ABCC7 p.Arg297Cys
| ClinVar: |
c.890G>A
,
p.Arg297Gln
N
, Benign/Likely benign
c.889C>T , p.Arg297Trp ? , not provided |
| CF databases: |
c.889C>T
,
p.Arg297Trp
(CFTR1)
?
, Missense mutation R297W was identified in a Vietnamese CBAVD patient who is heterozygous for R297W and for the 5T allele. Both chromosomes also carry the Q1352H missense variant in exon 22.
c.890G>A , p.Arg297Gln (CFTR1) ? , This charge from a basic to an uncharged amino acid is probably consistent with disease and the mutation occurs at a CG dinucleotide, a known mutation hot spot. This mutation was detected in 2 sibs with CF and is associated with an X2 K1 haplotype, the other mutation in this family is also on a X2 K1 haplotype and is undefined. In the original report, R297Q was not detected in a further 54 CF chromosomes with an unidefined mutations and 50 normal chromosomes, all samples were of Northern Irish origin. Dubourg argued that R297Q is a rare polymorphism rather than a deleterious mutation as usually reported. The first supportive evidence came from a family where R297Q was associated with two of the most severe molecular defects DF508 or N1303K on healthy subjects (DORVAL, JEZEQUEL, CHAUVEL, DUBOURG et al. (1995) Human Mutation, 6 : 334-335). More recently, Dubourg et al. identified the same aminoacid change (R297Q) in association with the 574delA mutation in an healthy subject. (Christèle DUBOURG, Laboratoire de GENETIQUE MOLECULAIRE, CHRU PONTCHAILLOU, 35033 RENNES Cedex FRANCE; Tel : 33.2.99.28.41.31; Fax : 33.2.99.28.41.85; E-mail : blayau@sunaimed.univ-rennes1.fr ) |
| Predicted by SNAP2: | A: D (91%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (91%), I: D (91%), K: D (71%), L: D (91%), M: D (85%), N: D (95%), P: D (95%), Q: D (63%), S: D (91%), T: D (91%), 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: D, K: N, L: D, M: D, N: D, P: D, Q: N, S: D, T: D, V: D, W: D, Y: D, |
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[hide] Functional Architecture of the Cytoplasmic Entranc... J Biol Chem. 2015 Jun 19;290(25):15855-65. doi: 10.1074/jbc.M115.656181. Epub 2015 May 5. El Hiani Y, Linsdell P
Functional Architecture of the Cytoplasmic Entrance to the Cystic Fibrosis Transmembrane Conductance Regulator Chloride Channel Pore.
J Biol Chem. 2015 Jun 19;290(25):15855-65. doi: 10.1074/jbc.M115.656181. Epub 2015 May 5., [PMID:25944907]
Abstract [show]
As an ion channel, the cystic fibrosis transmembrane conductance regulator must form a continuous pathway for the movement of Cl(-) and other anions between the cytoplasm and the extracellular solution. Both the structure and the function of the membrane-spanning part of this pathway are well defined. In contrast, the structure of the pathway that connects the cytoplasm to the membrane-spanning regions is unknown, and functional roles for different parts of the protein forming this pathway have not been described. We used patch clamp recording and substituted cysteine accessibility mutagenesis to identify positively charged amino acid side chains that attract cytoplasmic Cl(-) ions to the inner mouth of the pore. Our results indicate that the side chains of Lys-190, Arg-248, Arg-303, Lys-370, Lys-1041, and Arg-1048, located in different intracellular loops of the protein, play important roles in the electrostatic attraction of Cl(-) ions. Mutation and covalent modification of these residues have charge-dependent effects on the rate of Cl(-) permeation, demonstrating their functional role in maximization of Cl(-) flux. Other nearby positively charged side chains were not involved in electrostatic interactions with Cl(-). The location of these Cl(-)-attractive residues suggests that cytoplasmic Cl(-) ions enter the pore via a lateral portal located between the cytoplasmic extensions to the fourth and sixth transmembrane helices; a secondary, functionally less relevant portal might exist between the extensions to the 10th and 12th transmembrane helices. These results define the cytoplasmic mouth of the pore and show how it attracts Cl(-) ions from the cytoplasm.
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No. Sentence Comment
111 Other mutants studied (K254C, K294C, R297C, K298C, H1085C, R1162C, and K1165C) were not significantly affected by either MTSES or MTSET (Fig. 3), suggesting that cysteine side chains at these positions were not modified by cytoplasmic MTS reagents.
X
ABCC7 p.Arg297Cys 25944907:111:37
status: NEW