ABCMdb

PMID: 8662892

Seibert FS, Linsdell P, Loo TW, Hanrahan JW, Clarke DM, Riordan JR
Disease-associated mutations in the fourth cytoplasmic loop of cystic fibrosis transmembrane conductance regulator compromise biosynthetic processing and chloride channel activity.
J Biol Chem. 1996 Jun 21;271(25):15139-45., [PubMed]

Sentences

No. Mutations Sentence Comment

64 ABCC7 p.Arg1070Gln ABCC7 p.Phe1052Val ABCC7 p.Arg1070Trp ABCC7 p.Arg1070Trp ABCC7 p.Lys1060Thr ABCC7 p.Gly1069Arg ABCC7 p.Ala1067Thr ABCC7 p.Ala1067Thr The mature forms of the other six mutants (F1052V, K1060T, A1067T, G1069R, R1070W, R1070Q) were produced in relatively normal amounts (band C), although for A1067T and R1070W CFTR the ratio of the complex-glycosylated to core-glycosylated bands was significantly lower than for wild-type CFTR. Login to comment 71 ABCC7 p.Arg1070Gln ABCC7 p.Phe1052Val ABCC7 p.Arg1070Trp ABCC7 p.Arg1070Trp ABCC7 p.Lys1060Thr ABCC7 p.Gly1069Arg ABCC7 p.Ala1067Thr ABCC7 p.Ala1067Thr The mature forms of the other six mutants (F1052V, K1060T, A1067T, G1069R, R1070W, R1070Q) were produced in relatively normal amounts (band C), although for A1067T and R1070W CFTR the ratio of the complex-glycosylated to core-glycosylated bands was significantly lower than for wild-type CFTR. Login to comment 81 ABCC7 p.Phe1052Val ABCC7 p.Lys1060Thr ABCC7 p.Gly1069Arg This showed that the level of activity for cells expressing each CFTR mutant did approximately correspond to the amount of mature protein in the sample, i.e. in COS-1 cells F1052V, K1060T, and G1069R produced efflux levels similar to wild-type CFTR in accordance with a level of protein expression similar to wild type. Login to comment 82 ABCC7 p.Arg1070Gln ABCC7 p.Arg1070Trp ABCC7 p.Ala1067Thr A1067T, R1070W, and R1070Q CFTR had significantly lower efflux levels and significantly lower protein expression than wild-type CFTR in COS-1 cells. Login to comment 88 ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His ABCC7 p.Phe1052Val ABCC7 p.Lys1060Thr ABCC7 p.Gly1069Arg Other disease-causing CFTR mutants, which are appropriately processed and trafficked to the plasma membrane, show defective ion conduction properties (e.g. R334W, R347H, and R347P; Sheppard et al., 1993; Tabcharani et al., 1993) or defective regulation of channel activity (e.g. G551S, G1244E, S1255P, and G1349D; Anderson and Welsh, 1992). Login to comment 89 ABCC7 p.Arg1070Gln ABCC7 p.Arg1070Trp ABCC7 p.Ala1067Thr A1067T, R1070W, and R1070Q CFTR had significantly lower efflux levels and significantly lower protein expression than wild-type CFTR in COS-1 cells. Login to comment 94 ABCC7 p.Phe1052Val ABCC7 p.Arg1070Trp ABCC7 p.Gly1069Arg As shown in Fig. 5, B and C, in some mutants this reduction in open probability was associated with a significant reduction in mean burst duration (F1052V, G1069R) or an increase in mean interburst duration (R1070W). Login to comment 95 ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Arg347His Other disease-causing CFTR mutants, which are appropriately processed and trafficked to the plasma membrane, show defective ion conduction properties (e.g. R334W, R347H, and R347P; Sheppard et al., 1993; Tabcharani et al., 1993) or defective regulation of channel activity (e.g. G551S, G1244E, S1255P, and G1349D; Anderson and Welsh, 1992). Login to comment 101 ABCC7 p.Phe1052Val ABCC7 p.Arg1070Trp ABCC7 p.Gly1069Arg As shown in Fig. 5, B and C, in some mutants this reduction in open probability was associated with a significant reduction in mean burst duration (F1052V, G1069R) or an increase in mean interburst duration (R1070W). Login to comment 127 ABCC7 p.Phe1052Val ABCC7 p.Lys1060Thr ABCC7 p.Ala1067Thr Symbols are as follows: A: छ, WT; E, F1052V; Ç, K1060T; µ, A1067T; Ⅺ, vector only control. Login to comment 128 ABCC7 p.Arg1070Gln ABCC7 p.Arg1070Trp ABCC7 p.Gly1069Arg B: छ, WT; E, G1069R; µ, R1070Q; Ç, R1070W; Ⅺ, control. Login to comment 129 ABCC7 p.Leu1065Pro ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Leu ABCC7 p.Arg1066His ABCC7 p.His1054Asp ABCC7 p.Gly1061Arg C: छ, WT; छϩ, R1066C; E, H1054D; µ, L1065P; Ⅺ, control; Ç, G1061R, Q, R1066H; É, R1066L. Login to comment 130 ABCC7 p.Met1101Lys ABCC7 p.His1085Arg ABCC7 p.Met1101Arg ABCC7 p.Leu1077Pro ABCC7 p.Trp1098Arg ABCC7 p.Gln1071Pro D: छ, WT; E, Q1071P; छϩ, W1098R; Ⅺ, H1085R; Ç, M1101K; µ, M1101R; Q, control; É, L1077P. Login to comment 132 ABCC7 p.Met1101Lys ABCC7 p.Arg1070Gln ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Leu ABCC7 p.Met1101Arg ABCC7 p.Arg1070Trp ABCC7 p.Arg1066His Different substitutions at the same residue always produced the same effect, i.e. R1066C, R1066H, and R1066L, as well as M1101K and M1101R all inhibited maturation, whereas R1070W and R1070Q were both normally processed. Login to comment 133 ABCC7 p.Phe1052Val ABCC7 p.Lys1060Thr ABCC7 p.Ala1067Thr Symbols are as follows: A: L, WT; E, F1052V; &#c7;, K1060T; &#b5;, A1067T; M, vector only control. Login to comment 134 ABCC7 p.Arg1070Gln ABCC7 p.Arg1070Trp ABCC7 p.Gly1069Arg B: L, WT; E, G1069R; &#b5;, R1070Q; &#c7;, R1070W; M, control. Login to comment 135 ABCC7 p.Leu1065Pro ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Leu ABCC7 p.Arg1066His ABCC7 p.His1054Asp ABCC7 p.Gly1061Arg C: L, WT; L 1, R1066C; E, H1054D; &#b5;, L1065P; M, control; &#c7;, G1061R, Q, R1066H; &#c9;, R1066L. Login to comment 136 ABCC7 p.Met1101Lys ABCC7 p.His1085Arg ABCC7 p.Met1101Arg ABCC7 p.Leu1077Pro ABCC7 p.Trp1098Arg ABCC7 p.Gln1071Pro D: L, WT; E, Q1071P; L 1, W1098R; M, H1085R; &#c7;, M1101K; &#b5;, M1101R; Q, control; &#c9;, L1077P. Login to comment 138 ABCC7 p.Met1101Lys ABCC7 p.Arg1070Gln ABCC7 p.Arg1066Cys ABCC7 p.Arg1066Leu ABCC7 p.Met1101Arg ABCC7 p.Arg1070Trp ABCC7 p.Arg1066His Different substitutions at the same residue always produced the same effect, i.e. R1066C, R1066H, and R1066L, as well as M1101K and M1101R all inhibited maturation, whereas R1070W and R1070Q were both normally processed. Login to comment 142 ABCC7 p.Arg1070Gln ABCC7 p.Phe1052Val ABCC7 p.Arg1070Trp ABCC7 p.Lys1060Thr ABCC7 p.Gly1069Arg ABCC7 p.Ala1067Thr A, examples of wild-type, F1052V, K1060T, A1067T, G1069R, R1070Q, and R1070W CFTR single channel currents recorded from inside-out membrane patches at a membrane potential of -30 mV. Login to comment 144 ABCC7 p.Gly1069Arg B, mean single-channel current-voltage relationships for wild type (E) and an example of a CL4 mutant (q, G1069R). Login to comment 148 ABCC7 p.Arg1070Gln ABCC7 p.Phe1052Val ABCC7 p.Arg1070Trp ABCC7 p.Lys1060Thr ABCC7 p.Gly1069Arg ABCC7 p.Ala1067Thr A, examples of wild-type, F1052V, K1060T, A1067T, G1069R, R1070Q, and R1070W CFTR single channel currents recorded from inside-out membrane patches at a membrane potential of 230 mV. Login to comment 150 ABCC7 p.Gly1069Arg B, mean single-channel current-voltage relationships for wild type (E) and an example of a CL4 mutant (cf;, G1069R). Login to comment 155 ABCC7 p.Gly1069Arg Interestingly in murine CFTR, Gly1069 is replaced by Arg, a human mutation that we found to leave biosynthetic processing unaffected but to reduce channel open probability. Login to comment 161 ABCC7 p.Gly1069Arg Interestingly in murine CFTR, Gly1069 is replaced by Arg, a human mutation that we found to leave biosynthetic processing unaffected but to reduce channel open probability. Login to comment