ABCC7 p.Ile1383*
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[hide] C-terminal truncations destabilize the cystic fibr... J Biol Chem. 1999 Jul 30;274(31):21873-7. Haardt M, Benharouga M, Lechardeur D, Kartner N, Lukacs GL
C-terminal truncations destabilize the cystic fibrosis transmembrane conductance regulator without impairing its biogenesis. A novel class of mutation.
J Biol Chem. 1999 Jul 30;274(31):21873-7., 1999-07-30 [PMID:10419506]
Abstract [show]
Defective cAMP-stimulated chloride conductance of the plasma membrane of epithelial cell is the hallmark of cystic fibrosis (CF) and results from mutations in the cystic fibrosis transmembrane conductance regulator, CFTR. In the majority of CF patients, mutations in the CFTR lead to its misfolding and premature degradation at the endoplasmic reticulum (ER). Other mutations impair the cAMP-dependent activation or the ion conductance of CFTR chloride channel. In the present work we identify a novel mechanism leading to reduced expression of CFTR at the cell surface, caused by C-terminal truncations. The phenotype of C-terminally truncated CFTR, representing naturally occurring premature termination and frameshift mutations, were examined in transient and stable heterologous expression systems. Whereas the biosynthesis, processing, and macroscopic chloride channel function of truncated CFTRs are essentially normal, the degradation rate of the mature, complex-glycosylated form is 5- to 6-fold faster than the wild type CFTR. These experiments suggest that the C terminus has a central role in maintaining the metabolic stability of the complex-glycosylated CFTR following its exit from the ER and provide a plausible explanation for the severe phenotype of CF patients harboring C-terminal truncations.
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No. Sentence Comment
39 T70 CFTR (corresponding to Q1411X) and T98 CFTR (corresponding to I1383X) were engineered by polymerase chain reaction mutagenesis (sense primer, 5Ј-TGC AAG AAT GGC CAA CTC TCG CC-3Ј; antisense primers, 5Ј-A AAG GGC CCG CTA GCA TTC CAG CAT TGC TTC-3Ј and 5Ј-AAA GGG CCC CTA TTG GTA TGT TAC TGG ATC C-3Ј) by introducing a TAG stop codon flanked with an ApaI restriction site 3Ј to nucleotides 4362 and 4278, respectively.
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ABCC7 p.Ile1383* 10419506:39:66
status: NEW