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Cell Physiol Biochem. 2009;24(5-6):335-46. doi: 10.1159/000257426. Epub 2009 Nov 4.

Deletion of CFTR translation start site reveals functional isoforms of the protein in CF patients.

Author information

1
University of Lisboa, Centre for Biodiversity, Functional and Integrative Genomics, Lisboa, Portugal.

Abstract

BACKGROUND/AIMS:

Mutations in the CFTR gene cause Cystic Fibrosis (CF) the most common life-threatening autosomal recessive disease affecting Caucasians. We identified a CFTR mutation (c.120del23) abolishing the normal translation initiation codon, which occurs in two Portuguese CF patients. This study aims at functionally characterizing the effect of this novel mutation.

METHODS:

RNA and protein techniques were applied to both native tissues from CF patients and recombinant cells expressing CFTR constructs to determine whether c.120del23 allows CFTR protein production through usage of alternative internal codons, and to characterize the putative truncated CFTR form(s).

RESULTS:

Our data show that two shorter forms of CFTR protein are produced when the initiation translation codon is deleted indicating usage of internal initiation codons. The N-truncated CFTR generated by this mutation has decreased stability, very low processing efficiency, and drastically reduced function. Analysis of mutants of four methionine codons downstream to M1 (M82, M150, M152, M156) revealed that each of the codons M150/M152/M156 (exon 4) can mediate CFTR alternative translation.

CONCLUSIONS:

The CFTR N-terminus has an important role in avoiding CFTR turnover and in rendering effective its plasma membrane traffic. These data correlate well with the severe clinical phenotype of CF patients bearing the c.120del23 mutation.

PMID:
19910674
PMCID:
PMC2793277
DOI:
10.1159/000257426
[Indexed for MEDLINE]
Free PMC Article
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