ABCC7 p.Gly1247Asp
| ClinVar: |
c.3739G>C
,
p.Gly1247Arg
?
, not provided
|
| CF databases: |
c.3739G>A
,
p.Gly1247Arg
(CFTR1)
D
, Patient was from Brazil and is of Afro-American origin. The G1247R mutation was detected by DGGE and direct sequencing. The patient is homozygous for the mutation, with PI and mild lung disease.
c.3739G>C , p.Gly1247Arg (CFTR1) ? , This mutation was identified on one Italian CF chromosome, applying a protocol of extended mutational search (5?-flanking region, all the exons and adjacent intronic regions) by direct sequencing. No other mutations were found on the same allele. The mutation W1282X was found on the other allele. The G1247R(GtoC) mutation was not found in 232 alleles from the general population. This mutation may produce anomalous genetic characterization by PCR/OLA/SCS 31 mutation assay, interfering with exon 20 amplification or OLA probing. |
| Predicted by SNAP2: | A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: D (95%), R: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, R: D, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Regulation of Cl-/ HCO3- exchange by cystic fibros... J Biol Chem. 1999 Feb 5;274(6):3414-21. Lee MG, Wigley WC, Zeng W, Noel LE, Marino CR, Thomas PJ, Muallem S
Regulation of Cl-/ HCO3- exchange by cystic fibrosis transmembrane conductance regulator expressed in NIH 3T3 and HEK 293 cells.
J Biol Chem. 1999 Feb 5;274(6):3414-21., 1999-02-05 [PMID:9920885]
Abstract [show]
A central function of cystic fibrosis transmembrane conductance regulator (CFTR)-expressing tissues is the secretion of fluid containing 100-140 mM HCO3-. High levels of HCO3- maintain secreted proteins such as mucins (all tissues) and digestive enzymes (pancreas) in a soluble and/or inactive state. HCO3- secretion is impaired in CF in all CFTR-expressing, HCO3--secreting tissues examined. The mechanism responsible for this critical problem in CF is unknown. Since a major component of HCO3- secretion in CFTR-expressing cells is mediated by the action of a Cl-/HCO3- exchanger (AE), in the present work we examined the regulation of AE activity by CFTR. In NIH 3T3 cells stably transfected with wild type CFTR and in HEK 293 cells expressing WT and several mutant CFTR, activation of CFTR by cAMP stimulated AE activity. Pharmacological and mutagenesis studies indicated that expression of CFTR in the plasma membrane, but not the Cl- conductive function of CFTR was required for activation of AE. Furthermore, mutations in NBD2 altered regulation of AE activity by CFTR independent of their effect on Cl- channel activity. At very high expression levels CFTR modified the sensitivity of AE to 4,4'-diisothiocyanatostilbene-2, 2'-disulfonate. The novel finding of regulation of Cl-/HCO3- exchange by CFTR reported here may have important physiological implications and explain, at least in part, the impaired HCO3- secretion in CF.
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No. Sentence Comment
52 The mutagenesis primers were as follows: P205S primer, 5Ј-CGT GTG GAT CGC TTC TTT GCA AGT GGC-3Ј; W846term, 5Ј-GAG CAT ACC AGC AGT GAC TAC ATA GAA CAC ATA CCT TCG ATA TAT TAC-3Ј; G1247D/G1249E, 5Ј-GTG GGC CTC TTG GGA AGA ACT GAT TCA GAG AAG AGT ACT TTG TTA TCA GC-3Ј; K1250M, 5Ј-CTT GGG AAG AAC TGG ATC AGG GAT GAG TAC TTT GTT ATC AGC-3Ј; D1370N, 5Ј-GTA AGG CGA AGA TCT TGC TGC TTA ATG AAC CCA GTG CTC ATT TGG ATC-3Ј.
X
ABCC7 p.Gly1247Asp 9920885:52:203
status: NEW163 Fig. 6 (i-k) shows the plasma membrane localization of K1250M CFTR, D1370N CFTR, and the double mutant G1247D/ G1249E CFTR, respectively.
X
ABCC7 p.Gly1247Asp 9920885:163:103
status: NEW239 For example, the G1247D/G1249E CFTR double mutant was reported to have no Cl-channel activity (32), was expressed in the plasma membrane (Fig. 6k), and had no effect on AE activity (Fig. 12a).
X
ABCC7 p.Gly1247Asp 9920885:239:17
status: NEW264 The G1247D/G1249E double mutant was expressed in the plasma membrane but had no effect on AE activity (a).
X
ABCC7 p.Gly1247Asp 9920885:264:4
status: NEW[hide] Control of CFTR channel gating by phosphorylation ... Physiol Rev. 1999 Jan;79(1 Suppl):S77-S107. Gadsby DC, Nairn AC
Control of CFTR channel gating by phosphorylation and nucleotide hydrolysis.
Physiol Rev. 1999 Jan;79(1 Suppl):S77-S107., [PMID:9922377]
Abstract [show]
Control of CTFR Channel Gating by Phosphorylation and Nucleotide Hydrolysis. Physiol. Rev. 79, Suppl.: S77-S107, 1999. - The cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel is the protein product of the gene defective in cystic fibrosis, the most common lethal genetic disease among Caucasians. Unlike any other known ion channel, CFTR belongs to the ATP-binding cassette superfamily of transporters and, like all other family members, CFTR includes two cytoplasmic nucleotide-binding domains (NBDs), both of which bind and hydrolyze ATP. It appears that in a single open-close gating cycle, an individual CFTR channel hydrolyzes one ATP molecule at the NH2-terminal NBD to open the channel, and then binds and hydrolyzes a second ATP molecule at the COOH-terminal NBD to close the channel. This complex coordinated behavior of the two NBDs is orchestrated by multiple protein kinase A-dependent phosphorylation events, at least some of which occur within the third large cytoplasmic domain, called the regulatory domain. Two or more kinds of protein phosphatases selectively dephosphorylate distinct sites. Under appropriately controlled conditions of progressive phosphorylation or dephosphorylation, three functionally different phosphoforms of a single CFTR channel can be distinguished on the basis of channel opening and closing kinetics. Recording single CFTR channel currents affords an unprecedented opportunity to reproducibly examine, and manipulate, individual ATP hydrolysis cycles in a single molecule, in its natural environment, in real time.
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No. Sentence Comment
563 Second, mutant G1247D/G1249E CFTRphorylation status) of the closings are expected to be rate limited by ATP hydrolysis.
X
ABCC7 p.Gly1247Asp 9922377:563:15
status: NEW[hide] ClC and CFTR chloride channel gating. Annu Rev Physiol. 1998;60:689-717. Foskett JK
ClC and CFTR chloride channel gating.
Annu Rev Physiol. 1998;60:689-717., [PMID:9558482]
Abstract [show]
Chloride channels are widely expressed and play important roles in cell volume regulation, transepithelial transport, intracellular pH regulation, and membrane excitability. Most chloride channels have yet to be identified at a molecular level. The ClC gene family and the cystic fibrosis transmembrane conductance regulator (CFTR) are distinct chloride channels expressed in many cell types, and mutations in their genes are the cause of several diseases including myotonias, cystic fibrosis, and kidney stones. Because of their molecular definition and roles in disease, these channels have been studied intensively over the past several years. The focus of this review is on recent studies that have provided new insights into the mechanisms governing the opening and closing, i.e. gating, of the ClC and CFTR chloride channels.
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No. Sentence Comment
331 Mutations predicted to abolish nucleotide binding at NBD2, a G1247D/G1249E double mutant, exhibit low Po because of extended closed times and only brief openings (to O1 only), which are independent of ATP (150).
X
ABCC7 p.Gly1247Asp 9558482:331:61
status: NEW[hide] Conformational states of CFTR associated with chan... Cell. 1995 Jul 28;82(2):231-9. Gunderson KL, Kopito RR
Conformational states of CFTR associated with channel gating: the role ATP binding and hydrolysis.
Cell. 1995 Jul 28;82(2):231-9., [PMID:7543023]
Abstract [show]
CFTR is a member of the traffic ATPase superfamily and a Cl- ion channel that appears to require ATP hydrolysis for gating. Analysis of single CFTR Cl- channels reconstituted into planar lipid bilayers revealed the presence of two open conductance states that are connected to each other and to the closed state by an asymmetric cycle of gating events. We show here that the transition between the two open conductance states is directly coupled to ATP hydrolysis by one of the consensus nucleotide-binding folds, designated NBF2. Moreover, the transition between the closed state and one of the open states is linked to the binding of ATP. This analysis permits real-time visualization of conformational changes associated with a single cycle of ATP hydrolysis by a single protein molecule and suggests a model describing a role for ATP in CFTR gating.
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No. Sentence Comment
117 The effect of this double mutation, G1247D and G1249E, is to introduce negative charge into the P loop, which should severely attenuate nucleotide binding to NBF2.
X
ABCC7 p.Gly1247Asp 7543023:117:36
status: NEW121 The simplest interpretation of these data is that ATP binding ConformationalStatesof CFTR 09 08 07 06 Oo 05 040.3 * 32 wildtype K464A K1250A G1247D/ D1370N 01249E 6~se' B 2500 20O0 5 1500 1OO0 500 o~ 0 w[Id{ype K464A K1250A C1247D/ Ol 370N G1249E Figure5.
X
ABCC7 p.Gly1247Asp 7543023:121:143
status: NEW178 The proposal that ATP binding to NBF2 opens the channel to the O1 state is supported by the virtual absence of ATP-dependent openings in the G1247D, G1249E P loop mutant.
X
ABCC7 p.Gly1247Asp 7543023:178:141
status: NEW118 The effect of this double mutation, G1247D and G1249E, is to introduce negative charge into the P loop, which should severely attenuate nucleotide binding to NBF2.
X
ABCC7 p.Gly1247Asp 7543023:118:36
status: NEW122 The simplest interpretation of these data is that ATP binding ConformationalStatesof CFTR 09 08 07 06 Oo 05 040.3 * 32 wildtype K464A K1250A G1247D/ D1370N 01249E 6~se' B 2500 20O0 5 1500 1OO0 500 o ~ 0 w[Id{ype K464A K1250A C1247D/ Ol 370N G1249E Figure5.
X
ABCC7 p.Gly1247Asp 7543023:122:143
status: NEW179 The proposal that ATP binding to NBF2 opens the channel to the O1 state is supported by the virtual absence of ATP-dependent openings in the G1247D, G1249E P loop mutant.
X
ABCC7 p.Gly1247Asp 7543023:179:141
status: NEW