT still appeared unchanged, but clinical symptoms or signs were absent. Conclusions: In children suspected of inborn errors of pulmonary surfactant metabolism who do not have a recognized genetic mutation, lung biopsy with consistent histology may help physicians to address the definitive diagnosis.
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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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    ABSTRACT: Most genes are processed by alternative splicing for gene expression, resulting in the complexity of the transcriptome in eukaryotes. It allows a limited number of genes to encode various proteins with intricate functions. Alternative splicing is regulated by genetic mutations in cis-regulatory factors and epigenetic events. Furthermore, splicing events occur differently according to cell type, developmental stage, and various diseases, including cancer. Genome instability and flexible proteomes by alternative splicing could affect cancer cells to grow and survive, leading to metastasis. Cancer cells that are transformed by aberrant and uncontrolled mechanisms could produce alternative splicing to maintain and spread them continuously. Splicing variants in various cancers represent crucial roles for tumorigenesis. Taken together, the identification of alternative spliced variants as biomarkers to distinguish between normal and cancer cells could cast light on tumorigenesis.
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