ABCMdb

ABCC7 p.Asp979Arg

ClinVar:	c.2936A>T , p.Asp979Val ? , not provided c.2936A>C , p.Asp979Ala ? , not provided
CF databases:	c.2936A>T , p.Asp979Val (CFTR1) D , The above mutation was detected by DGGE and direct sequencing, and was observed in a French family with 2 CF patients carrying [delta]F508 on their other CF chromosomes. c.2936A>C , p.Asp979Ala (CFTR1) D , D979A was found in a Vietnamese CBAVD patient carrying a yet unknown mutation on the other allele.
Predicted by SNAP2:	A: D (85%), C: D (85%), E: D (80%), F: D (91%), G: D (91%), H: D (91%), I: D (91%), K: D (95%), L: D (91%), M: D (91%), N: D (85%), P: D (91%), Q: D (85%), R: D (91%), S: D (85%), T: D (85%), V: D (91%), W: D (95%), Y: D (91%),
Predicted by PROVEAN:	A: D, C: D, E: D, F: D, G: 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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Publications
[hide] Two mild cystic fibrosis-associated mutations resu... J Biol Chem. 2001 Mar 23;276(12):9045-9. Epub 2000 Dec 15. Clain J, Fritsch J, Lehmann-Che J, Bali M, Arous N, Goossens M, Edelman A, Fanen P
Two mild cystic fibrosis-associated mutations result in severe cystic fibrosis when combined in cis and reveal a residue important for cystic fibrosis transmembrane conductance regulator processing and function.
J Biol Chem. 2001 Mar 23;276(12):9045-9. Epub 2000 Dec 15., 2001-03-23 [PMID:11118444]

Abstract [show]
The number of complex cystic fibrosis transmembrane conductance regulator (CFTR) genotypes identified as having double-mutant alleles with two mutations inherited in cis has been growing. We investigated the structure-function relationships of a severe cystic fibrosis (CF)-associated double mutant (R347H-D979A) to evaluate the contribution of each mild mutation to the phenotype. CFTR mutants expressed in HeLa cells were analyzed for protein biosynthesis and Cl(-) channel activity. Our data show that R347H is associated with mild defective Cl(-) channel activity and that the D979A defect leads to misprocessing. The mutant R347H-D979A combines both defects for a dramatic decrease in Cl(-) current. To decipher the molecular mechanism of this phenotype, single and double mutants with different charge combinations at residues 347 and 979 were constructed as charged residues were involved in this complex genotype. These studies revealed that residue 979, located in the third cytoplasmic loop, is critical for CFTR processing and Cl(-) channel activity highlighting the role of charged residues. These results have also important implications for CF, as they show that two mutations in cis can act in concert to alter dramatically CFTR function contributing to the wide phenotypic variability of CF disease.

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Sentences [show]
No. Sentence Comment
72 Asp-979 was changed to Val (small hydrophobic residue; D979V), Arg (positively charged residue; D979R), or Glu (negatively charged residue; D979E). Login to comment
73 D979V (also a naturally occurring mutant) and D979R had impaired processing FIG. 1. Login to comment
101 Charge-reversal Mutants-Taking into account the functional defects that result when Arg-347 and Asp-979 are each replaced with an uncharged amino acid such as His (uncharged at pH 7.3) and Ala (R347H and D979A), we constructed additional mutants with different charge combinations at residues 347 and 979, including the R347D-D979R double mutant in which the positive and negative charges were swapped. Login to comment
118 essing of D979R, R347H-D979R, and R347D-D979R was differently impaired (Fig. 3; gray bars). Login to comment
120 This suggests that 347 residue could interact directly or indirectly with Arg-979 (D979R). Login to comment
121 Whole-cell measurements indicated that D979R resulted in a much greater decrease in chloride current (4.5 Ϯ 2.4 pA/pF; n ϭ 6) than D979A (Fig. 2D), although both proteins were processed similarly. Login to comment
123 The Cl- current of R347D-D979R (2.8 Ϯ 1.7 pA/pF; n ϭ 9) was not significantly different from those of D979R and R347H-D979A (Fig. 2D). Login to comment
124 This result is consistent with the poor amount of R347D-D979R protein at the cell surface. Login to comment
134 Our data strongly suggest that mutation D979R alters the properties of the chloride channel, and mutational analysis of 979 residue also confirmed that the requirements for channel processing and function are different, consistent with data for other residues (17, 18, 21). Login to comment
143 First, several lines of experimental evidence indicate that there is probably no direct salt bridge between Arg-347 and Asp-979: (i) removal of either the positive charge at position 347 (R347H and R347D) or the negative charge at position 979 (D979A, D979V, and D979R) has different effects on CFTR processing; (ii) the double-neutral (R347H-D979A) and reversed-charged (R347D-D979R) replacements for Arg-347 and Asp-979 do not lead to the recovery of wild-type processing. Login to comment
146 This is supported by the decrease in the processing efficiency of D979R mutants combined with positive, neutral, and negative charges at residue 347. Login to comment