Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene

Osborne, Lucy R.; Santis, George; Schwarz, Martin; Klinger, Katherine W.; Dörk, Thilo; McIntosh, Iain; Schwartz, Marianne; Nunes, Virginia; Maçek, Milan; Reiss, Jochen; Highsmith, W. Edward; McMahon, R.; Novelli, Giuseppe; Malik, N; Bürger, Joachim; Anvret, Maria; Wallace, Andrew; Williams, Cathy V.; Mathew, Christopher G.; Rozen, Rima; Graham, Colin A.; Gasparini, Paolo; Bal, Jerzy; Jj, Cassiman; Balassopoulou, Angeliki; Davidow, Lance S.; Raskin, Salmo; Kalaydjieva, Luba; Kerem, Batsheva; Richards, Sue; Simon‐Bouy, Brigitte; Super, Maurice; Wulbrand, Ulrich; Keston, M.; Estivill, Xavier; Vávrová, V.; Friedman, Kenneth J.; Barton, D. E.; Dallapiccola, Bruno; Stuhrmann, Manfred; Beards, Frances; Hill, Alison; Pignatti, Pf.; Cuppens, Harry; Angelicheva, Dora; Tümmler, Burkhard; Brock, D. J. H.; Casals, Teresa; Schmidtke, Jörg; Magee, Alex; Bonizzato, Alberto; Boeck, Christiane De; Kuffardjieva, A.; Hodson, Margaret E.; Knight, Richard

doi:10.1007/bf00221957

Cited by 64 publications

(51 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The opposite was seen in Chilean ΔF508 chromosomes in our study, with over 90% of them present on XK haplotype B. This finding evidences marked linkage disequilibrium between them, as it has been shown in other populations Highsmith et al, 1990;Dork et al, 1992;Morral, Bertranpetit et al, 1994). A European origin for the ΔF508 mutation observed in Chilean patients is therefore suggested.…”

Section: Discussionsupporting

confidence: 65%

“…Subsequent research confirmed that this observation reflected the presence of strong linkage disequilibrium, that is, non-random association of alleles at two or more loci on a chromosome, between the most common European mutation, deltaF508 (ΔF508), and haplotype B. This finding supported the theory of a single origin of this mutation (Dork et al, 1992;Highsmith et al, 1990;Morral, Bertranpetit et al, 1994). Several other common mutations are predominantly present on one haplotype.…”

Section: Introductionmentioning

confidence: 71%

“…For example, G542X, a mutation of high prevalence in Mediterranean countries and having the third highest frequency in Chilean patients, is also associated with XK haplotype B (Loirat et al, 1997). Mutations N1303K, G551D, W1282X, 394delTT and 3120+1 G>A also appear to have a single origin each (Cashman et al, 1995;Osborne et al, 1992;Dork et al, 2000;Kerem et al, 1995;Shoshani et al, 1992;Dork et al, 1998). In contrast, other mutations have been found on several haplotypes, suggesting multiple origins for them (Morral, Llevadot et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

XV-2c and KM: 19 haplotype analysis in Chilean patients with cystic fibrosis and unknown CFTR gene mutations

2007

View full text Add to dashboard Cite

Cystic fibrosis (CF) is caused by mutations in the CFTR gene. More than 1600 mutations have been described, with frequencies that differ worldwide according to the ethnic origin of patients. A small group of mutations are recurrent on several populations. It has been shown that they each tend occur on specific chromosome 7 haplotypes, supporting the notion of a single origin for them. Less than 50% of mutations in Chilean patients have been identified to date. To indirectly assess the possible presence of a predominant founder mutation in the remaining unknown alleles, we evaluated 2 polymorphic markers, XV-2c and KM.19, tightly linked to the CFTR locus. The study was done in Chilean CF patients with unknown or deltaF508 (ΔF508) CFTR mutations and their haplotypes were compared to affected family-based controls. ΔF508 showed marked linkage disequilibrium with XV-2c/KM.19 haplotype B, with 90% of alleles on that haplotype. There was no difference in haplotype distribution between unknown mutations and normal controls. These results support a European origin for ΔF508 alleles in Chilean patients, and make unlikely the presence of a predominant founder mutation in the so-far unknown alleles.

show abstract

Section: Discussionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 71%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

XV-2c and KM: 19 haplotype analysis in Chilean patients with cystic fibrosis and unknown CFTR gene mutations

2007

View full text Add to dashboard Cite

show abstract

“…The G551D ( p.Gly551Asp) arose in the Celtic population more recently and is still prevalent in Ireland and Brittany (Scotet et al 2003b), and the N1303K ( p.Asn1303Lys) is also rather frequent in populations from the center of Europe (Osborne et al 1992). Besides these rather common mutations, which are largely distributed in the Caucasian population, there are also some founder effects of mutated alleles observed as, for example, in the Reunion Island, where the Y122X ( p.Tyr122X) mutation displays a frequency of 24% (Duguépéroux et al 2004), or the 394delTT ( p.Leu88IlefsX22) referred to as a Nordic mutation found in countries bordering the Baltic sea (Schwartz et al 1994).…”

Section: Distribution Worldwidementioning

confidence: 99%

Assessing the Disease-Liability of Mutations in CFTR

Férec

Cutting

2012

Cold Spring Harbor Perspectives in Medicine

View full text Add to dashboard Cite

“…We next compared the trypsin proteolysis patterns of misfolded CFTR from CAS-treated cells with the patterns observed from CFTR⌬F508, CFTRG91R, and CFTR N1303K, which contain mutations localized to the NBD1, MSD1, and NBD2 domains, respectively (Osborne et al, 1992;Xiong et al, 1997). Similar to what we observed upon CAS treatment, the sizes of the N-terminal fragments produced by trypsin digestion of the CFTR⌬F508 and CFTRG91R mutants did not change significantly, but a significant increase in the sensitivity of the 40-kDa fragment to digestion by 25 g/ml trypsin was observed ( Figure 6B).…”

Section: Global Misfolding Of Cftr As Assayed By Limited Proteolysismentioning

confidence: 99%

Assembly and Misassembly of Cystic Fibrosis Transmembrane Conductance Regulator: Folding Defects Caused by Deletion of F508 Occur Before and After the Calnexin-dependent Association of Membrane Spanning Domain (MSD) 1 and MSD2

Rosser

Grove

Chen

et al. 2008

MBoC

115

View full text Add to dashboard Cite

Cystic fibrosis transmembrane conductance regulator (CFTR) is a polytopic membrane protein that functions as a Cl ؊ channel and consists of two membrane spanning domains (MSDs), two cytosolic nucleotide binding domains (NBDs), and a cytosolic regulatory domain. Cytosolic 70-kDa heat shock protein (Hsp70), and endoplasmic reticulum-localized calnexin are chaperones that facilitate CFTR biogenesis. Hsp70 functions in both the cotranslational folding and posttranslational degradation of CFTR. Yet, the mechanism for calnexin action in folding and quality control of CFTR is not clear. Investigation of this question revealed that calnexin is not essential for CFTR or CFTR⌬F508 degradation. We identified a dependence on calnexin for proper assembly of CFTR's membrane spanning domains. Interestingly, efficient folding of NBD2 was also found to be dependent upon calnexin binding to CFTR. Furthermore, we identified folding defects caused by deletion of F508 that occurred before and after the calnexin-dependent association of MSD1 and MSD2. Early folding defects are evident upon translation of the NBD1 and R-domain and are sensed by the RMA-1 ubiquitin ligase complex. INTRODUCTIONCystic fibrosis transmembrane conductance regulator (CFTR) is a membrane glycoprotein that is localized to the apical surface of epithelial cells that line ducts of glands and airways. CFTR functions as an ATP-gated Cl Ϫ channel that is critical for proper hydration of the mucosal layer that lines lung airways (Welsh and Smith, 1993). Individuals who inherit two mutant forms of CFTR have exceedingly viscous mucous and, due to chronic lung infections, develop cystic fibrosis and often die from lung failure. CFTR is a member of the ATP-binding cassette (ABC) transporter superfamily (Hyde et al., 1990) and is a 1480-amino acid protein that contains two membrane spanning domains (MSDs), MSD1 and MSD2; two cytosolic nucleotide binding domains (NBDs), NBD1 and NBD2; and a regulatory (R) domain (Riordan et al., 1989). The proper folding and assembly of CFTR subdomains in the endoplasmic reticulum (ER) is required for CFTR to engage the COPII machinery and be packaged into vesicles for transport to the plasma membrane (Kopito, 1999;Wang et al., 2004). The folding pathway of this complex polytopic membrane protein has been a topic of great interest, because misfolding results in premature recognition of CFTR by the ER quality control system (ERQC) and degradation by the ubiquitin proteasome system (Skach, 2000). In fact, the most common disease-causing mutation of CFTR, ⌬F508CFTR, results in almost complete degradation of the protein by the ERQC system, which gives rise to a loss of function phenotype and lung disease (Ward and Kopito, 1994).The assembly of CFTR into an ion channel is complicated because it requires the coordinated folding and assembly of its membrane and cytoplasmic domains into a functional unit (Du et al., 2005;Riordan, 2005;Cui et al., 2007). CFTR is a modular protein, and its domains can collapse to a protease-resistant conformation i...

show abstract

Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene

Cited by 64 publications

References 22 publications

XV-2c and KM: 19 haplotype analysis in Chilean patients with cystic fibrosis and unknown CFTR gene mutations

XV-2c and KM: 19 haplotype analysis in Chilean patients with cystic fibrosis and unknown CFTR gene mutations

Assessing the Disease-Liability of Mutations in CFTR

Assembly and Misassembly of Cystic Fibrosis Transmembrane Conductance Regulator: Folding Defects Caused by Deletion of F508 Occur Before and After the Calnexin-dependent Association of Membrane Spanning Domain (MSD) 1 and MSD2

Contact Info

Product

Resources

About