ABCMdb

PMID: 10940786

Zeitlin PL
Future pharmacological treatment of cystic fibrosis.
Respiration. 2000;67(4):351-7., [PubMed]

Sentences

No. Mutations Sentence Comment

22 ABCC7 p.Gly551Asp ABCC7 p.Arg117His ABCC7 p.Pro574His ABCC7 p.Pro574His ABCC7 p.Ala455Glu ABCC7 p.Ala455Glu ABCC7 p.Trp1282* ABCC7 p.Arg553* ABCC7 p.Gly551Ser ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro ABCC7 p.Gly314Glu ABCC7 p.Asn1303Lys ABCC7 p.Gly542* Examples of CFTR mutations organized by classification of the defect in CFTR biosynthesis Type Genotype Phenotype Defect Cell diagram Drugs that may improve phenotype G542X 621+1 G → T 3905insT W1282X R553X 1717-1 G → A PI no CFTR protein no cell surface chloride transport gentamicin G418 Class II [64] 'F508 N1303K (P574H)a (A455E)a PI defective CFTR processing defective CFTR trafficking no cell surface chloride transport chemical chaperones CPX phenylbutyrate deoxyspergualin Class III [64] G551D G551S PI defective chloride channel regulation reduced or absent cell surface chloride transport genistein pyrophosphate Class IV [64, 66] R117H R334W G314E R347P ('F508)a P574H PS reduced chloride conductance reduced levels of cell surface chloride transport genistein milrinone phenylbutyrate Class V [64] 3849+10 kb C → T 2789+5 G → A 3272-26 A → G A455E 3120+1 G → A 1811+1.6 kb A → G 5Tb PS normal CFTR channels reduced numbers of normal CFTR reduced cell surface chloride transport genistein milrinone phenylbutyrate a Some mutants have features of more than one class of defect. Login to comment 27 ABCC7 p.Trp1282* ABCC7 p.Arg553* Mutations such as R553X or W1282X contain a premature stop codon and produce an unstable mRNA transcript that is not successfully translated into protein. Login to comment 29 ABCC7 p.Gly551Asp CFTR mutants that move successfully through the cell to the plasma membrane but are defective in cAMP regulation of chloride transport (e.g. G551D) are called class III mutations. Login to comment 31 ABCC7 p.Arg117His CFTR mutants that traffick successfully through the cell to the plasma membrane but are only partially activated through the cAMP signaling pathway (e.g. R117H) are called class IV conductance mutants and are associated with some degree of pancreatic sufficiency and milder phenotype. Login to comment 72 ABCC7 p.Gly551Asp Laboratory investigations have demonstrated in vitro activity in the form of increased production of mature CFTR and chloride transport at the cell surface for both wild type, 'F508, and G551D [43-46]. Login to comment 75 ABCC7 p.Pro574His Another misprocessed mutant, P574H, has been shown to associate with Hsp70 in a prolonged state unless the temperature of the culture was reduced to 26°C [48]. Login to comment 86 ABCC7 p.Gly551Asp Genistein has also been shown to restore function of the class III mutation G551D [46]. Login to comment 96 ABCC7 p.Gly551Asp Milrinone appears to be more successful in mouse nasal mucosa than human mucosa with respect to 'F508 and G551D defects. Login to comment 100 ABCC7 p.Gly551Asp ABCC7 p.Gly551Ser Whereas G551D is severely defective, G551S is a milder mutant. Login to comment 104 ABCC7 p.Arg117His ABCC7 p.Gly551Ser Interestingly, inorganic pyrophosphate stimulated G551S and R117H, a class IV mutation. Login to comment 106 ABCC7 p.Gly551Asp G551D has been shown to respond to the flavonoid compounds as mentioned above. Login to comment 107 ABCC7 p.Gly551Asp ATP binding to G551D is severely affected, but overcome by interaction with the flavonoids. Login to comment 109 ABCC7 p.Gly551Asp CF subjects bearing at least one G551D allele underwent nasal potential difference testing in which genistein was superfused following isoproterenol activation of CFTR. Login to comment 111 ABCC7 p.Gly551Asp This degree of chloride transport (17% of that observed in normal subjects) might be augmented overall by increasing the level of G551D expression in nasal mucosa. Login to comment 115 ABCC7 p.Arg117His ABCC7 p.Arg334Trp ABCC7 p.Arg347Pro R117H, R334W, and R347P are class IV mutants with reduced single-channel conductances [66]. Login to comment 118 ABCC7 p.Arg117His Adenosine and its nucleotides have been shown to activate wild-type and R117H forms of CFTR in cell cultures through the A2B receptor that is present in human bronchial epithelium [67]. Login to comment