ABCC7 p.Arg1070Asp
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.
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ABCC7 p.Arg1070Asp 20590134:5:53
status: NEW86 Mutant ΔF508/V510R/R1070D was constructed to reverse the positions of the charged residues.
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ABCC7 p.Arg1070Asp 20590134:86:25
status: NEW87 Figure 4C shows that the V510R/R1070D mutations promoted maturation of ΔF508-CFTR.
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ABCC7 p.Arg1070Asp 20590134:87:31
status: NEW88 Both mutations were required because the presence of V510R (Figure 1H) or R1070D (Figure 4D) alone did not promote maturation of ΔF508-CFTR.
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ABCC7 p.Arg1070Asp 20590134:88:74
status: NEW158 Mutation of Arg1070 to a neutral amino acid abolished V510D rescue of ΔF508-CFTR while V510R only rescued the mutant when the R1070D change was introduced (Figure 4C).
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ABCC7 p.Arg1070Asp 20590134:158:132
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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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).
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ABCC7 p.Arg1070Asp 23378596:256:454
status: NEW[hide] Dynamics intrinsic to cystic fibrosis transmembran... Cold Spring Harb Perspect Med. 2013 Mar 1;3(3):a009522. doi: 10.1101/cshperspect.a009522. Chong PA, Kota P, Dokholyan NV, Forman-Kay JD
Dynamics intrinsic to cystic fibrosis transmembrane conductance regulator function and stability.
Cold Spring Harb Perspect Med. 2013 Mar 1;3(3):a009522. doi: 10.1101/cshperspect.a009522., [PMID:23457292]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) requires dynamic fluctuations between states in its gating cycle for proper channel function, including changes in the interactions between the nucleotide-binding domains (NBDs) and between the intracellular domain (ICD) coupling helices and NBDs. Such motions are also linked with fluctuating phosphorylation-dependent binding of CFTR's disordered regulatory (R) region to the NBDs and partners. Folding of CFTR is highly inefficient, with the marginally stable NBD1 sampling excited states or folding intermediates that are aggregation-prone. The severe CF-causing F508del mutation exacerbates the folding inefficiency of CFTR and leads to impaired channel regulation and function, partly as a result of perturbed NBD1-ICD interactions and enhanced sampling of these NBD1 excited states. Increased knowledge of the dynamics within CFTR will expand our understanding of the regulated channel gating of the protein as well as of the F508del defects in folding and function.
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No. Sentence Comment
98 Similar results are seen with an R1070W mutation, which might be expected to enhance the hydrophobic contacts at this interface or fill the void introduced by deletion of F508, or with a combined R1070D/V510R mutation, which would reverse the proposed salt bridge (Farinha et al. 2010; Loo et al. 2010).
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ABCC7 p.Arg1070Asp 23457292:98:196
status: NEW