PMID: 11118444

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 [PubMed]
Sentences
No. Mutations Sentence Comment
1 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:1:112
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:1:118
status: NEW
view ABCC7 p.Asp979Ala details
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. Login to comment
3 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:3:19
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:3:92
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:3:93
status: NEW
view ABCC7 p.Asp979Ala details
Our data show that R347H is associated with mild defective Cl-channel activity and that the D979A defect leads to misprocessing. Login to comment
4 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:4:11
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:4:17
status: NEW
view ABCC7 p.Asp979Ala details
The mutant R347H-D979A combines both defects for a dramatic decrease in Cl- cur- rent. Login to comment
13 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:13:66
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:13:223
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:13:72
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:13:229
status: NEW
view ABCC7 p.Asp979Ala details
The recent discovery of severe CF associated with a ⌬F508/ R347H-D979A compound heterozygote genotype in two related patients suffering from pancreatic insufficiency and severe respiratory symptoms suggests that the R347H-D979A mutation has an important influence on CFTR processing and/or function (7). Login to comment
14 ABCC7 p.Arg347Pro
X
ABCC7 p.Arg347Pro 11118444:14:114
status: NEW
view ABCC7 p.Arg347Pro details
ABCC7 p.Arg347Cys
X
ABCC7 p.Arg347Cys 11118444:14:89
status: NEW
view ABCC7 p.Arg347Cys details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:14:96
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347Leu
X
ABCC7 p.Arg347Leu 11118444:14:103
status: NEW
view ABCC7 p.Arg347Leu details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:14:146
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Val
X
ABCC7 p.Asp979Val 11118444:14:156
status: NEW
view ABCC7 p.Asp979Val details
At least four CF-associated mutations have been identified in isolation at position 347 (R347C, R347H, R347L, and R347P) and two at position 979 (D979A and D979V), suggesting that Arg-347 and Asp-979 are important for CFTR structure and/or function. Login to comment
15 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:15:123
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:15:13
status: NEW
view ABCC7 p.Asp979Ala details
The mutation D979A was found in isolation in a patient with a congenital bilateral absence of the vas deferens (8) and the R347H mutation in CF patients with pancreatic sufficiency, congenital bilateral absence of the vas deferens, and no or mild pulmonary symptoms (7). Login to comment
16 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:16:7
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:16:166
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:16:83
status: NEW
view ABCC7 p.Asp979Ala details
As the R347H mutation is mostly associated with mild CF, it was suggested that the D979A mutation has a significant effect on CFTR function when combined in cis with R347H. Login to comment
18 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:18:14
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:18:24
status: NEW
view ABCC7 p.Asp979Ala details
The mutations R347H and D979A replace positively charged (Arg) and negatively charged (Asp) residues with ones that are uncharged (His and Ala, respectively) at physiological pH. Login to comment
19 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:19:75
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:19:81
status: NEW
view ABCC7 p.Asp979Ala details
The present study investigates the structure-function relationships of the R347H-D979A double mutant, and as charged residues are involved in this complex genotype, single and double mutants with different charge combinations at residues 347 and 979 were constructed. Login to comment
21 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:21:19
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:21:93
status: NEW
view ABCC7 p.Asp979Ala details
Our data show that R347H is associated with defective chloride channel activity and that the D979A defect leads to misprocessing. Login to comment
22 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:22:11
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:22:17
status: NEW
view ABCC7 p.Asp979Ala details
The mutant R347H-D979A combines both defects for a dramatic decrease in Cl- current. Login to comment
58 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:58:89
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:58:95
status: NEW
view ABCC7 p.Asp979Ala details
We first studied the maturation of CFTR in HeLa cells to determine why patients with the R347H-D979A-CFTR allele suffered from severe CF. Login to comment
64 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:64:83
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:64:101
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:64:90
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:64:107
status: NEW
view ABCC7 p.Asp979Ala details
Immunoprecipitation experiments show that both wild-type and CF-associated mutants R347H, D979A, and R347H-D979A-CFTR cells produced mature, fully glycosylated protein (Fig. 1A; band C), whereas none of the mock-transfected cells produced CFTR (data not shown). Login to comment
65 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:65:23
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:65:149
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:65:13
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:65:29
status: NEW
view ABCC7 p.Asp979Ala details
However, the D979A and R347H-D979A mutants produced significantly less band C (59 and 56% of the total CFTR; ratio C/(BϩC)) than wild-type and R347H-CFTR (92 and 91%; see Fig. 1B). Login to comment
66 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:66:24
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:66:30
status: NEW
view ABCC7 p.Asp979Ala details
This indicates that the R347H-D979A mutation caused a misprocessing defect. Login to comment
67 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:67:59
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:67:65
status: NEW
view ABCC7 p.Asp979Ala details
The turnover of immature and mature forms of wild-type and R347H-D979A-CFTR proteins was further investigated by pulse-chase experiments (Fig. 1C). Login to comment
68 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:68:30
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:68:36
status: NEW
view ABCC7 p.Asp979Ala details
The kinetics of wild-type and R347H-D979A core-glycosylated and mature forms of CFTR were identical, whereas the efficiency of conversion to mature band C was lower for the mutant. Login to comment
69 ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:69:39
status: NEW
view ABCC7 p.Asp979Ala details
Similar results were obtained with the D979A mutant (data not shown). Login to comment
71 ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:71:57
status: NEW
view ABCC7 p.Asp979Ala details
Other mutants were generated to further characterize the D979A defect. Login to comment
72 ABCC7 p.Asp979Val
X
ABCC7 p.Asp979Val 11118444:72:0
status: NEW
view ABCC7 p.Asp979Val details
ABCC7 p.Asp979Val
X
ABCC7 p.Asp979Val 11118444:72:55
status: NEW
view ABCC7 p.Asp979Val details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:72:96
status: NEW
view ABCC7 p.Asp979Arg details
ABCC7 p.Asp979Glu
X
ABCC7 p.Asp979Glu 11118444:72:140
status: NEW
view ABCC7 p.Asp979Glu details
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 ABCC7 p.Asp979Val
X
ABCC7 p.Asp979Val 11118444:73:0
status: NEW
view ABCC7 p.Asp979Val details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:73:46
status: NEW
view ABCC7 p.Asp979Arg details
D979V (also a naturally occurring mutant) and D979R had impaired processing FIG. 1. Login to comment
82 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:82:98
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:82:104
status: NEW
view ABCC7 p.Asp979Ala details
C, pulse-chase experiments showing the turnover of the immature and mature forms of wild-type and R347H-D979A-CFTR (results are representative of two independent experiments). Login to comment
83 ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:83:11
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Glu
X
ABCC7 p.Asp979Glu 11118444:83:26
status: NEW
view ABCC7 p.Asp979Glu details
similar to D979A, whereas D979E permitted the complete maturation of the protein (Fig. 1B). Login to comment
84 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:84:93
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:84:40
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:84:99
status: NEW
view ABCC7 p.Asp979Ala details
Altogether, these results indicate that D979A is responsible for the defective processing of R347H-D979A-CFTR and that a negative charge at 979 residue is necessary for proper CFTR processing. Login to comment
93 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:93:38
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:93:67
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:93:48
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:93:73
status: NEW
view ABCC7 p.Asp979Ala details
We separated the contributions of the R347H and D979A mutations to R347H-D979A-CFTR whole-cell Cl- current production studying both single and double mutants. Login to comment
96 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:96:63
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:96:159
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:96:109
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:96:165
status: NEW
view ABCC7 p.Asp979Ala details
Mean changes in cAMP-activated currents recorded at 20 mV from R347H (29.4 Ϯ 12.2 pA/pF; n ϭ 8), D979A (67.9 Ϯ 18.9 pA/pF; n ϭ 5), and R347H-D979A (1.2 Ϯ 0.8 pA/pF; n ϭ 9) mutants were significantly different (p Ͻ 0.05) from wild-type (130.2 Ϯ 34.7 pA/pF; n ϭ 5), corresponding to 23, 52, and 1% of the wild-type Cl- current (Fig. 2D). Login to comment
97 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:97:0
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:97:18
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:97:7
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:97:24
status: NEW
view ABCC7 p.Asp979Ala details
R347H, D979A, and R347H-D979A were also significantly different from each other (p Ͻ 0.01). Login to comment
98 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:98:3
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:98:79
status: NEW
view ABCC7 p.Arg347His details
As R347H processing is similar to wild-type, the small Cl- current produced by R347H reflected defective channel properties, as demonstrated by single-channel studies (9). Login to comment
99 ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:99:66
status: NEW
view ABCC7 p.Asp979Ala details
The decreased whole-cell Cl- cAMP-dependent current observed with D979A probably reflected CFTR protein misprocessing, although we cannot firmly exclude altered channel properties. Login to comment
100 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:100:34
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:100:106
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:100:40
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:100:78
status: NEW
view ABCC7 p.Asp979Ala details
Thus these data indicate that the R347H-D979A double mutant combined at least D979A misprocessing and the R347H Cl-channel defect to produce a very severe phenotype. Login to comment
101 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:101:194
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347Asp
X
ABCC7 p.Arg347Asp 11118444:101:320
status: NEW
view ABCC7 p.Arg347Asp details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:101:204
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:101:326
status: NEW
view ABCC7 p.Asp979Arg details
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
102 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:102:48
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347Asp
X
ABCC7 p.Arg347Asp 11118444:102:18
status: NEW
view ABCC7 p.Arg347Asp details
The processing of R347D was similar to those of R347H and the wild-type (Fig. 3, open bars). Login to comment
109 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:109:56
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:109:108
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:109:79
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:109:114
status: NEW
view ABCC7 p.Asp979Ala details
C, current-voltage (I-V) curve in HeLa cells expressing R347H (filled circle), D979A (filled triangle), and R347H-D979A (filled square) mutants. Login to comment
118 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:118:17
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347Asp
X
ABCC7 p.Arg347Asp 11118444:118:34
status: NEW
view ABCC7 p.Arg347Asp details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:118:10
status: NEW
view ABCC7 p.Asp979Arg details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:118:23
status: NEW
view ABCC7 p.Asp979Arg details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:118:40
status: NEW
view ABCC7 p.Asp979Arg details
essing of D979R, R347H-D979R, and R347D-D979R was differently impaired (Fig. 3; gray bars). Login to comment
120 ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:120:83
status: NEW
view ABCC7 p.Asp979Arg details
This suggests that 347 residue could interact directly or indirectly with Arg-979 (D979R). Login to comment
121 ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:121:143
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:121:39
status: NEW
view ABCC7 p.Asp979Arg details
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 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:123:124
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347Asp
X
ABCC7 p.Arg347Asp 11118444:123:19
status: NEW
view ABCC7 p.Arg347Asp details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:123:130
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:123:25
status: NEW
view ABCC7 p.Asp979Arg details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:123:114
status: NEW
view ABCC7 p.Asp979Arg details
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 ABCC7 p.Arg347Asp
X
ABCC7 p.Arg347Asp 11118444:124:50
status: NEW
view ABCC7 p.Arg347Asp details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:124:56
status: NEW
view ABCC7 p.Asp979Arg details
This result is consistent with the poor amount of R347D-D979R protein at the cell surface. Login to comment
125 ABCC7 p.Arg334Trp
X
ABCC7 p.Arg334Trp 11118444:125:105
status: NEW
view ABCC7 p.Arg334Trp details
ABCC7 p.Arg1158*
X
ABCC7 p.Arg1158* 11118444:125:111
status: NEW
view ABCC7 p.Arg1158* details
ABCC7 p.Arg553Gln
X
ABCC7 p.Arg553Gln 11118444:125:59
status: NEW
view ABCC7 p.Arg553Gln details
ABCC7 p.Val1212Ile
X
ABCC7 p.Val1212Ile 11118444:125:93
status: NEW
view ABCC7 p.Val1212Ile details
DISCUSSION Complex alleles have been described clinically (R553Q- ⌬F508, ⌬F508-V1212I, and R334W-R1158X), and most of them are considered to reverse the phenotype, as they are associated with milder symptoms than the most common mutation in isolation. Login to comment
127 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:127:29
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:127:39
status: NEW
view ABCC7 p.Asp979Ala details
Clinical data suggested that R347H and D979A, two mild CF-associated mutations, can produce severe CF similar to that of ⌬F508 homozygotes when combined in cis. Login to comment
129 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:129:71
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:129:0
status: NEW
view ABCC7 p.Asp979Ala details
D979A reduces the amount of CFTR protein at the cell membrane, whereas R347H generates a defective Cl-channel. Login to comment
130 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:130:11
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:130:17
status: NEW
view ABCC7 p.Asp979Ala details
The mutant R347H-D979A combines both defects for a dramatic decrease in Cl- current. Login to comment
131 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:131:148
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:131:172
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:131:83
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:131:178
status: NEW
view ABCC7 p.Asp979Ala details
The magnitude of Cl- current in vitro paralleled the severity of the disease, with D979A (congenital bilateral absence of the vas deferens) Ͼ R347H (mild CF) Ͼ R347H-D979A (severe CF). Login to comment
134 ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:134:40
status: NEW
view ABCC7 p.Asp979Arg details
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
136 ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:136:41
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Val
X
ABCC7 p.Asp979Val 11118444:136:41
status: NEW
view ABCC7 p.Asp979Val details
Our data support this view, as replacing Asp-979 by Ala, Val, or Arg significantly impaired processing. Login to comment
143 ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:143:188
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347His
X
ABCC7 p.Arg347His 11118444:143:337
status: NEW
view ABCC7 p.Arg347His details
ABCC7 p.Arg347Asp
X
ABCC7 p.Arg347Asp 11118444:143:198
status: NEW
view ABCC7 p.Arg347Asp details
ABCC7 p.Arg347Asp
X
ABCC7 p.Arg347Asp 11118444:143:372
status: NEW
view ABCC7 p.Arg347Asp details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:143:245
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Ala
X
ABCC7 p.Asp979Ala 11118444:143:343
status: NEW
view ABCC7 p.Asp979Ala details
ABCC7 p.Asp979Val
X
ABCC7 p.Asp979Val 11118444:143:252
status: NEW
view ABCC7 p.Asp979Val details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:143:263
status: NEW
view ABCC7 p.Asp979Arg details
ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:143:378
status: NEW
view ABCC7 p.Asp979Arg details
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 ABCC7 p.Asp979Arg
X
ABCC7 p.Asp979Arg 11118444:146:66
status: NEW
view ABCC7 p.Asp979Arg details
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