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Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations

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Abstract

The alternatively spliced exon 9 of the cystic fibrosis transmembrane conductance regulator (CFTR) gene codes for the initial part of the amino-terminal nucleotide-binding fold of CFTR. A unique feature of the acceptor splice site preceding this exon is a variable length polymorphism within the polypyrimidine tract influencing the extent of exon 9 skipping in CFTR mRNA. We investigated this repeat for its relationship to CFTR mutations and intragenic markers on 200 chromosomes from German patients with cystic fibrosis (CF). Four frequent length variations were strongly associated with the four predominant haplotypes previously defined by intragenic marker dimorphisms. One of these alleles displayed absolute linkage disequilibrium to the major CF mutation ΔF508. Other frequent CFTR mutations were linked to one particular splice site haplotype indicating that differential exon 9 skipping contributes little to the clinical heterogeneity among CF patients with an identical mutation. We also identified a novel missense mutation (V456F) and a novel nonsense mutation (Q414X) within the coding region of exon 9. The missense mutation V456F adjacent to Walker motif A was present in a pancreas-sufficient CF patient. In contrast, the pancreas-insufficient Q414X/ΔF508 compound heterozygote suffered from a severe form of the disease, indicating that alternative splicing of exon 9 does not overcome the deleterious effect of a stop codon within this exon.

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Authors and Affiliations

  1. Klinische Forschergruppe “Molekulare Pathologie der Mukoviszidose”, Zentrum Biochemie OE 4350 und Zentrum Kinderheilkunde OE 6711, Medizinische Hochschule Hannover, D-30625, Hannover, Germany

    Thilo Dörk, Rainer Fislage, Thomas Neumann, Brigitte Wulf & Burkhard Tümmler

  2. Abteilung Biophysikalische Chemie, OE 4350, Medizinische Hochschule Hannover, Konstanty-Gut-schow-Strasse 8, D-30625, Hannover, Germany

    Thilo Dörk

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  1. Thilo Dörk
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  4. Brigitte Wulf
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Dörk, T., Fislage, R., Neumann, T. et al. Exon 9 of the CFTR gene: splice site haplotypes and cystic fibrosis mutations. Hum Genet 93, 67–73 (1994). https://doi.org/10.1007/BF00218916

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  • DOI: https://doi.org/10.1007/BF00218916

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