ABCMdb

ABCC7 p.Leu571Asp

ClinVar:	c.1712T>C , p.Leu571Ser ? , not provided
CF databases:	c.1712T>C , p.Leu571Ser (CFTR1) ? , This mutation was detected by SSCP analysis of exon 12 followed by direct sequencing. L571S was detected to a single CF allele out of 119 non-[delta] CF chromosomes screened. It has not been found on any of the 65 normal alleles screened. The mutation was found in the paternal CF allele in a patient of Turkish origin. The amternal chromosomes carries the R347P mutation. The patient has severe cystic fibrosis with pancreatic insufficiency and pulmonary involovement.
Predicted by SNAP2:	A: D (95%), C: D (91%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (85%), K: D (95%), M: D (91%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (59%), T: D (95%), V: D (91%), W: D (95%), Y: D (95%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D,

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Publications
[hide] Cooperative assembly and misfolding of CFTR domain... Mol Biol Cell. 2009 Apr;20(7):1903-15. Epub 2009 Jan 28. Du K, Lukacs GL
Cooperative assembly and misfolding of CFTR domains in vivo.
Mol Biol Cell. 2009 Apr;20(7):1903-15. Epub 2009 Jan 28., [PMID:19176754]

Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) architecture consists of two membrane spanning domains (MSD1 and -2), two nucleotide binding domains (NBD1 and -2), and a regulatory (R) domain. Several point mutations lead to the channel misprocessing, with limited structural perturbation of the mutant domain. To gain more insight into the basis of CFTR folding defect, the contribution of domain-wise and cooperative domain folding was assessed by determining 1) the minimal domain combination that is recognized as native and can efficiently escape the endoplasmic reticulum (ER) retention and 2) the impact of mutation on the conformational coupling among domains. One-, two-, three-, and most of the four-domain assemblies were retained at the ER. Solubilization mutations, however, rescued the NBD1 processing defect conceivably by thermodynamic stabilization. The smallest folding unit that traversed the secretory pathway was composed of MSD1-NBD1-R-MSD2 as a linear or split polypeptide. Cystic fibrosis-causing missense mutations in the MSD1, NBD1, MSD2, and NBD2 caused conformational defect in multiple domains. We propose that cooperative posttranslational folding is required for domain stabilization and provides a plausible explanation for the global misfolding caused by point mutations dispersed along the full-length CFTR.

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No. Sentence Comment
53 After the insertion of the 2D (I601D/L602D) mutations, the L570D/L571D mutations were introduced into the 2D CFTR-3HA by PCR mutagenesis. Login to comment
152 Abbreviations: N1⌬F, NBD1⌬F508; N14D, NBD1(L570D/L571D/ I601D/L602D); N2K, NBD2(N1303K); N1R, NBD1-R; N1⌬R, ⌬F508-NBD1-R (also see Supplemental Table S1). Login to comment
170 Similar results were obtained upon replacing four hydrophobic core residues with aspartic acids (4D: L570D/L571D/I601D/ L602D) to disrupt the NBD1 folding (Figure 3, a and b, and Supplemental Figure S2b). Login to comment