ABCC7 p.Arg117Gln
ClinVar: |
c.350G>C
,
p.Arg117Pro
?
, not provided
c.349C>G , p.Arg117Gly ? , not provided c.350G>T , p.Arg117Leu ? , not provided c.349C>T , p.Arg117Cys D , Pathogenic c.350G>A , p.Arg117His D , Pathogenic |
CF databases: |
c.350G>A
,
p.Arg117His
?
, Varying clinical consequence ; CFTR1:
c.349C>T , p.Arg117Cys D , CF-causing ; CFTR1: The haplotype is 2-1-1-2 (XV2c-KM19-D9-J44) with seven GATT repeats. The mutation creates a new Bsml site. c.349C>G , p.Arg117Gly (CFTR1) ? , Was reported previously in one study of CBAVD. R117G/UND 7T/9T (Daudin et al., Fertility and Sterility, 74:1164-1174, 2000). c.350G>C , p.Arg117Pro (CFTR1) ? , A new missense mutation was found in exon 4 : R 117 P. The mutation was detected by DGGE analysis and identified by remplacement of an arginine residue by a proline at codon 117. The mutation creates new MnlI and NlaIV sites. The mutation was identified in one french CF chromosome. The patient has a mild lung disease and is sufficient pancreatic. c.350G>T , p.Arg117Leu (CFTR1) ? , This mutation was identified by DGGE and direct sequencing and was identified on one CF chromosome of Italian origin. |
Predicted by SNAP2: | A: D (91%), C: D (63%), D: D (95%), E: D (95%), F: D (91%), G: D (95%), H: N (53%), I: D (85%), K: D (95%), L: D (63%), M: D (85%), N: D (95%), P: D (66%), Q: D (95%), S: D (95%), T: D (95%), V: D (91%), W: D (95%), Y: D (95%), |
Predicted by PROVEAN: | A: N, C: D, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, S: N, T: N, V: N, W: N, Y: N, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] Identification of positive charges situated at the... Pflugers Arch. 2008 Nov;457(2):351-60. Epub 2008 May 1. Zhou JJ, Fatehi M, Linsdell P
Identification of positive charges situated at the outer mouth of the CFTR chloride channel pore.
Pflugers Arch. 2008 Nov;457(2):351-60. Epub 2008 May 1., [PMID:18449561]
Abstract [show]
We have used site-directed mutagenesis and functional analysis to identify positively charged amino acid residues in the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel that interact with extracellular anions. Mutation of two positively charged arginine residues in the first extracellular loop (ECL) of CFTR, R104, and R117, as well as lysine residue K335 in the sixth transmembrane region, leads to inward rectification of the current-voltage relationship and decreased single channel conductance. These effects are dependent on the charge of the substituted side chain and on the Cl(-) concentration, suggesting that these positive charges normally act to concentrate extracellular Cl(-) ions near the outer mouth of the pore. Side chain charge-dependent effects are mimicked by manipulating charge in situ by mutating these amino acids to cysteine followed by covalent modification with charged cysteine-reactive reagents, confirming the location of these side chains within the pore outer vestibule. State-independent modification of R104C and R117C suggests that these residues are located at the outermost part of the pore. We suggest that ECL1 contributes to the CFTR pore external vestibule and that positively charged amino acid side chains in this region act to attract Cl(-) ions into the pore. In contrast, we find no evidence that fixed positive charges in other ECLs contribute to the permeation properties of the pore.
Comments [show]
None has been submitted yet.
No. Sentence Comment
62 To investigate the role of charge on these residues in controlling I-V shape, neutral substitutions (R104Q, R117Q, K335A, R1128Q) were also investigated.
X
ABCC7 p.Arg117Gln 18449561:62:108
status: NEW91 All mutants depicted (R104Q, R117Q, K335A, R1128Q, R104E, R117E, K335E, R1128E) showed rectification ratios significantly different from wild type (asterisk P<0.05).
X
ABCC7 p.Arg117Gln 18449561:91:29
status: NEW116 All mutants depicted (R104Q, R117Q, K335A, R104E, R117E, K335E) significantly different from wild type (asterisk P<0.05).
X
ABCC7 p.Arg117Gln 18449561:116:29
status: NEW122 Considering the data at +80 mV, where the inhibitory effects of Pt(NO2)4 2- are strongest, suggests that Pt(NO2)4 2- inhibition is significantly weakened in R104Q, K335A, and (to a lesser extent) R1128Q but not significantly altered in K114C, R117Q, K329A, K829Q, or R899Q (Fig. 8c).
X
ABCC7 p.Arg117Gln 18449561:122:243
status: NEW125 Similar effects were observed in R117Q and R1128Q (Fig. 9b), consistent with the minor effects of these mutations on Pt(NO2)4 2- inhibition inferred from the rectification of macroscopic currents (Fig. 8).
X
ABCC7 p.Arg117Gln 18449561:125:33
status: NEW[hide] Evidence that extracellular anions interact with a... Can J Physiol Pharmacol. 2009 May;87(5):387-95. doi: 10.1139/y09-023. Zhou JJ, Linsdell P
Evidence that extracellular anions interact with a site outside the CFTR chloride channel pore to modify channel properties.
Can J Physiol Pharmacol. 2009 May;87(5):387-95. doi: 10.1139/y09-023., [PMID:19448737]
Abstract [show]
Extracellular anions enter into the pore of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel, interacting with binding sites on the pore walls and with other anions inside the pore. There is increasing evidence that extracellular anions may also interact with sites away from the channel pore to influence channel properties. We have used site-directed mutagenesis and patch-clamp recording to identify residues that influence interactions with external anions. Anion interactions were assessed by the ability of extracellular Pt(NO2)42- ions to weaken the pore-blocking effect of intracellular Pt(NO2)42- ions, a long-range ion-ion interaction that does not appear to reflect ion interactions inside the pore. We found that mutations that remove positive charges in the 4th extracellular loop of CFTR (K892Q and R899Q) significantly alter the interaction between extracellular and intracellular Pt(NO2)42- ions. These mutations do not affect unitary Cl- conductance or block of single-channel currents by extracellular Pt(NO2)42- ions, however, suggesting that the mutated residues are not in the channel pore region. These results suggest that extracellular anions can regulate CFTR pore properties by binding to a site outside the pore region, probably by a long-range conformational change. Our findings also point to a novel function of the long 4th extracellular loop of the CFTR protein in sensing and (or) responding to anions in the extracellular solution.
Comments [show]
None has been submitted yet.
No. Sentence Comment
63 In each case, intracellular Pt(NO2)4 2- caused a voltage-dependent block with broadly similar affinity and voltage dependence (Fig. 1), although the apparent affinity of block was significantly increased in R117Q (Fig. 1D).
X
ABCC7 p.Arg117Gln 19448737:63:207
status: NEW68 In contrast, external Pt(NO2)4 2- ions did not significantly affect the apparent affinity of block by internal Pt(NO2)4 2- in R104Q, R117Q, or R899Q (Fig. 2).
X
ABCC7 p.Arg117Gln 19448737:68:133
status: NEW80 Nevertheless, the apparent Cl- dependence of block was significantly reduced in both K335A and R899Q, and significantly enhanced in R117Q (Fig. 4D).
X
ABCC7 p.Arg117Gln 19448737:80:132
status: NEW89 (C) Mean fraction of control current remaining (I / I0) at different voltages after the addition of Pt(NO2)4 2- in wild type (*), R104Q (*), and R117Q (!).
X
ABCC7 p.Arg117Gln 19448737:89:145
status: NEW90 Curves were fitted to mean data by eq. 1, giving Kd(0) = 89.5 mmol/L and -zd = -0.270 for wild type, Kd(0) = 131.1 mmol/L and -zd = -0.261 for R104Q, and Kd(0) = 44.8 mmol/L and -zd = -0.222 for R117Q.
X
ABCC7 p.Arg117Gln 19448737:90:195
status: NEW104 Curves were fitted to mean data by eq. 1, giving the following values: for wild type, (*) Kd(0) = 89.5 mmol/L and -zd = -0.270, (*) Kd(0) = 274.1 mmol/L and -zd = -0.262; for R104Q, (*) Kd(0) = 131.1 mmol/L and -zd = -0.261, (*) Kd(0) = 200.41 mmol/L and -zd = -0.326; for R117Q, (*) Kd(0) = 44.8 mmol/L and -zd = -0.222, (*) Kd(0) = 65.0 mmol/L and -zd = -0.304; for K892Q, (*) Kd(0) = 58.4 mmol/L and -zd = -0.275, (*) Kd(0) = 21.1 mmol/L and -zd = -0.250; and for R899Q, (*) Kd(0) = 102.8 mmol/L and -zd = -0.312, (*) Kd(0) = 92.8 mmol/L and -zd = -0.334.
X
ABCC7 p.Arg117Gln 19448737:104:273
status: NEW136 For 154 mmol/L Cl- (*), fitted curves gave the following values: Kd(0) = 308.8 mmol/L and -zd = -0.441 for wild type; Kd(0) = 356.4 mmol/L and -zd = -0.378 for R104Q; Kd(0) = 234.9 mmol/L and -zd = -0.376 for R117Q; Kd(0) = 204.2 mmol/L and -zd = -0.395 for K892Q; and Kd(0) = 169.4 mmol/L and -zd = -0.462 for R899Q.
X
ABCC7 p.Arg117Gln 19448737:136:209
status: NEW146 R117Q shows apparently increased sensitivity of internal Pt(NO2)4 2- block to external Cl-ions (Fig. 4D); however, this appears to reflect strong block under low-Cl- conditions (Fig. 2) more than weak block under high-Cl- conditions (Fig. 4).
X
ABCC7 p.Arg117Gln 19448737:146:0
status: NEW154 Thus, whereas direct pore block by externally applied Pt(NO2)4 2- ions is weakened in R104Q but not in R117Q (Zhou et al. 2008), loss of the interactions with external Pt(NO2)4 2- that influence the blocking effects of internal Pt(NO2)4 2- appears similar in both R104Q and R117Q (Fig. 2).
X
ABCC7 p.Arg117Gln 19448737:154:103
status: NEWX
ABCC7 p.Arg117Gln 19448737:154:274
status: NEW[hide] The cystic fibrosis transmembrane conductance regu... Pflugers Arch. 2015 Aug;467(8):1783-94. doi: 10.1007/s00424-014-1618-8. Epub 2014 Oct 4. Broadbent SD, Ramjeesingh M, Bear CE, Argent BE, Linsdell P, Gray MA
The cystic fibrosis transmembrane conductance regulator is an extracellular chloride sensor.
Pflugers Arch. 2015 Aug;467(8):1783-94. doi: 10.1007/s00424-014-1618-8. Epub 2014 Oct 4., [PMID:25277268]
Abstract [show]
The cystic fibrosis transmembrane conductance regulator (CFTR) is a Cl(-) channel that governs the quantity and composition of epithelial secretions. CFTR function is normally tightly controlled as dysregulation can lead to life-threatening diseases such as secretory diarrhoea and cystic fibrosis. CFTR activity is regulated by phosphorylation of its cytosolic regulatory (R) domain, and ATP binding and hydrolysis at two nucleotide-binding domains (NBDs). Here, we report that CFTR activity is also controlled by extracellular Cl(-) concentration ([Cl(-)]o). Patch clamp current recordings show that a rise in [Cl(-)]o stimulates CFTR channel activity, an effect conferred by a single arginine residue, R899, in extracellular loop 4 of the protein. Using NBD mutants and ATP dose response studies in WT channels, we determined that [Cl(-)]o sensing was linked to changes in ATP binding energy at NBD1, which likely impacts NBD dimer stability. Biochemical measurements showed that increasing [Cl(-)]o decreased the intrinsic ATPase activity of CFTR mainly through a reduction in maximal ATP turnover. Our studies indicate that sensing [Cl(-)]o is a novel mechanism for regulating CFTR activity and suggest that the luminal ionic environment is an important physiological arbiter of CFTR function, which has significant implications for salt and fluid homeostasis in epithelial tissues.
Comments [show]
None has been submitted yet.
No. Sentence Comment
112 To explore the role of phosphorylation further, we studied the effect of deleting the R domain from CFTR (residues 634-836) [12, 7], which removes all the major PKA/PKC Table 1 Summary of the FSK stimulation of whole cell currents and Erev shifts observed with the CFTR constructs used in this study CFTR Construct n FSK Stimulation (%&#b1;SEM) Erev shift (mV&#b1;SEM) WT (50 bc;M ATP) 5 180&#b1;96 15.0&#b1;3.6 WT (100 bc;M ATP) 6 12,000&#b1;6,000 15.2&#b1;3.0 WT (300 bc;M ATP) 8 1,200&#b1;600 17.0&#b1;3.0 WT (1 mM ATP) 24 13,000&#b1;6,000 23.7&#b1;1.8 WT (1.3 mM ATP) 9 1,400&#b1;900 16.7&#b1;2.6 WT (2 mM ATP) 24 6,100&#b1;5,300 16.7&#b1;1.6 WT (5 mM ATP) 7 1,600&#b1;1,000 20.1&#b1;4.4 WT (50 bc;M ATP + 50 bc;M P-ATP) 7 224&#b1;130 15.3&#b1;1.0 WT + Genistein 4 7,600&#b1;5,200 26.1&#b1;5.4 WT + AMP-PNP 5 2,800&#b1;2,500 21.8&#b1;5.5 WT (3 mM MgCl2) 7 28,000&#b1;17,000 18.3&#b1;3.1 R104Q 5 4,600&#b1;1,600 28.6&#b1;4.7 K114C 5 12,000&#b1;6,700 29.2&#b1;3.0 R117Q 4 33,000&#b1;20,000 30.1&#b1;3.4 K329A 5 13,000&#b1;10,000 33.7&#b1;2.1 R334Q 9 13,000&#b1;6,700 27.3&#b1;2.9 K335A 5 3,200&#b1;1,500 20.8&#b1;7.1 W401G 7 2,600&#b1;1,800 18.5&#b1;4.8 Delta-R (No Stim) 5 - 25.1&#b1;2.7 Delta-R (No FSK, Genistein) 5 140&#b1;13 22.7&#b1;3.0 Delta-R (FSK, No Genistein) 4 89&#b1;14 15.6&#b1;6.0 Delta-R (FSK + Genistein) 6 639&#b1;432 25.1&#b1;4.9 Delta-R-E1371S (No FSK) 9 - 21.4&#b1;4.8 Delta-R-E1371S (FSK) 4 2,600&#b1;1,400 15.3&#b1;4.7 K892Q 7 16,000&#b1;9,500 36.8&#b1;4.8 R899E 4 1,200&#b1;400 25.0&#b1;2.7 R899K 4 1,600&#b1;900 26.6&#b1;2.9 R899Q 7 5,400&#b1;2,800 30.0&#b1;1.3 R899Q + AMP-PNP 4 72,000&#b1;50,000 15.2&#b1;2.8 R899Q-E1371Q (No FSK) 4 - 18.4&#b1;5.9 R899Q-E1371Q (FSK) 6 107&#b1;48 15.6&#b1;3.0 R1128Q 6 14,000&#b1;6,100 41.1&#b1;4.2 Y1219G 6 3,200&#b1;2,500 19.2&#b1;3.3 E1371Q (No FSK) 6 - 25.5&#b1;3.5 E1371Q (FSK) 8 -28&#b1;9 22.3&#b1;4.0 E1371Q (FSK, No ATP, No GTP) 8 270&#b1;130 19.4&#b1;4.5 E1371Q + AMP-PNP (No FSK) 4 - 24.7&#b1;6.5 E1371Q + AMP-PNP (FSK) 8 180&#b1;170 17.4&#b1;4.0 Vector Control 4 15&#b1;38 - FSK stimulation was calculated as the percentage increase in current density at -60 mV from the Erev, after 5-min exposure to 10 bc;M FSK.
X
ABCC7 p.Arg117Gln 25277268:112:981
status: NEW162 In support of this conclusion, the stimulating effect of [Cl- ]o cannot be due to the ion entering the pore, since mutations that do affect CFTR Cl-conductance (R104Q, R117Q, R334Q, K335A) have no effect on [Cl- ]o stimulation (Fig. 2), and the one site that is important for sensing (R899) does not affect Cl-conductance [45, 47].
X
ABCC7 p.Arg117Gln 25277268:162:168
status: NEW