ABCC7 p.Arg1070Ala
| ClinVar: |
c.3209G>C
,
p.Arg1070Pro
?
, not provided
c.3209G>A , p.Arg1070Gln D , Pathogenic/Likely pathogenic, not provided c.3208C>T , p.Arg1070Trp ? , not provided |
| CF databases: |
c.3209G>A
,
p.Arg1070Gln
?
, Varying clinical consequence ; CFTR1: This missense mutation was found in one Italian CF patient. The nucleotide change was G->A at position 3341 of exon 17b leading to R 1070 Q amino acid change. It was found once using DGGE screening and DNA sequencing among 50 Italian CF chromosomes.
c.3208C>T , p.Arg1070Trp ? , Varying clinical consequence ; CFTR1: Teh R1070W mutation was detected on 1 US Caucasian chromosome out of 48 screened. ASO analysis of 100 non-CF Caucasian chromosomes did not reveal this mutation on any of the tested chromosomes. The 15 months old CBAVD patient carries the [delta]F508 mutation on the other allele. c.3209G>C , p.Arg1070Pro (CFTR1) ? , This 26 year old individual of Polish extraction with mild CF presented at age 11 with nasal polyps. He had noted salt crystals on his skin in warm weather, but did not have a chronic cough or gastrointestinal complaints. Pulmonary function tests and chest X-ray were normal. Sweat chloride was 121 mMol/L (repeat value was 104 mMol/L). No formal pancreatic function testing was performed. Most recent pulmonary function tests show mild obstructive airways disease. This individual is a compound heterozygote for the 2143delT CF mutations. R1070P was originally detected by SSC/HA and can be detected by virtue of the creation of a Sau96I or destruction of a BslI site. Mutation R1070P was also reported by Dörk T, Hughes D, Dworniczak B, Stuhrmann M (Jan 30, (NL#69)) in a CF patient from Northern Ireland who carried R1070P on his paternal and [delta]F508 on his maternal allele. |
| Predicted by SNAP2: | A: N (66%), C: D (53%), D: D (85%), E: D (75%), F: D (91%), G: D (71%), H: N (57%), I: D (63%), K: N (66%), L: D (63%), M: D (66%), N: D (63%), P: D (71%), Q: D (75%), S: D (53%), T: D (63%), V: D (63%), W: D (95%), Y: D (71%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: D, G: D, H: N, I: D, K: N, L: D, M: N, N: N, P: D, Q: N, S: N, T: N, V: D, W: D, Y: N, |
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[hide] The V510D suppressor mutation stabilizes DeltaF508... Biochemistry. 2010 Aug 3;49(30):6352-7. Loo TW, Bartlett MC, Clarke DM
The V510D suppressor mutation stabilizes DeltaF508-CFTR at the cell surface.
Biochemistry. 2010 Aug 3;49(30):6352-7., 2010-08-03 [PMID:20590134]
Abstract [show]
Deletion of Phe508 (DeltaF508) in the first nucleotide-binding domain (NBD1) of CFTR causes cystic fibrosis. The mutation severely reduces the stability and folding of the protein by disrupting interactions between NBD1 and the second transmembrane domain (TMD2). We found that replacement of Val510 with acidic residues (but not neutral or positive residues) promoted maturation of DeltaF508-CFTR with V510D more efficiently than V510E. Promotion of DeltaF508-CFTR maturation did not require NBD2 as introduction of V510D into a DeltaNBD2/DeltaF508-CFTR mutant restored maturation to levels similar to that of full-length protein. The V510D mutation increased the half-life of mature DeltaF508-CFTR at the cell surface by about 5-fold to resemble the half-life of wild-type CFTR. It was also observed that introduction of the V510R/R1070D mutations into DeltaF508-CFTR also promoted maturation whereas the V510D/R1070A mutations did not. We propose that the V510D mutation in NBD1 promotes maturation and stabilizes DeltaF508-CFTR at the cell surface through formation of a salt bridge with Arg1070 in TMD2.
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No. Sentence Comment
5 It was also observed that introduction of the V510R/ R1070D mutations into ΔF508-CFTR also promoted maturation whereas the V510D/R1070A mutations did not.
X
ABCC7 p.Arg1070Ala 20590134:5:135
status: NEW80 We tested the contribution of Arg1070 by introducing the R1070A change intoΔF508/V510D.
X
ABCC7 p.Arg1070Ala 20590134:80:57
status: NEW81 Asshownin Figure 4A, mature protein was not detectable in mutant ΔF508/ V510D/R1070A.
X
ABCC7 p.Arg1070Ala 20590134:81:84
status: NEW82 To test if the R1070A mutation alone affected maturation of ΔF508, mutants ΔF508/R1070A and ΔF508 were expressed at 30 °C.
X
ABCC7 p.Arg1070Ala 20590134:82:15
status: NEWX
ABCC7 p.Arg1070Ala 20590134:82:93
status: NEW84 Therefore, it was unlikely that the R1070A mutant caused further misfolding of ΔF508-CFTR.
X
ABCC7 p.Arg1070Ala 20590134:84:36
status: NEW85 This is consistent with the observation that introduction of the R1070A mutation into wild-type CFTR also did not affect its maturation (data not shown).
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ABCC7 p.Arg1070Ala 20590134:85:65
status: NEW[hide] Cystic fibrosis transmembrane conductance regulato... Cold Spring Harb Perspect Med. 2013 Feb 1;3(2):a009514. doi: 10.1101/cshperspect.a009514. Hunt JF, Wang C, Ford RC
Cystic fibrosis transmembrane conductance regulator (ABCC7) structure.
Cold Spring Harb Perspect Med. 2013 Feb 1;3(2):a009514. doi: 10.1101/cshperspect.a009514., [PMID:23378596]
Abstract [show]
Structural studies of the cystic fibrosis transmembrane conductance regulator (CFTR) are reviewed. Like many membrane proteins, full-length CFTR has proven to be difficult to express and purify, hence much of the structural data available is for the more tractable, independently expressed soluble domains. Therefore, this chapter covers structural data for individual CFTR domains in addition to the sparser data available for the full-length protein. To set the context for these studies, we will start by reviewing structural information on model proteins from the ATP-binding cassette (ABC) transporter superfamily, to which CFTR belongs.
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No. Sentence Comment
256 Moreover, restoration of the trafficking of F508del-NBD1 by the V510D suppressor mutation, which introduces a negative charge into a generally apolar region J.F. Hunt et al. 16 Cite this article as Cold Spring Harb Perspect Med 2012;3:a009514 www.perspectivesinmedicine.org by Cold Spring Harbor Laboratory Press at SEMMELWEIS UNIV OF MEDICINE on December 5, of the interdomain interface (Fig. 4C,D), is strongly attenuated by introducing the R1070A or R1070D mutations that remove a complementary positive charge from the proximal surface of the TMD (Loo et al. 2010).
X
ABCC7 p.Arg1070Ala 23378596:256:444
status: NEW[hide] VX-809 corrects folding defects in cystic fibrosis... Mol Biol Cell. 2013 Oct;24(19):3016-24. doi: 10.1091/mbc.E13-05-0240. Epub 2013 Aug 7. Ren HY, Grove DE, De La Rosa O, Houck SA, Sopha P, Van Goor F, Hoffman BJ, Cyr DM
VX-809 corrects folding defects in cystic fibrosis transmembrane conductance regulator protein through action on membrane-spanning domain 1.
Mol Biol Cell. 2013 Oct;24(19):3016-24. doi: 10.1091/mbc.E13-05-0240. Epub 2013 Aug 7., [PMID:23924900]
Abstract [show]
Cystic fibrosis (CF) is a fatal genetic disorder associated with defective hydration of lung airways due to the loss of chloride transport through the CF transmembrane conductance regulator protein (CFTR). CFTR contains two membrane-spanning domains (MSDs), two nucleotide-binding domains (NBDs), and a regulatory domain, and its channel assembly requires multiple interdomain contacts. The most common CF-causing mutation, F508del, occurs in NBD1 and results in misfolding and premature degradation of F508del-CFTR. VX-809 is an investigational CFTR corrector that partially restores CFTR function in people who are homozygous for F508del-CFTR. To identify the folding defect(s) in F508del-CFTR that must be repaired to treat CF, we explored the mechanism of VX-809 action. VX-809 stabilized an N-terminal domain in CFTR that contains only MSD1 and efficaciously restored function to CFTR forms that have missense mutations in MSD1. The action of VX-809 on MSD1 appears to suppress folding defects in F508del-CFTR by enhancing interactions among the NBD1, MSD1, and MSD2 domains. The ability of VX-809 to correct F508del-CFTR is enhanced when combined with mutations that improve F508del-NBD1 interaction with MSD2. These data suggest that the use of VX-809 in combination with an additional CFTR corrector that suppresses folding defects downstream of MSD1 may further enhance CFTR function in people with F508del-CFTR.
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No. Sentence Comment
134 To determine whether formation of a salt bridge between D510 and R1070 was important for this effect, we introduced the R1070A mutation into V510D/F508del-CFTR.
X
ABCC7 p.Arg1070Ala 23924900:134:120
status: NEW135 In the presence of VX-809, the accumulation of the C-band of R1070A/V510D/ F508del-CFTR was reduced by 75% relative to V510D/F508 -CFTR (Figure 6B, lane 7).
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ABCC7 p.Arg1070Ala 23924900:135:61
status: NEW136 Yet VX-809 was still able to increase folded R1070A/V510D/F508-CFTR to levels that were significantly higher than those for VX-809-treated F508del-CFTR.
X
ABCC7 p.Arg1070Ala 23924900:136:45
status: NEW137 Because the V510D mutation can modestly improve the thermodynamic stability of purified NBD1 (Lewis et al., 2010; Wang et al., 2010), the residual VX-809 corrector function on R1070A/V501D/F508del-CFTR could result from thermodynamic stabilization of NBD1 that would occur in the absence of salt-bridge formation between D510 and R1070.
X
ABCC7 p.Arg1070Ala 23924900:137:176
status: NEW