ABCMdb

PMID: 7686820

Welsh MJ, Smith AE
Molecular mechanisms of CFTR chloride channel dysfunction in cystic fibrosis.
Cell. 1993 Jul 2;73(7):1251-4., [PubMed]

Sentences

No. Mutations Sentence Comment

17 ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Asn1303Lys ABCC7 p.Ser549Arg ABCC7 p.Ala559Thr Classes of CFTR Mutations That Cause CF Class Defect Examples Do- Fre- Clin- main quency ical Protein production Nonsense mutations Frameshift Splice Processing Conduction 6542X NBDI 3.4 3905 insT NBD2 2.1 621 + G-T MSDl 1.3 Al507 NBDl AF506 NBDl s5491 NBDl S549R NED1 A559T NED1 N1303K NBDP G551 D NBDl G551S NBDl G1244E NBDP S1255P NBDP G1349D NBDP RI 17H MSDI R334W MSDl R347P MSDl 0.5 67.2 Rare 0.3 Rare 1.a 2.4 Rare Rare Rare Rare 0.6 0.4 0.5 PI PI PI PI PI PI PI PI PS PI PI PI PS PS PS NED, nucleotide-binding domain; MSD, membrane-spanning domain; PI, pancreatic insufficiency; PS, pancreatic sufficiency. Login to comment 21 ABCC7 p.Arg117His For example, AF506 causes defective processing but may also cause defective regulation, and R117H causes both defective conduction and decreases the time that the channel is open. Login to comment 56 ABCC7 p.Gly551Asp ABCC7 p.Gly551Ser ABCC7 p.Gly1244Glu ABCC7 p.Gly1349Asp ABCC7 p.Ser1255Pro Some nucleotide-binding domain mutants (such as G551D) have very little function, in some (such as S1255P) ATP is less potent at stimulating activity, and the absolute activity of others (such as G551S, G1244E, and G1349D) is reduced (Anderson and Welsh, 1992; Drumm et al., 1991). Login to comment 66 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Three mutations in the first membrane-spanning domain (R117H, R334W, and R347P) affect arginine residues located in putative membrane-spanning sequences. Login to comment 69 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro Nevertheless, the amount of current is reduced, with wild-type CFTR > R347P > R117H > R334W. Login to comment 72 ABCC7 p.Arg117His In addition, at least for R117H, the amount of time that the channel is open is reduced to one-third that of wild-type CFTR. Login to comment 89 ABCC7 p.Arg553Gln ABCC7 p.Arg553Met In a study identifying second-site revertants of the AF508 mutation using STEG-CFTR chimeras in yeast, R553M and, to a lesser extent, R553Q partially reversed the localization and functional effects of the AF508 mutation (Teem et al., 1993). Login to comment 98 ABCC7 p.Arg117His In class IV mutants in which channel regulation appears intact but ion flow through an open Cl-channel is reduced, the residual activity may be sufficient to confer a pancreatic-sufficient phenotype. In fact, some individuals with these mutations (e.g., R117H) do not exhibit classic CF symptoms at all and have only a single manifestation of disease: male infertility (Anguiano et al., 1992). Login to comment 99 ABCC7 p.Gly551Asp ABCC7 p.Gly551Ser Some individuals with class Ill mutants (e.g., G551S) are also pancreatic sufficient (Strong et al., 1991), whereas most others (e.g., G551D) are pancreatic insufficient (Cutting et al., 1990). Login to comment