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  • CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR

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Original article
CFTR transcription defects in pancreatic sufficient cystic fibrosis patients with only one mutation in the coding region of CFTR
  1. Molly B Sheridan1,2,
  2. Timothy W Hefferon3,
  3. Nulang Wang1,
  4. Christian Merlo4,
  5. Carlos Milla5,6,
  6. Drucy Borowitz7,
  7. Eric D Green3,8,
  8. Peter J Mogayzel Jr9,
  9. Garry R Cutting1
  1. 1McKusick–Nathans Institute of Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
  2. 2Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  3. 3National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  4. 4Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
  5. 5Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota, USA
  6. 6Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, USA
  7. 7Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York, USA
  8. 8NIH Intramural Sequencing Center, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA
  9. 9Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins Medical Institutions, Baltimore, Maryland, USA
  1. Correspondence to Dr Garry R Cutting, BRB 559; 733 North Broadway, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA; gcutting{at}jhmi.edu

Abstract

Background Patients with cystic fibrosis (CF) manifest a multisystem disease due to deleterious mutations in each gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). However, the role of dysfunctional CFTR is uncertain in individuals with mild forms of CF (ie, pancreatic sufficiency) and mutation in only one CFTR gene.

Methods Eleven pancreatic sufficient (PS) CF patients with only one CFTR mutation identified after mutation screening (three patients), mutation scanning (four patients) or DNA sequencing (four patients) were studied. Bi-directional sequencing of the coding region of CFTR was performed in patients who had mutation screening or scanning. If a second CFTR mutation was not identified, CFTR mRNA transcripts from nasal epithelial cells were analysed to determine if any PS-CF patients harboured a second CFTR mutation that altered RNA expression.

Results Sequencing of the coding regions of CFTR identified a second deleterious mutation in five of the seven patients who previously had mutation screening or mutation scanning. Five of the remaining six patients with only one deleterious mutation identified in the coding region of one CFTR gene had a pathologic reduction in the amount of RNA transcribed from their other CFTR gene (8.4–16% of wild type).

Conclusions These results show that sequencing of the coding region of CFTR followed by analysis of CFTR transcription could be a useful diagnostic approach to confirm that patients with mild forms of CF harbour deleterious alterations in both CFTR genes.

  • Cystic fibrosis
  • DNA sequencing
  • mRNA expression
  • diagnosis
  • diagnostics tests
  • genetic screening/counselling

https://doi.org/10.1136/jmg.2010.083287

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    Footnotes

    • Funding This work was supported by grants from the National Institutes of Health (NIDDK R37 99003 to GRC) and the Cystic Fibrosis Foundation.

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval All studies were approved by the Johns Hopkins University and University of Minnesota IRBs and written consent was obtained from all patients or their parents.

    • Provenance and peer review Not commissioned; externally peer reviewed.