PMID: 25042876

Sharma H, Jollivet Souchet M, Callebaut I, Prasad R, Becq F
Function, pharmacological correction and maturation of new Indian CFTR gene mutations.
J Cyst Fibros. 2015 Jan;14(1):34-41. doi: 10.1016/j.jcf.2014.06.008. Epub 2014 Jul 16., [PubMed]
Sentences
No. Mutations Sentence Comment
4 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:4:214
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:4:160
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:4:179
status: NEW
view ABCC7 p.Gly126Ser details
ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:4:193
status: NEW
view ABCC7 p.Phe157Cys details
ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:4:166
status: NEW
view ABCC7 p.Phe87Ile details
ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:4:221
status: NEW
view ABCC7 p.Tyr852Phe details
ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:4:207
status: NEW
view ABCC7 p.Glu543Ala details
ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:4:231
status: NEW
view ABCC7 p.Asp1270Glu details
ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:4:186
status: NEW
view ABCC7 p.His139Gln details
ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:4:172
status: NEW
view ABCC7 p.Ser118Pro details
ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:4:200
status: NEW
view ABCC7 p.Phe494Leu details
Methods: We used Western blot, pharmacology and iodide efflux to study CFTR maturation and chloride transport in BHK cells expressing pEGFP-CFTR constructs for L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E. Login to comment
5 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:5:40
status: NEW
view ABCC7 p.Leu69His details
Results: Among these CFTR mutants, only L69H is not processed as a c-band and not functional at 37 &#b0;C. Login to comment
6 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:6:35
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:6:26
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:6:63
status: NEW
view ABCC7 p.Leu69His details
However, the functions of L69H and S549N and the maturation of L69H are corrected at 27 &#b0;C and by the investigational drug VX809. Login to comment
8 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:8:14
status: NEW
view ABCC7 p.Leu69His details
We identified L69H as a novel class II CF mutation. Login to comment
10 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:10:51
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:10:40
status: NEW
view ABCC7 p.Leu69His details
Keywords: Missense CF mutations; India; L69H-CFTR; S549N-CFTR; Low temperature; VX809 1. Login to comment
33 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:33:242
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:33:188
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:33:207
status: NEW
view ABCC7 p.Gly126Ser details
ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:33:221
status: NEW
view ABCC7 p.Phe157Cys details
ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:33:194
status: NEW
view ABCC7 p.Phe87Ile details
ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:33:249
status: NEW
view ABCC7 p.Tyr852Phe details
ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:33:235
status: NEW
view ABCC7 p.Glu543Ala details
ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:33:259
status: NEW
view ABCC7 p.Asp1270Glu details
ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:33:214
status: NEW
view ABCC7 p.His139Gln details
ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:33:200
status: NEW
view ABCC7 p.Ser118Pro details
ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:33:228
status: NEW
view ABCC7 p.Phe494Leu details
Because the cellular and functional data on these mutations can improve CF genetic counseling, we examined here the functional and cellular consequences of eleven rare missense mutations, L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E present in CFTR gene from both classical CF patients and CBAVD patients, which have been detected during molecular diagnosis of Indian CF patients (Fig. 1). Login to comment
38 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:38:11
status: NEW
view ABCC7 p.Leu69His details
Except for L69H and F508del, the profiles of core-glycosylated and mature glycosylated forms were similar to that of WT-CFTR protein. Login to comment
39 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:39:41
status: NEW
view ABCC7 p.Leu69His details
Mature glycosylated c-band was absent in L69H mutant expressing cells. Login to comment
44 ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:44:49
status: NEW
view ABCC7 p.Gly126Ser details
ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:44:63
status: NEW
view ABCC7 p.Phe157Cys details
ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:44:36
status: NEW
view ABCC7 p.Phe87Ile details
ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:44:84
status: NEW
view ABCC7 p.Tyr852Phe details
ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:44:77
status: NEW
view ABCC7 p.Glu543Ala details
ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:44:94
status: NEW
view ABCC7 p.Asp1270Glu details
ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:44:56
status: NEW
view ABCC7 p.His139Gln details
ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:44:42
status: NEW
view ABCC7 p.Ser118Pro details
ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:44:70
status: NEW
view ABCC7 p.Phe494Leu details
The activation of nine CFTR mutants F87I, S118P, G126S, H139Q, F157C, F494L, E543A, Y852F and D1270E was not significantly different from WT-CFTR (Fig. 3A for example of traces and Fig. 3B for a summary). Login to comment
45 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:45:28
status: NEW
view ABCC7 p.Ser549Asn details
The response to agonists of S549N-CFTR mutant was reduced (Fig. 3A) compared to WT-CFTR (Fig. 3B). Login to comment
46 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:46:47
status: NEW
view ABCC7 p.Leu69His details
The most dramatic effect was observed with the L69H-CFTR mutant, whose response to F + G was null (Fig. 3A) and not significantly different from F508del-CFTR (Fig. 3B). Login to comment
47 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:47:108
status: NEW
view ABCC7 p.Leu69His details
This result is in agreement with the Western blot data showing lack of mature fully glycosylated c-band for L69H- and F508del-CFTR proteins. Login to comment
49 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:49:601
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:49:79
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:49:369
status: NEW
view ABCC7 p.Gly126Ser details
ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:49:461
status: NEW
view ABCC7 p.Phe157Cys details
ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:49:278
status: NEW
view ABCC7 p.Phe87Ile details
ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:49:554
status: NEW
view ABCC7 p.Glu543Ala details
ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:49:415
status: NEW
view ABCC7 p.His139Gln details
ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:49:323
status: NEW
view ABCC7 p.Ser118Pro details
ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:49:507
status: NEW
view ABCC7 p.Phe494Leu details
Mutation Nucleotide change Location in CFTR Patient phenotype CFTR dysfunction L69H T to A at 338 N-terminal Patient 1: Pancreatic insufficient, sweat chloride N 60 mEq/L, S. aureus positive; Patient 2: CBAVD Defective CFTR maturation and channel activity, class-II CF mutation F87I T to A at 391 MSD1 CBAVD No dysfunction S118P T to C at 484 MSD1 CBAVD No dysfunction G126S G to A at 508 MSD1 CBAVD No dysfunction H139Q C to G at 549 MSD1 CBAVD No dysfunction F157C T to G at 602 MSD1 CBAVD No dysfunction F494L T to C at 1612 NBD1 CBAVD No dysfunction E543A A to C at 1760 NBD1 CBAVD No dysfunction S549N G to A at 1778 NBD1 Patient 1: Frequent respiratory infection. Login to comment
50 ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:50:64
status: NEW
view ABCC7 p.Tyr852Phe details
ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:50:160
status: NEW
view ABCC7 p.Asp1270Glu details
Patient 2: CBAVD Defective channel activity, class III mutation Y852F A to T at 2687 Cytoplasmic region between regulatory domain and MSD2 CBAVD No dysfunction D1270E T to A at 3942 NBD2 CBAVD No dysfunction MSD: membrane spanning domain, NBD: nucleotide binding domain, CBAVD: congenital bilateral absence of the vas deferens. Login to comment
57 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:57:47
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:57:29
status: NEW
view ABCC7 p.Leu69His details
Rescue by low temperature of L69H, F508del and S549N-CFTR mutants F508del protein is temperature sensitive, that is the mutant can be rescued from its abnormal ER location to the plasma membrane by lowering the temperature of the cells from 37 &#b0;C to 27 &#b0;C [10]. Login to comment
58 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:58:72
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:58:63
status: NEW
view ABCC7 p.Leu69His details
We studied the effect of low-temperature with cells expressing L69H and S549N compared to F508del-CFTR. Login to comment
61 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:61:26
status: NEW
view ABCC7 p.Leu69His details
Immunoblots confirmed for L69H that at 27 &#b0;C the proteins acquired a mature state as c-band can be detected (Fig. 4C, lane 6) but not at 37 &#b0;C (Fig. 4C, lane 4). Login to comment
64 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:64:44
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:64:119
status: NEW
view ABCC7 p.Leu69His details
Rescue by the investigational drug VX809 of L69H and F508del The pharmacological corrector VX809 [11] was evaluated on L69H and compared to F508del. Login to comment
65 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:65:18
status: NEW
view ABCC7 p.Leu69His details
The activation of L69H and F508del were both significantly corrected when cells were treated with VX809 (24 h, 10 bc;M, Fig. 4B). Login to comment
66 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:66:91
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:66:36
status: NEW
view ABCC7 p.Leu69His details
We also performed Western blot with L69H and F508del in the presence of VX809 but not with S549N because it is already mature (Fig. 2A). Login to comment
67 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:67:41
status: NEW
view ABCC7 p.Leu69His details
Remarkably we detected mature c-band for L69H (Fig. 4C, lane 6) as with the low-temperature protocol. Login to comment
70 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:70:234
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:70:257
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:70:228
status: NEW
view ABCC7 p.Gly126Ser details
ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:70:170
status: NEW
view ABCC7 p.Phe157Cys details
ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:70:153
status: NEW
view ABCC7 p.Phe87Ile details
ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:70:240
status: NEW
view ABCC7 p.Tyr852Phe details
ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:70:338
status: NEW
view ABCC7 p.Glu543Ala details
ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:70:328
status: NEW
view ABCC7 p.Asp1270Glu details
ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:70:164
status: NEW
view ABCC7 p.His139Gln details
ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:70:158
status: NEW
view ABCC7 p.Ser118Pro details
ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:70:322
status: NEW
view ABCC7 p.Phe494Leu details
Discussion The present study investigated the potential deleterious functional consequence of novel rare missense mutations 0 2 4 6 8 0.0 0.1 0.2 0.3 WT F87I S118P H139Q F157C NT Time (min) k (min -1 ) 0 2 4 6 8 0.0 0.1 0.2 0.3 G126S S549N Y852F WT F508del L69H Time (min) k (min -1 ) 0 2 4 6 8 0.0 0.1 0.2 0.3 WT F508del F494L D1270E NT E543A Time (min) k (min -1 ) W T F 8 7 I S 1 1 8 P G 1 2 6 S H 1 3 9 Q F 1 5 7 C F 4 9 4 L E 5 4 3 A Y 8 5 2 F D 1 2 7 0 E S 5 4 9 N L 6 9 H F 5 0 8 d e l 0.0 0.5 1.0 1.5 2.0 ns *** *** *** *** ns (k peak - k basal) mutant / (k peak - k basal) WT A B Fig. 3. Login to comment
72 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:72:118
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:72:64
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:72:83
status: NEW
view ABCC7 p.Gly126Ser details
ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:72:97
status: NEW
view ABCC7 p.Phe157Cys details
ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:72:70
status: NEW
view ABCC7 p.Phe87Ile details
ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:72:125
status: NEW
view ABCC7 p.Tyr852Phe details
ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:72:111
status: NEW
view ABCC7 p.Glu543Ala details
ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:72:135
status: NEW
view ABCC7 p.Asp1270Glu details
ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:72:90
status: NEW
view ABCC7 p.His139Gln details
ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:72:76
status: NEW
view ABCC7 p.Ser118Pro details
ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:72:104
status: NEW
view ABCC7 p.Phe494Leu details
Iodide efflux experiments in transfected BHK-21 cells, WT-CFTR, L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E. Login to comment
80 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:80:39
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:80:21
status: NEW
view ABCC7 p.Leu69His details
Functional rescue of L69H, F508del and S549N by low temperature and VX809. Login to comment
82 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:82:67
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:82:61
status: NEW
view ABCC7 p.Leu69His details
Iodide efflux experiments with BHK-21 cells transfected with L69H, S549N and F508del-CFTR as indicated. Login to comment
88 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:88:121
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:88:136
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:88:162
status: NEW
view ABCC7 p.Leu69His details
Each experimental condition is indicated on each lane with WT-CFTR (lane 1), F508del (lane 2), F508del + VX809 (lane 3), L69H (lane 4), L69H + VX809 (lane 5) and L69H at 27 &#b0;C (lane 6). Login to comment
94 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:94:218
status: NEW
view ABCC7 p.Leu69His details
Global view (a) of the model of the 3D structure of human CFTR (open channel), based on the experimental 3D structure of Sav1866, in an outward-facing conformation according to Mornon et al.[15], on which the mutation L69H is located (yellow square) MSD1 and 2 are membrane-spanning domains 1 and 2 (in blue and red, respectively). Login to comment
100 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:100:97
status: NEW
view ABCC7 p.Ser549Asn details
ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:100:43
status: NEW
view ABCC7 p.Leu69His details
ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:100:62
status: NEW
view ABCC7 p.Gly126Ser details
ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:100:76
status: NEW
view ABCC7 p.Phe157Cys details
ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:100:49
status: NEW
view ABCC7 p.Phe87Ile details
ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:100:104
status: NEW
view ABCC7 p.Tyr852Phe details
ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:100:90
status: NEW
view ABCC7 p.Glu543Ala details
ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:100:114
status: NEW
view ABCC7 p.Asp1270Glu details
ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:100:69
status: NEW
view ABCC7 p.His139Gln details
ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:100:55
status: NEW
view ABCC7 p.Ser118Pro details
ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:100:83
status: NEW
view ABCC7 p.Phe494Leu details
In our study, the eleven CFTR mutants i.e. L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F and D1270E produced different results. Login to comment
101 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:101:56
status: NEW
view ABCC7 p.Leu69His details
The first salient result is the fact that we identified L69H as a novel class II CF mutation. Login to comment
102 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:102:42
status: NEW
view ABCC7 p.Leu69His details
The trafficking to the plasma membrane of L69H-CFTR is abnormal as corroborated by our Western blot analysis, which revealed only the presence of b-band. Login to comment
103 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:103:60
status: NEW
view ABCC7 p.Leu69His details
Further confocal microscopy imaging showed the abundance of L69H mutated CFTR proteins in the ER and absence on the plasma membrane (data not shown). Login to comment
108 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:108:39
status: NEW
view ABCC7 p.Leu69His details
Our results clearly indicated that the L69H mutant is responsive to VX809 as well as to rescue following low temperature incubation of cells. Login to comment
110 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:110:30
status: NEW
view ABCC7 p.Leu69His details
We propose thus to categorize L69H as a class II form of CF mutation. Login to comment
111 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:111:199
status: NEW
view ABCC7 p.Leu69His details
Interestingly, using the structural information provided by the model of the 3D structure of CFTR, based on the Sav1866 experimental 3D structure [15] (Fig. 4Ea), we evaluated the possible impact of L69H on CFTR (Fig. 4Eb). Login to comment
115 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:115:292
status: NEW
view ABCC7 p.Leu69His details
The network formed by these hydrophobic amino acids in the cytosolic N-terminal extension (L69), in the intracellular loop ICL1 (F191) and in the MSD1-NBD1 linker (I368) might thus play an important role for MSD1 folding and stabilization of this domain at the membrane and, accordingly, the L69H may perturb these mechanisms. Login to comment
116 ABCC7 p.Leu206Trp
X
ABCC7 p.Leu206Trp 25042876:116:242
status: NEW
view ABCC7 p.Leu206Trp details
ABCC7 p.Pro67Leu
X
ABCC7 p.Pro67Leu 25042876:116:236
status: NEW
view ABCC7 p.Pro67Leu details
Supporting this hypothesis is the fact that VX-809 has been shown to act on MSD1 folding and that it also rescues functional defects in CFTR caused by disease-related mutations in the vicinity of the three amino acids highlighted here (P67L, L206W) [16]. Login to comment
118 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:118:0
status: NEW
view ABCC7 p.Ser549Asn details
S549N causes reduction in Cl-channel activity classifying it as a class III CF mutation [17]. Login to comment
119 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:119:21
status: NEW
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Normal maturation of S549N-CFTR protein was observed in our Western blot analysis as reported by others [17]. Login to comment
120 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:120:27
status: NEW
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It is noteworthy here that S549N defective channel activity was nevertheless potentiated after incubating cells at 27 &#b0;C or VX809, a result which on the contrary was not anticipated. Login to comment
121 ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:121:103
status: NEW
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ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:121:117
status: NEW
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ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:121:90
status: NEW
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ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:121:138
status: NEW
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ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:121:131
status: NEW
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ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:121:148
status: NEW
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ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:121:110
status: NEW
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ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:121:96
status: NEW
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ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:121:124
status: NEW
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The functional characterization of nine other novel mutations associated with CBAVD viz., F87I, S118P, G126S, H139Q, F157C, F494L, E543A, Y852F and D1270E revealed that these mutants did not cause any effect on normal CFTR maturation process and Cl-channel activity. Login to comment
129 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:129:107
status: NEW
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ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:129:53
status: NEW
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ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:129:72
status: NEW
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ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:129:86
status: NEW
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ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:129:59
status: NEW
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ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:129:114
status: NEW
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ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:129:100
status: NEW
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ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:129:125
status: NEW
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ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:129:79
status: NEW
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ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:129:65
status: NEW
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ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:129:93
status: NEW
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Patients profile Eleven rare missense mutations i.e. L69H, F87I, S118P, G126S, H139Q, F157C, F494L, E543A, S549N, Y852F, and D1270E were characterized by using single stranded conformation polymorphism and subsequently by DNA sequencing in Indian infertile CBAVD male patients [7,8]. Login to comment
131 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:131:34
status: NEW
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All the detected mutations except S549N are novel, rare mutations identified only from the Indian population, however, the exact frequency is still not known [7,8]. Login to comment
132 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:132:22
status: NEW
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ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:132:13
status: NEW
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Additionally L69H and S549N mutations were also observed in Indian patients diagnosed with classical CF [7]. Login to comment
133 ABCC7 p.Leu69His
X
ABCC7 p.Leu69His 25042876:133:4
status: NEW
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The L69H missense mutation was identified in three-month-old child having classical phenotype like elevated level of sweat chloride and lung Staphylococcus aureus infection with respiratory distress. Login to comment
135 ABCC7 p.Ser549Asn
X
ABCC7 p.Ser549Asn 25042876:135:9
status: NEW
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Moreover S549N missense mutation was also observed in two patients. Login to comment
138 ABCC7 p.Gly126Ser
X
ABCC7 p.Gly126Ser 25042876:138:39
status: NEW
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ABCC7 p.Phe157Cys
X
ABCC7 p.Phe157Cys 25042876:138:73
status: NEW
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ABCC7 p.Phe87Ile
X
ABCC7 p.Phe87Ile 25042876:138:53
status: NEW
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ABCC7 p.Tyr852Phe
X
ABCC7 p.Tyr852Phe 25042876:138:46
status: NEW
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ABCC7 p.Glu543Ala
X
ABCC7 p.Glu543Ala 25042876:138:87
status: NEW
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ABCC7 p.Asp1270Glu
X
ABCC7 p.Asp1270Glu 25042876:138:98
status: NEW
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ABCC7 p.His139Gln
X
ABCC7 p.His139Gln 25042876:138:66
status: NEW
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ABCC7 p.Ser118Pro
X
ABCC7 p.Ser118Pro 25042876:138:59
status: NEW
view ABCC7 p.Ser118Pro details
ABCC7 p.Phe494Leu
X
ABCC7 p.Phe494Leu 25042876:138:80
status: NEW
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The remaining all nine mutations viz., G126S, Y852F, F87I, S118P, H139Q, F157C, F494L, E543A, and D1270E were identified in Indian infertile males diagnosed with only CBAVD. Login to comment